bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of White Matter Injury and Promising Therapeutic Strategies of MSCs After Intracerebral Hemorrhage
Authors: Li Jing , Xiao Linglong , He Dian , Luo Yunhao , Sun Haitao
Published: April 2021

Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.
Comparative Assessment of Familiarity/Novelty Preferences in Rodents
Authors: Beery Annaliese K. , Shambaugh Katharine L.
Published: April 2021

Sociality—i.e., life in social groups—has evolved many times in rodents, and there is considerable variation in the nature of these groups. While many species-typical behaviors have been described in field settings, the use of consistent behavioral assays in the laboratory provides key data for comparisons across species. The preference for interaction with familiar or novel individuals is an important dimension of social behavior. Familiarity preference, in particular, may be associated with more closed, less flexible social groups. The dimension from selectivity to gregariousness has been used as a factor in classification of social group types. Laboratory tests of social choice range from brief (10 minutes) to extended (e.g., 3 hours). As familiarity preferences typically need long testing intervals to manifest, we used 3-hour peer partner preference tests to test for the presence of familiarity preferences in same-sex cage-mates and strangers in rats. We then conducted an aggregated analysis of familiarity preferences across multiple rodent species (adult male and female rats, mice, prairie voles, meadow voles, and female degus) tested with the same protocol. We found a high degree of consistency within species across data sets, supporting the existence of strong, species-typical familiarity preferences in prairie voles and meadow voles, and a lack of familiarity preferences in other species tested. Sociability, or total time spent near conspecifics, was unrelated to selectivity in social preference. These findings provide important background for interpreting the neurobiological mechanisms involved in social behavior in these species.
The SMART Registry: Long-Term Results on the Utility of the Penumbra SMART COIL System for Treatment of Intracranial Aneurysms and Other Malformations
Authors: Spiotta Alejandro M. , Park Min S. , Bellon Richard J. , Bohnstedt Bradley N. , Yoo Albert J. , Schirmer Clemens M. , DeLeacy Reade A. , Fiorella David J. , Woodward B. Keith , Hawk Harris E. , Nanda Ashish , Zaidat Osama O. , Sunenshine Peter J. , Liu Kenneth C. , Kabbani Mouhammed R. , Snyder Kenneth V. , Sivapatham Thinesh , Dumont Travis M. , Reeves Alan R. , Starke Robert M. ,   The SMART Registry Investigators
Published: April 2021

Introduction: Penumbra SMART COIL® (SMART) System is a novel generation embolic coil with varying stiffness. The study purpose was to report real-world usage of the SMART System in patients with intracranial aneurysms (ICA) and non-aneurysm vascular lesions.

Materials and Methods: The SMART Registry is a post-market, prospective, multicenter registry requiring ≥75% Penumbra Coils, including SMART, PC400, and/or POD coils. The primary efficacy endpoint was retreatment rate at 1-year and the primary safety endpoint was the procedural device-related serious adverse event rate.

Results: Between June 2016 and August 2018, 995 patients (mean age 59.6 years, 72.1% female) were enrolled at 68 sites in the U.S. and Canada. Target lesions were intracranial aneurysms in 91.0% of patients; 63.5% were wide-neck and 31.8% were ruptured. Adjunctive devices were used in 55.2% of patients. Mean packing density was 32.3%. Procedural device-related serious adverse events occurred in 2.6% of patients. The rate of immediate post-procedure adequate occlusion was 97.1% in aneurysms and the rate of complete occlusion was 85.2% in non-aneurysms. At 1-year, the retreatment rate was 6.8%, Raymond Roy Occlusion Classification (RROC) I or II was 90.0% for aneurysms, and Modified Rankin Scale (mRS) 0-2 was achieved in 83.1% of all patients. Predictors of 1-year for RROC III or retreatment (incomplete occlusion) were rupture status (P < 0.0001), balloon-assisted coiling (P = 0.0354), aneurysm size (P = 0.0071), and RROC III immediate post-procedure (P = 0.0086) in a model that also included bifurcation aneurysm (P = 0.7788). Predictors of aneurysm retreatment at 1-year was rupture status (P < 0.0001).

Conclusions: Lesions treated with SMART System coils achieved low long-term retreatment rates.

Clinical Trial Registration:https://www.clinicaltrials.gov/, identifier NCT02729740.
Association of Polyvascular Disease and Elevated Interleukin-6 With Outcomes in Acute Ischemic Stroke or Transient Ischemic Attack
Authors: Tian Ye , Jing Jing , Wang Huijuan , Wang Anxin , Zhang Yijun , Jiang Yong , Lin Jinxi , Zhao Xingquan , Li Hao , Wang Yongjun , Guo Li , Meng Xia
Published: April 2021

Background: Polyvascular disease (PolyVD) and interleukin (IL)-6 are associated with poor outcomes in patients with stroke respectively. However, whether combined PolyVD and elevated IL-6 levels would increase the risk of poor outcomes of stroke patients is yet unclear.

Methods: Data were obtained from the Third China National Stroke Registry (CNSR-III). PolyVD was defined as acute ischemic stroke (AIS) or transient ischemic attack (TIA) with coronary artery disease (CAD) and/or peripheral artery disease (PAD). Patients were divided into four groups according to the combination of vascular beds number (non-PolyVD or PolyVD) and IL-6 levels (IL-6 < 2.64 pg/mL or IL-6 ≥ 2.64 pg/mL). The primary outcome was a recurrent stroke at 1-year follow-up. Cox proportional hazard models were employed to identify the association of the combined effect of PolyVD and IL-6 with the prognosis of patients.

Results: A total of 10,773 patients with IL-6 levels and 1-year follow-up were included. The cumulative incidence of recurrent stroke was 9.87% during the 1-year follow-up. Compared to non-PolyVD and IL-6<2.64 pg/mL patients, patients had non-PolyVD with IL-6 ≥ 2.64 pg/mL (HR 1.245 95%CI 1.072–1.446; P < 0.001) and PolyVD with IL-6 <2.64 pg/mL (HR 1.251 95%CI 1.002–1.563; P = 0.04) were associated with an increased risk of recurrent stroke during 1-year follow-up. Likewise, patients with PolyVD and IL-6 ≥ 2.64 pg/mL (HR 1.290; 95% CI 1.058–1.572; P = 0.01) had the highest risk of recurrent stroke at 1-year follow-up among groups.

Conclusion: PolyVD and elevated IL-6 levels are both associated with poor outcomes in patients with AIS or TIA. Moreover, the combination of them increases the efficiency of stroke risk stratification compared with when used alone. More attention and intensive treatment should be given to those patients with both PolyVD and elevated IL-6 levels.
Brain Density Clustering Analysis: A New Approach to Brain Functional Dynamics
Authors: Faghiri Ashkan , Damaraju Eswar , Belger Aysenil , Ford Judith M. , Mathalon Daniel , McEwen Sarah , Mueller Bryon , Pearlson Godfrey , Preda Adrian , Turner Jessica A. , Vaidya Jatin G. , Van Erp Theodorus , Calhoun Vince D.
Published: April 2021

Background

A number of studies in recent years have explored whole-brain dynamic connectivity using pairwise approaches. There has been less focus on trying to analyze brain dynamics in higher dimensions over time.

Methods

We introduce a new approach that analyzes time series trajectories to identify high traffic nodes in a high dimensional space. First, functional magnetic resonance imaging (fMRI) data are decomposed using spatial ICA to a set of maps and their associated time series. Next, density is calculated for each time point and high-density points are clustered to identify a small set of high traffic nodes. We validated our method using simulations and then implemented it on a real data set.

Results

We present a novel approach that captures dynamics within a high dimensional space and also does not use any windowing in contrast to many existing approaches. The approach enables one to characterize and study the time series in a potentially high dimensional space, rather than looking at each component pair separately. Our results show that schizophrenia patients have a lower dynamism compared to healthy controls. In addition, we find patients spend more time in nodes associated with the default mode network and less time in components strongly correlated with auditory and sensorimotor regions. Interestingly, we also found that subjects oscillate between state pairs that show opposite spatial maps, suggesting an oscillatory pattern.

Conclusion

Our proposed method provides a novel approach to analyze the data in its native high dimensional space and can possibly provide new information that is undetectable using other methods.
Selenoprotein P Modulates Methamphetamine Enhancement of Vesicular Dopamine Release in Mouse Nucleus Accumbens Via Dopamine D2 Receptors
Authors: Torres Daniel J. , Yorgason Jordan T. , Mitchell Catherine C. , Hagiwara Ayaka , Andres Marilou A. , Kurokawa Suguru , Steffensen Scott C. , Bellinger Frederick P.
Published: April 2021

Dopamine (DA) transmission plays a critical role in processing rewarding and pleasurable stimuli. Increased synaptic DA release in the nucleus accumbens (NAc) is a central component of the physiological effects of drugs of abuse. The essential trace element selenium mitigates methamphetamine-induced neurotoxicity. Selenium can also alter DA production and turnover. However, studies have not directly addressed the role of selenium in DA neurotransmission. Selenoprotein P (SELENOP1) requires selenium for synthesis and transports selenium to the brain, in addition to performing other functions. We investigated whether SELENOP1 directly impacts (1) DA signaling and (2) the dopaminergic response to methamphetamine. We used fast-scan cyclic voltammetry to investigate DA transmission and the response to methamphetamine in NAc slices from C57/BL6J SELENOP1 KO mice. Recordings from SELENOP1 KO mouse slices revealed reduced levels of evoked DA release and slower DA uptake rates. Methamphetamine caused a dramatic increase in vesicular DA release in SELENOP1 KO mice not observed in wild-type controls. This elevated response was attenuated by SELENOP1 application through a selenium-independent mechanism involving SELENOP1-apolipoprotein E receptor 2 (ApoER2) interaction to promote dopamine D2 receptor (D2R) function. In wild-type mice, increased vesicular DA release in response to methamphetamine was revealed by blocking D2R activation, indicating that the receptor suppresses the methamphetamine-induced vesicular increase. Our data provide evidence of a direct physiological role for SELENOP1 in the dopaminergic response to methamphetamine and suggest a signaling role for the protein in DA transmission.
Multiparametric Analysis of Cerebral Development in Preterm Infants Using Magnetic Resonance Imaging
Authors: Dubois Marine , Legouhy Antoine , Corouge Isabelle , Commowick Olivier , Morel Baptiste , Pladys Patrick , Ferré Jean-Christophe , Barillot Christian , Proisy Maïa
Published: April 2021

Objectives

The severity of neurocognitive impairment increases with prematurity. However, its mechanisms remain poorly understood. Our aim was firstly to identify multiparametric magnetic resonance imaging (MRI) markers that differ according to the degree of prematurity, and secondly to evaluate the impact of clinical complications on these markers.

Materials and Methods

We prospectively enrolled preterm infants who were divided into two groups according to their degree of prematurity: extremely preterm (<28 weeks’ gestational age) and very preterm (28–32 weeks’ gestational age). They underwent a multiparametric brain MRI scan at term-equivalent age including morphological, diffusion tensor and arterial spin labeling (ASL) perfusion sequences. We quantified overall and regional volumes, diffusion parameters, and cerebral blood flow (CBF). We then compared the parameters for the two groups. We also assessed the effects of clinical data and potential MRI morphological abnormalities on those parameters.

Results

Thirty-four preterm infants were included. Extremely preterm infants (n= 13) had significantly higher frontal relative volumes (p= 0.04), frontal GM relative volumes (p= 0.03), and regional CBF than very preterm infants, but they had lower brainstem and insular relative volumes (respectivelyp= 0.008 and 0.04). Preterm infants with WM lesions on MRI had significantly lower overall GM CBF (13.3 ± 2 ml/100 g/min versus 17.7 ± 2.5, < ml/100 g/minp= 0.03).

Conclusion

Magnetic resonance imaging brain scans performed at term-equivalent age in preterm infants provide quantitative imaging parameters that differ with respect to the degree of prematurity, related to brain maturation.
Optimized Parameters for Transducing the Locus Coeruleus Using Canine Adenovirus Type 2 (CAV2) Vector in Rats for Chemogenetic Modulation Research
Authors: Stevens Latoya , Larsen Lars Emil , Van Lysebettens Wouter , Carrette Evelien , Boon Paul , Raedt Robrecht , Vonck Kristl
Published: April 2021

Introduction

The locus coeruleus noradrenergic (LC-NA) system is studied for its role in various neurological and psychiatric disorders such as epilepsy and Major Depression Dissorder. Chemogenetics is a powerful technique for specific manipulation of the LC to investigate its functioning. Local injection of AAV2/7 viral vectors has limitations with regards to efficiency and specificity of the transduction, potentially due to low tropism of AAV2/7 for LC neurons. In this study we used a canine adenovirus type 2 (CAV2) vector with different volumes and viral particle numbers to achieve high and selective expression of hM3Dq, an excitatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD), for chemogenetic modulation of LC neurons.

Methods

Adult male Sprague-Dawley rats were injected in the LC with different absolute numbers of CAV2-PRSx8-hM3Dq-mCherry physical particles (0.1E9, 1E9, 5E9,10E9, or 20E9 pp) using different volumes (LowV = 3 nl × 300 nl, MediumV = 3 × 600 nl, HighV = 3 × 1200 nl). Two weeks post-injection, double-labeling immunohistochemistry for dopamine β hydroxylase (DBH) and mCherry was performed to determine hM3Dq expression and its specificity for LC neurons. The size of the transduced LC was compared to the contralateral LC to identify signs of toxicity.

Results

Administration of Medium volume (3 × 600 nl) and 1E9 particles resulted in high expression levels with 87.3 ± 9.8% of LC neurons expressing hM3Dq, but low specificity with 36.2 ± 17.3% of hM3Dq expression in non-LC neurons. The most diluted conditions (Low volume_0.1E pp and Medium Volume_0.1E pp) presented similar high transduction of LC neurons (70.9 ± 12.7 and 77.2 ± 9.8%) with lower aspecificity (5.5 ± 3.5 and 4.0 ± 1.9%, respectively). Signs of toxicity were observed in all undiluted conditions as evidenced by a decreased size of the transduced LC.

Conclusion

This study identified optimal conditions (Low and Medium Volume with 0.1E9 particles of CAV2-PRSx8-hM3Dq-mCherry) for safe and specific transduction of LC neurons with excitatory DREADDs to study the role of the LC-NA system in health and disease.
Ocular Health of Octodon degus as a Clinical Marker for Age-Related and Age-Independent Neurodegeneration
Authors: Chang Lily Y. -L. , Palanca-Castan Nicolas , Neira David , Palacios Adrian G. , Acosta Monica L.
Published: April 2021

The aging process and age-related diseases such as Alzheimer’s disease (AD), are very heterogeneous and multifactorial, making it challenging to diagnose the disease based solely on genetic, behavioral tests, or clinical history. It is yet to be explained what ophthalmological tests relate specifically to aging and AD. To this end, we have selected the common degu (Octodon degus) as a model for aging which develops AD-like signs to conduct ophthalmological screening methods that could be clinical markers of aging and AD. We investigated ocular health using ophthalmoscopy, fundus photography, intraocular pressure (IOP), and pupillary light reflex (PLR). The results showed significant presence of cataracts in adult degus and IOP was also found to increase significantly with advancing age. Age had a significant effect on the maximum pupil constriction but other pupil parameters changed in an age-independent manner (PIPR retention index, resting pupil size, constriction velocity, redilation plateau). We concluded that degus have underlying factors at play that regulate PLR and may be connected to sympathetic, parasympathetic, and melanopsin retinal ganglion cell (ipRGC) deterioration. This study provides the basis for the use of ocular tests as screening methods for the aging process and monitoring of neurodegeneration in non-invasive ways.
Valorization of Heat-Treated Brewers' Spent Grain Through the Identification of Bioactive Phenolics by UPLC-PDA and Evaluation of Their Antioxidant Activities
Authors: Rahman Md. Jiaur , Malunga Lovemore Nkhata , Eskin Michael , Eck Peter , Thandapilly Sijo Joseph , Thiyam-Hollander Usha
Published: April 2021

Thermal processing not only disrupts cell membranes and cell walls, but also cleaves covalent bonds releasing low molecular phenolic. This study examined the impact of various heat treatments (100, 140, and 160°C) on the composition of phenolic acids and antioxidant activities in extracts obtained from defatted brewers spent grain (BSG) meal. Heating BSG at 160°C resulted in a 2-fold increase in total phenolic content [TPC, 172.98 ± 7.3 mg Gallic acid equivalent (GAE)/100 g defatted meal] and total flavonoid content [TFC, 16.15 ± 2.22 catechin equivalents (CE)/100 g defatted meal] compared to the untreated BSG extracts. The antioxidant activities of treated BSG extracts, determined by radical scavenging and ferric reducing antioxidant power (FRAP) were significantly (p< 0.5) higher than the corresponding untreated BSG extracts. Eleven phenolic acids were identified and quantified in BSG extracts by Ultra Performance Liquid Chromatography with Photodiode Array (UPLC-PDA). The amounts varied significantly (p< 0.05) depending on the degree of toasting BSG was subjected to. Chlorogenic acid, an ester of caffeic and quinic acid was the predominant phenolic acid present in all fractions. Significant (p< 0.05) increases in TPC, TFC, individual phenolic acids and antioxidant activity were observed in BSG extracts exposed to increasing oven temperatures. These results confirm the ability of heat processing to release bioactive phenolic from their bound forms thereby enhancing the phenolic acids and the digestibility of BSG meal in the intestinal tract.
Protein Considerations for Athletes With a Spinal Cord Injury
Authors: Flueck Joelle Leonie , Parnell Jill A.
Published: April 2021

Athlete participation in the Paralympic games is steadily increasing; prompting research focused on the unique needs of this population. While the Paralympic Games includes a diversity of athletes, athletes with a spinal cord injury (PARA-SCI) represent a subgroup that requires specialized recommendations. Nutritional guidelines designed to optimize performance, in the context of the neurological impairments, are required. This narrative review summarizes the current literature regarding the importance of dietary protein for optimal health and performance. Factors with the potential to affect protein needs in PARA-SCI including loss of active muscle mass, reduced energy expenditure, and secondary complications are examined in detail. Furthermore, we analyze protein intakes in PARA-SCI from the available research to provide context around current practices and trends. In conclusion, we make the case that protein recommendations for able-bodied athletes may not be directly transferable to PARA-SCI. Consequently, PARA-SCI need their own guidelines to maximize performance and ensure long-term health.
Personal Neoantigens From Patients With NSCLC Induce Efficient Antitumor Responses
Authors: Zhang Wei , Yin Qi , Huang Haidong , Lu Jingjing , Qin Hao , Chen Si , Zhang Wenjun , Su Xiaoping , Sun Weihong , Dong Yuchao , Li Qiang
Published: April 2021

Objective

To develop a neoantigen-targeted personalized cancer treatment for non-small cell lung cancer (NSCLC), neoantigens were obtained from collected human lung cancer samples, and the utility of neoantigen and neoantigen-reactive T cells (NRTs) was assessed.

Methods

Tumor specimens from three patients with NSCLC were obtained and analyzed by whole-exome sequencing, and neoantigens were predicted accordingly. Dendritic cells and T lymphocytes were isolated, NRTs were elicited and IFN-γ ELISPOT tests were conducted. HLA-A2.1/Kb transgenic mice were immunized with peptides from HLA-A*02:01+patient with high immunogenicity, and NRTs were subjected to IFN-γ, IL-2 and TNF-α ELISPOT as well as time-resolved fluorescence assay for cytotoxicity assays to verify the immunogenicity in vitro. The HLA-A*02:01+lung cancer cell line was transfected with minigene and inoculated into the flanks of C57BL/6nu/nu mice and the NRTs induced by the immunogenic polypeptides from autologous HLA-A2.1/Kb transgenic mice were adoptively transfused to verify their immunogenicity in vivo.

Results

Multiple putative mutation-associated neoantigens with strong affinity for HLA were selected from each patient. Immunogenic neoantigen were identified in all three NSCLC patients, the potency of ACAD8-T105I, BCAR1-G23V and PLCG1-M425L as effective neoantigen to active T cells in suppressing tumor growth was further proven both in vitro and in vivo using HLA-A2.1/Kb transgenic mice and tumor-bearing mouse models.

Conclusion

Neoantigens with strong immunogenicity can be screened from NSCLC patients through the whole-exome sequencing of patient specimens and machine-learning-based neoantigen predictions. NRTs shown efficient antitumor responses in transgenic mice and tumor-bearing mouse models. Our results indicate that the development of neoantigen-based personalized immunotherapies in NSCLC is possible.

Precis

Neoantigens with strong immunogenicity were screened from NSCLC patients. This research provides evidence suggesting that neoantigen-based therapy might serve as feasible treatment for NSCLC.
Main N6-Methyladenosine Readers: YTH Family Proteins in Cancers
Authors: Dai Xin-Yuan , Shi Liang , Li Zhi , Yang Hai-Yan , Wei Ji-Fu , Ding Qiang
Published: April 2021

Among the over 150 RNA modifications, N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNAs, not only in messenger RNAs, but also in microRNAs and long non-coding RNAs. It is a dynamic and reversible process in mammalian cells, which is installed by “writers,” consisting of METTL3, METTL14, WTAP, RBM15/15B, and KIAA1429 and removed by “erasers,” including FTO and ALKBH5. Moreover, m6A modification is recognized by “readers,” which play the key role in executing m6A functions. IYT521-B homology (YTH) family proteins are the first identified m6A reader proteins. They were reported to participate in cancer tumorigenesis and development through regulating the metabolism of targeted RNAs, including RNA splicing, RNA export, translation, and degradation. There are many reviews about function of m6A and its role in various diseases. However, reviews only focusing on m6A readers, especially YTH family proteins are few. In this review, we systematically summarize the recent advances in structure and biological function of YTH family proteins, and their roles in human cancer and potential application in cancer therapy.
Fucoidan Inhibits the Progression of Hepatocellular Carcinoma via Causing lncRNA LINC00261 Overexpression
Authors: Ma Danhui , Wei Jiayi , Chen Sinuo , Wang Heming , Ning Liuxin , Luo Shi-Hua , Liu Chieh-Lun , Song Guangqi , Yao Qunyan
Published: April 2021

Hepatocellular carcinoma (HCC) as a main type of primary liver cancers has become one of the most deadly tumors because of its high morbidity and poor prognosis. Fucoidan is a family of natural, heparin-like sulfated polysaccharides extracted from brown algae. It is not only a widely used dietary supplement, but also participates in many biological activities, such as anti-oxidation, anti-inflammation and anti-tumor. However, the mechanism of fucoidan induced inhibition of HCC is elusive. In our study, we demonstrated that fucoidan contributes to inhibiting cell proliferation in vivo and in vitro, restraining cell motility and invasion and inducing cell cycle arrest and apoptosis. According to High-Throughput sequencing of long-non-coding RNA (lncRNA) in MHCC-97H cells treated with 0.5 mg/mL fucoidan, we found that 56 and 49 lncRNAs were correspondingly up- and down-regulated. LINC00261, which was related to the progression of tumor, was highly expressed in fucoidan treated MHCC-97H cells. Moreover, knocking down LINC00261 promoted cell proliferation by promoting the expression level of miR-522-3p, which further decreased the expression level of downstream SFRP2. Taken together, our results verified that fucoidan effectively inhibits the progression of HCC via causing lncRNA LINC00261 overexpression.
Resveratrol and Angiogenin-2 Combined With PEGDA/TCS Hydrogel for the Targeted Therapy of Hypoxic Bone Defects via Activation of the Autophagy Pathway
Authors: Fan Dehui , Liu Hengping , Zhang Zhenning , Su Meiyi , Yuan Zhixian , Lin Ying , Yang Shuquan , Li Wenqiang , Zhang Xintao
Published: April 2021

The guarantee of cell survival under hypoxic conditions and rapid vascularization is a key in tissue engineering strategies for treating bone defects. Our study aimed to establish the protective role of bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) in hypoxic conditions and realize rapid vascularization in bone defects. Resveratrol (Res), a non-flavonoid polyphenolic compound, and angiopoietin-2 (ANG2), a vascular activating factor, were applied to enhance BMSC and HUVEC survival, osteogenesis, and angiogenesis. The morphology, autophagy, viability, apoptosis, cycle, and osteogenic differentiation of BMSCs treated with Res were analyzed. The results indicated that Res could improve BMSC survival and differentiation via the autophagy pathway under hypoxic conditions. In addition, Res maintained HUVEC growth and proliferation in a hypoxic and ANG2 double-adverse environment via the autophagy pathway. To simulate a relatively hypoxic environment, small-aperture PEGDA/TCS hydrogels containing Res and ANG2 were prepared. BMSCs were cultured in the PEGDA/TCS scaffold and transplanted into a large tibial defect. CD31 immunofluorescence showed that the density and size of new blood vessels in the bone defect were significantly enhanced by ANG2 and Res at 8 weeks after surgery. H&E, Masson, and immunohistochemical staining results indicated that ANG2 combined with Res could promote new bone formation in defects. All these results suggested that Res combined with ANG2 may be a novel strategy for the targeted therapy of hypoxic bone defects with tissue engineering scaffolds.
MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer
Authors: Sun Lei , Li Man , Deng Ling , Niu Yuchun , Tang Yichun , Wang Yu , Guo Linlang
Published: April 2021

Background: Immune checkpoint inhibitors have changed the treatment landscape for advanced non-small cell lung cancer. However, only a small proportion of patients experience clinical benefit from ICIs. Thus, the discovery of predictive biomarkers is urgently warranted. Evidence have shown that genetic aberrations in cancer cells can modulate the tumor immune milieu. We therefore explored the association between oncogenic mutations and efficacy to ICIs in non-squamous NSCLC.

Methods: We curated genomic and clinical data of 314 non-squamous NSCLC patients receiving ICIs from four independent studies for the discovery cohort. For external validation, 305 patients from an ICI-treated cohort and 1,027 patients from two non-ICI-treated cohorts were used. Relations between oncogenic mutations and outcomes of immunotherapy were examined. Multivariate Cox regression models were applied to adjust confounding factors. Further investigation on tumor antigenicity and antitumor immunity was performed in The Cancer Genome Atlas lung adenocarcinoma cohort.

Results: A total of 82 oncogenes/tumor suppressor genes according to the Oncology Knowledge base database with a frequency greater than 3% were identified and investigated in the discovery cohort. Within these genes, MGA mutations were enriched in patients with durable clinical benefit (p = 0.001, false discovery rate q < 0.05). The objective response rate was also significantly higher in patients with MGA mutation (2.63-fold, p < 0.001, FDR q < 0.05). Longer progression-free survival was found in MGA-mutated patients (HR, 0.41; 95% CI, 0.23–0.73; p = 0.003), and the association remained significant after controlling for tumor mutational burden (TMB), programmed cell death ligand-1 expression, and treatment regimens. In the validation cohort, significant improvement in overall survival was found in patients harboring MGA mutation (HR, 0.39; 95% CI, 0.17–0.88; p = 0.02). Furthermore, the survival difference was not detected in non-ICI-treated cohorts. We also demonstrated that MGA mutation correlate with higher TMB, elevated neoantigen load and DNA damage repair deficiency. Gene set enrichment analysis revealed that gene sets regarding activated immune responses were enriched in MGA-mutated tumors.

Conclusion: Our work provides evidence that MGA mutation can be used as a novel predictive biomarker for ICI response in non-squamous NSCLC and merits further clinical and preclinical validation.
Radioresistant Nasopharyngeal Carcinoma Cells Exhibited Decreased Cisplatin Sensitivity by Inducing SLC1A6 Expression
Authors: Hao Wenwen , Wu Lisha , Cao Linhui , Yu Jinxiu , Ning Li , Wang Jingshu , Lin Xiaoping , Chen Yanfeng
Published: April 2021

Cisplatin-based regimens are commonly used for the treatment of nasopharyngeal carcinoma (NPC) in patients who receive concurrent chemoradiotherapy. The sensitivity of NPC cells to cisplatin is closely associated with the efficacy of radiation therapy. In this study, we established two radioresistant NPC cell lines, HONE1-IR and CNE2-IR, and found that both cell lines showed reduced sensitivity to cisplatin. RNA-sequence analysis showed that SLC1A6 was upregulated in both HONE1-IR and CNE2-IR cell lines. Downregulation of SLC1A6 enhanced cisplatin sensitivity in these two radioresistant NPC cell lines. It was also found that the expression of SLC1A6 was induced during radiation treatment and correlated with poor prognosis of NPC patients. Notably, we observed that upregulation of SLC1A6 led to elevating level of glutamate and the expression of drug-resistant genes, resulted in reduced cisplatin sensitivity. Our findings provide a rationale for developing a novel therapeutic target for NPC patients with cisplatin resistance.
Antiviral Activity of Isoimperatorin Against Influenza A Virus in vitro and its Inhibition of Neuraminidase
Authors: Lai Yanni , Han Tiantian , Zhan Shaofeng , Jiang Yong , Liu Xiaohong , Li Geng
Published: April 2021

Influenza A virus (IAV) poses a severe threat to human health and is a major public health problem worldwide. As global anti-influenza virus drug resistance has increased significantly, there is an urgent need to develop new antiviral drugs, especially drugs from natural products. Isoimperatorin, an active natural furanocoumarin, exhibits a broad range of pharmacologic activities including anticoagulant, analgesic, anti-inflammatory, antibacterial, anti-tumor, and other pharmacological effects, so it has attracted more and more attention. In this study, the antiviral and mechanistic effects of isoimperatorin on influenza A virus in vitro were studied. Isoimperatorin illustrated a broad-spectrum antiviral effect, especially against the A/FM/1/47 (H1N1), A/WSN/33 (H1N1, S31N, amantadine resistant), A/Puerto Rico/8/34 (H1N1), and A/Chicken/Guangdong/1996 (H9N2) virus strains. The experimental results of different administration modes showed that isoimperatorin had the best antiviral activity under the treatment mode. Further time-of-addition experiment results indicated that when isoimperatorin was added at the later stage of the virus replication cycle (6–8 h, 8–10 h), it exhibited an effective antiviral effect, and the virus yield was reduced by 81.4 and 84.6%, respectively. In addition, isoimperatorin had no effect on the expression of the three viral RNAs (mRNA, vRNA, and cRNA). Both the neuraminidase (NA) inhibition assay and CETSA demonstrated that isoimperatorin exerts an inhibitory effect on NA-mediated progeny virus release. The molecular docking experiment simulated the direct interaction between isoimperatorin and NA protein amino acid residues. In summary, isoimperatorin can be used as a potential agent for the prevention and treatment of influenza A virus.
Machine Learning Assisted Chimera and Solitary States in Networks
Authors: Kushwaha Niraj , Mendola Naveen Kumar , Ghosh Saptarshi , Kachhvah Ajay Deep , Jalan Sarika
Published: April 2021

Chimera and Solitary states have captivated scientists and engineers due to their peculiar dynamical states corresponding to co-existence of coherent and incoherent dynamical evolution in coupled units in various natural and artificial systems. It has been further demonstrated that such states can be engineered in systems of coupled oscillators by suitable implementation of communication delays. Here, using supervised machine learning, we predict (a) the precise value of delay which is sufficient for engineering chimera and solitary states for a given set of system's parameters, as well as (b) the intensity of incoherence for such engineered states. Ergo, using few initial data points we generate a machine learning model which can then create a more refined phase plot as well as by including new parameter values. We demonstrate our results for two different examples consisting of single layer and multi layer networks. First, the chimera states (solitary states) are engineered by establishing delays in the neighboring links of a node (the interlayer links) in a 2-D lattice (multiplex network) of oscillators. Then, different machine learning classifiers, K-nearest neighbors (KNN), support vector machine (SVM) and multi-layer perceptron neural network (MLP-NN) are employed by feeding the data obtained from the network models. Once a machine learning model is trained using the limited amount of data, it predicts the precise value of critical delay as well as the intensity of incoherence for a given unknown systems parameters values. Testing accuracy, sensitivity, and specificity analysis reveal that MLP-NN classifier is better suited than Knn or SVM classifier for the predictions of parameters values for engineered chimera and solitary states. The technique provides an easy methodology to predict critical delay values as well as intensity of incoherence for that delay value for designing an experimental setup to create solitary and chimera states.
On-Chip Broadband Mid-Infrared Supercontinuum Generation Based on Highly Nonlinear Chalcogenide Glass Waveguides
Authors: Xia Di , Huang Yufei , Zhang Bin , Yang Zelin , Zeng Pingyang , Shang Haiyan , Cheng Huanjie , Liu Linghao , Zhang Mingjie , Zhu Ying , Li Zhaohui
Published: April 2021

On-chip mid-infrared (MIR) supercontinuum generation (SCG) covering the molecular functional spectral region (3–12 μm) offers the advantages of robustness, simplicity, and compactness. Yet, the spectral range still cannot be expanded beyond 10 μm. In this study, on-chip ultrabroadband MIR SCG in a high numerical aperture chalcogenide (ChG) waveguide is numerically investigated. The ChG waveguide with a Ge-As-Se-Te core and Ge-Se upper and lower cladding is designed to optimize the nonlinear coefficients and dispersion profile. Assisted by dispersive wave generation in both short- and long-wavelength range, broadband SCG ranging from 2 to 13 µm is achieved. Besides, a fabrication scheme is proposed to realize precise manipulation of dispersion design. Such results demonstrate that such sources are suitable for compact, chip-integrated molecular spectroscopy applications.
Monte Carlo and Kinetic Monte Carlo Models for Deposition Processes: A Review of Recent Works
Authors: Cheimarios Nikolaos , To Deifilia , Kokkoris George , Memos George , Boudouvis Andreas G.
Published: April 2021

Monte Carlo (MC) and kinetic Monte Carlo (kMC) models are widely used for studying the physicochemical surface phenomena encountered in most deposition processes. This spans from physical and chemical vapor deposition to atomic layer and electrochemical deposition. MC and kMC, in comparison to popular molecular methods, such as Molecular Mechanics/Dynamics, have the ability to address much larger time and spatial scales. They also offer a far more detailed approach of the surface processes than continuum-type models, such as the reaction-diffusion models. This work presents a review of the modern applications of MC/kMC models employed in deposition processes.
KCNQ Current Contributes to Inspiratory Burst Termination in the Pre-Bötzinger Complex of Neonatal Rats in vitro
Authors: Revill Ann L. , Katzell Alexis , Del Negro Christopher A. , Milsom William K. , Funk Gregory D.
Published: April 2021

The pre-Bötzinger complex (preBötC) of the ventral medulla generates the mammalian inspiratory breathing rhythm. When isolated in explants and deprived of synaptic inhibition, the preBötC continues to generate inspiratory-related rhythm. Mechanisms underlying burst generation have been investigated for decades, but cellular and synaptic mechanisms responsible for burst termination have received less attention. KCNQ-mediated K+ currents contribute to burst termination in other systems, and their transcripts are expressed in preBötC neurons. Therefore, we tested the hypothesis that KCNQ channels also contribute to burst termination in the preBötC. We recorded KCNQ-like currents in preBötC inspiratory neurons in neonatal rat slices that retain respiratory rhythmicity. Blocking KCNQ channels with XE991 or linopirdine (applied via superfusion or locally) increased inspiratory burst duration by 2- to 3-fold. By contrast, activation of KCNQ with retigabine decreased inspiratory burst duration by ~35%. These data from reduced preparations suggest that the KCNQ current in preBötC neurons contributes to inspiratory burst termination.
Neurovascular Dysregulation During Exercise in Type 2 Diabetes
Authors: Grotle Ann-Katrin , Kaur Jasdeep , Stone Audrey J. , Fadel Paul J.
Published: April 2021

Emerging evidence suggests that type 2 diabetes (T2D) may impair the ability to properly adjust the circulation during exercise with augmented blood pressure (BP) and an attenuated contracting skeletal muscle blood flow (BF) response being reported. This review provides a brief overview of the current understanding of these altered exercise responses in T2D and the potential underlying mechanisms, with an emphasis on the sympathetic nervous system and its regulation during exercise. The research presented support augmented sympathetic activation, heightened BP, reduced skeletal muscle BF, and impairment in the ability to attenuate sympathetically mediated vasoconstriction (i.e., functional sympatholysis) as potential drivers of neurovascular dysregulation during exercise in T2D. Furthermore, emerging evidence supporting a contribution of the exercise pressor reflex and central command is discussed along with proposed future directions for studies in this important area of research.
Synergistic Effects of Exercise Training and Vitamin D Supplementation on Mitochondrial Function of Cardiac Tissue, Antioxidant Capacity, and Tumor Growth in Breast Cancer in Bearing-4T1 Mice
Authors: Jafari Ali , Sheikholeslami-Vatani Dariush , Khosrobakhsh Farnoosh , Khaledi Neda
Published: April 2021

Both regular exercise training and vitamin D consumption are beneficial for patients with cancer. The study investigated the effects of interval exercise training (IET) or/and vitamin D supplementation on the gene expression involved in mitochondrial function of heart tissue, tumor size, and total antioxidant capacity (TAC) in breast cancer (BC) model mice. We assigned random 40 female NMRI mice to five equal groups (n= 8); the healthy control group (H.C), cancer control group (Ca.C), cancer with the vitamin D group (Ca.VD), cancer exercise group (Ca.Ex), and cancer exercise along with the vitamin D group (Ca.Ex.VD). Forty-eight hours after treatment, we anesthetized the animals and performed the isolation of heart tissue and blood serum for further studies. The results showed that the lowest mean body weight at the end of the treatments was related to Ca.C (p= 0.001). Vitamin D treatment alone has increased tumor volume growth by approximately 23%; in contrast, co-treatment with exercise and vitamin D inhibited tumor growth in mice (P= 0.001), compared with the cancer control (12%). TAC levels were higher in the group that received both vitamin D and exercise training (Ca.Ex.VD) than in the other treatment groups (Ca.VD and Ca.Ex) (p= 0.001). In cardiac tissue, vitamin D treatment induces an elevation significantly of the mRNA expression ofPgc1−α,Mfn-1, andDrp-1genes (p= 0.001). The study has shown the overexpression of vitamin D in female mice, and synergistic effects of IET with vitamin D on weight loss controlling, antitumorigenesis, improvement of antioxidant defense, and the modulation of gene expression. The synergistic responses were likely by increasing mitochondrial fusion and TAC to control oxidative stress. We recommended being conducted further studies on mitochondrial dynamics and biogenesis focusing on risk factors of cardiovascular disease (CVD) in patients with BC.
Forearm Volume Changes Estimated by Photo-Plethysmography During an Original Candlestick/Prayer Maneuver in Patients With Suspected Thoracic Outlet Syndrome
Authors: Hersant Jeanne , Ramondou Pierre , Chavignier Victoire , Chavanon Axelle , Feuilloy Mathieu , Picquet Jean , Henni Samir , Abraham Pierre
Published: April 2021

Objective: Hemodynamic investigations in thoracic outlet syndrome (TOS) remain difficult, even in trained hands. Results are generally reported as either presence or absence of venous compression. In fact, in patients with suspected TOS but without chronic venous occlusion, the forearm volume changes may result from various combinations of forearm position from heart level, arterial inflow, and/or venous outflow positional impairment.

Design: Cross sectional, retrospective, single center study, accessible on Clinicaltrial.gov under reference NCT04376177.

Material: We used venous photo-plethysmography (V-PPG) in 151 patients with suspected TOS. The subjects elevated their arms to the “candlestick” (Ca) position for 30 s and then kept their arm elevated in front of the body for an additional 15 s (“prayer” position; Pra). This CA–Pra procedure was repeated three times by each patient with recording of both arms.

Method: We classified V-PPG recordings using an automatic clustering method.

Result: The blinded clustering classification of 893 V-PPG recordings (13 missing files) resulted in four out of seven clusters, allowing the classification of more than 99% of the available recordings. Each cluster included 65.73, 6.16, 17.13, and 10.8% of the recordings, respectively.

Conclusion: Venous hemodynamic profiles in TOS are not only either normal or abnormal. With V-PPG, four clusters were observed to be consistent with, and assumed to result from, the four possible associations of presence/absence of arterial inflow/venous outflow positional impairment: (1) normal response (maximal emptying in Ca and Pra), (2) isolated inflow impairment (emptying in Ca and filling in Pra due to post-ischemic vasodilation), (3) isolated venous outflow impairment (emptying then filling in Ca due to arterial inflow and emptying in Pra), and (4) simultaneous inflow/outflow impairment (emptying in Ca but no filling due to concomitant inflow impairment and further emptying in Pra).
Enhanced Lipid Production in Chlamydomonas reinhardtii Caused by Severe Iron Deficiency
Authors: Devadasu Elsinraju , Subramanyam Rajagopal
Published: April 2021

Microalgae are used as a source of lipids for the production of biofuels. Most algae produce neutral lipids under stress conditions. Here, lipid accumulation by the unicellular alga Chlamydomonas reinhardtii was examined during cultivation under iron-limiting conditions. Severe iron stress caused the cells to accumulate a significant amount of lipid, specifically triacylglycerols (TAGs), by compromising the growth. Semi-quantitative measurements by Fourier transform infrared (FTIR) spectroscopy showed an increase in both carbohydrate and lipid content in iron-stressed C. reinhardtii cells compared to control. Analysis by flow cytometry and thin layer chromatography confirmed that severe iron deficiency-induced TAG accumulation to fourfold higher than in iron-replete control cells. This accumulation of TAGs was mostly degraded from chloroplast lipids accompanied by overexpression of diacylglycerol acyltransferase (DGAT2A) protein. Furthermore, liquid chromatography-mass spectrometry (LC-MS) analysis demonstrated significantly enhanced levels of C16:0, C18:2, and C18:3 fatty acids (FAs). These results indicate that iron stress triggers the rapid accumulation of TAGs in C. reinhardtii cells. The enhanced production of these lipids caused by the iron deficiency may contribute to the efficient production of algal biofuels if we escalate to the photobioreactor’s growth conditions.