bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal Acclimation and Adaptation in Marine Protozooplankton and Mixoplankton
Authors: Calbet Albert , Saiz Enric
Published: March 2022

Proper thermal adaptation is key to understanding how species respond to long-term changes in temperature. However, this is seldom considered in protozooplankton and mixoplankton experiments. In this work, we studied how two heterotrophic dinoflagellates (Gyrodinium dominans and Oxyrrhis marina), one heterotrophic ciliate (Strombidium arenicola), and one mixotrophic dinoflagellate (Karlodinium armiger) responded to warming. To do so, we compared strains adapted at 16, 19, and 22°C and those adapted at 16°C and exposed for 3 days to temperature increases of 3 and 6°C (acclimated treatments). Neither their carbon, nitrogen or phosphorus (CNP) contents nor their corresponding elemental ratios showed straightforward changes with temperature, except for a modest increase in P contents with temperature in some grazers. In general, the performance of both acclimated and adapted grazers increased from 16 to 19°C and then dropped at 22°C, with a few exceptions. Therefore, our organisms followed the “hotter is better” hypothesis for a temperature rise of 3°C; an increase of >6°C, however, resulted in variable outcomes. Despite the disparity in responses among species and physiological rates, 19°C-adapted organisms, in general, performed better than acclimated-only (16°C-adapted organisms incubated at +3°C). However, at 22°C, most species were at the limit of their metabolic equilibrium and were unable to fully adapt. Nevertheless, adaptation to higher temperatures allowed strains to maintain physiological activities when exposed to sudden increases in temperature (up to 25°C). In summary, adaptation to temperature seems to confer a selective advantage to protistan grazers within a narrow range (i.e., ca. 3°C). Adaptation to much higher increases of temperatures (i.e., +6°C) does not confer any clear physiological advantage (with few exceptions; e.g., the mixotroph K. armiger), at least within the time frame of our experiments.
Biochar Amendment and Nitrogen Fertilizer Contribute to the Changes in Soil Properties and Microbial Communities in a Paddy Field
Authors: Ali Izhar , Yuan Pengli , Ullah Saif , Iqbal Anas , Zhao Quan , Liang He , Khan Abdullah , Imran  , Zhang Hua , Wu Xiaoyan , Wei Shanqing , Gu Minghua , Jiang Ligeng
Published: March 2022

Biochar amendment can influence the abundance, activity, and community structure of soil microbes. However, scare information is present about the effect of the combined application of biochar with synthetic nitrogen (N) fertilizer under paddy field condition. We aimed to resolve this research gap in rice field conditions through different biochar in combination with N fertilizers on soil nutrients, soil microbial communities, and rice grain yield. The present study involves eight treatments in the form of biochar (0, 10, 20, and 30 t ha–1) and N (135 and 180 kg ha–1) fertilizer amendments. The soil microbial communities were characterized using high-throughput sequencing of 16S and Internal transcribed spacer (ITS) ribosomal RNA gene amplicons. Experiential findings showed that the treatments had biochar amendments along with N fertilizer significantly advanced soil pH, soil organic carbon (SOC), total nitrogen (TN), soil microbial carbon (SMBC), soil microbial nitrogen (SMBN), and rice grain yield in comparison to sole N application. Furthermore, in comparison with control in the first year (2019), biochar amendment mixed with N fertilizer had more desirable relative abundance of microorganism, phyla Acidobacteria, Actinobacteria, Proteobacteria, and Verrucomicrobia with better relative abundance ranging from 8.49, 4.60, 46.30, and 1.51% in T7, respectively. Similarly, during 2020, bacteria phyla Acidobacteria, Actinobacteria, Bacteroidetes, Gemmatimonadetes, Planctomycetes, and Verrucomicrobia were resulted in higher and ranging from 8.69, 5.18, 3.5, 1.9, 4.0, and 1.6%, in biochar applied treatments, respectively, as compared to control (T1). Among the treatments, Sphingopyxis and Thiobacillus bacterial genus were in higher proportion in T7 and T3, respectively, as compared to other treatments and Bacillus was higher in T6. Interestingly, biochar addition significantly decreased the soil fungi phyla Ascomycota, Basidiomycota, Chytridiomycota, and Rozellomycota, in 2020 as compared to 2019. Whereas biochar addition to soil decreased Echria, Kohlmeyeriopsis, and Westerdykella fungal genus as compared to non-biochar treatments. The redundancy analysis showed that soil biochemical traits were positively correlated with soil bacteria. In addition, correlation analysis showed that soil bacteria including Acidobacteria, Actinobacteria, Bacteroidetes, Planctomycetes, and Proteobacteria strongly correlated with rice grain yield. This study demonstrated that soil nutrients and bacteria contribute to an increase in rice yield in combined biochar amendment with lower N treatments.
Metagenome-Assembled Genomes From Pyropia haitanensis Microbiome Provide Insights Into the Potential Metabolic Functions to the Seaweed
Authors: Wang Junhao , Tang Xianghai , Mo Zhaolan , Mao Yunxiang
Published: March 2022

Pyropiais an economically important edible red alga worldwide. The aquaculture industry andPyropiaproduction have grown considerably in recent decades. Microbial communities inhabit the algal surface and produce a variety of compounds that can influence host adaptation. Previous studies on thePyropiamicrobiome were focused on the microbial components or the function of specific microbial lineages, which frequently exclude metabolic information and contained only a small fraction of the overall community. Here, we performed a genome-centric analysis to study the metabolic potential of thePyropia haitanensisphycosphere bacteria. We reconstructed 202 unique metagenome-assembled genomes (MAGs) comprising all major taxa present within theP. haitanensismicrobiome. The addition of MAGs to the genome tree containing all publicly availablePyropia-associated microorganisms increased the phylogenetic diversity by 50% within the bacteria. Metabolic reconstruction of the MAGs showed functional redundancy across taxa for pathways including nitrate reduction, taurine metabolism, organophosphorus, and 1-aminocyclopropane-1-carboxylate degradation, auxin, and vitamin B12synthesis. Some microbial functions, such as auxin and vitamin B12synthesis, that were previously assigned to a fewPyropia-associated microorganisms were distributed across the diverse epiphytic taxa. Other metabolic pathways, such as ammonia oxidation, denitrification, and sulfide oxidation, were confined to specific keystone taxa.
A Nutrient-Based Cellular Model to Characterize Acetylation-Dependent Protein-Protein Interactions
Authors: Loehr Jérémy , Kougnassoukou Tchara Pata-Eting , Gonthier Kevin , Noufi Chahinez , Linteau Naomie , Audet-Walsh Étienne , Lambert Jean-Philippe
Published: March 2022

Cellular homeostasis requires the orderly expression of thousands of transcripts. Gene expression is regulated by numerous proteins that recognize post-translational modifications—in particular, the acetylation of lysine residues (Kac) on histones. In addition to affecting the general condensation state of the chromatin, acetylated histones act as anchor points for bromodomain (BRD)-containing adapter proteins. BRDs are the primary Kac reader domains in humans, and proteins containing them act as chromatin scaffolds that organize large networks of interactions to regulate transcription. To characterize BRD-dependent interaction networks, we established cell lines in which histone acetylation is dependent on acetate supplementation. To do this, we used genome editing to knock out ATP citrate lyase (ACLY), the enzyme responsible for converting citrate to oxaloacetate and acetyl-CoA in the cytoplasm and nucleus. In our cellular model, removing acetate from the culture medium resulted in the rapid catabolism of acetylated histones to restore the nucleocytoplasmic acetyl-CoA pool. Here we report the use of our new model in functional proteomics studies to characterize BRD-dependent interaction networks on the chromatin.
Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?
Authors: Wang Feixue , Wang Jiandong , Shen Ying , Li Hao , Rausch Wolf-Dieter , Huang Xiaobo
Published: March 2022

Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer’s disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development.
Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a
Authors: Shi Shu-qun , Mahoney Carrie E. , Houdek Pavel , Zhao Wenling , Anderson Matthew P. , Zhuo Xinming , Beaudet Arthur , Sumova Alena , Scammell Thomas E. , Johnson Carl Hirschie
Published: March 2022

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.
A Compliant Force Control Scheme for Industrial Robot Interactive Operation
Authors: Xue Xianfa , Huang Haohui , Zuo Lei , Wang Ning
Published: March 2022

To meet the enormous demand for smart manufacturing, industrial robots are playing an increasingly important role. For industrial operations such as grinding 3C products, numerous demands are placed on the compliant interaction ability of industrial robots to interact in a compliant manner. In this article, an adaptive compliant control framework for robot interaction is proposed. The reference trajectory is obtained by single-point demonstration and DMP generalization. The adaptive feedforward and impedance force controller is derived in terms of position errors, and they are input into an admittance controller to obtain the updated amount of position deviation. The compliant interaction effect is achieved, which is shown that the grinding head fits on the curved surface of a computer mouse, and the interaction force is within a certain expected range in the grinding experiment based on the performance an Elite robot. A comparative experiment was conducted to demonstrate the effectiveness of the proposed framework in a more intuitive way.
Significance of D-Dimer in Acute Ischemic Stroke Patients With Large Vessel Occlusion Accompanied by Active Cancer
Authors: Pan Kwang Hyun , Kim Jaeyoun , Chung Jong-Won , Kim Keon Ha , Bang Oh Young , Jeon Pyoung , Kim Gyeong-Moon , Seo Woo-Keun
Published: March 2022

Background

This study aimed to investigate clinical outcome predictors of acute stroke patients with large vessel occlusion and active cancer and validate the significance of D-dimer levels for endovascular thrombectomy decisions.

Methods

We analyzed a prospectively collected hospital-based stroke registry to determine clinical EVT outcomes of acute stroke patients within 24 h with following criteria: age ≥18 years, NIHSS ≥6, and internal carotid artery or middle cerebral artery lesion. All patients were classified into EVT and non-EVT groups. Patients were divided into two groups by initial D-dimer level. We explored variables potentially associated with successful recanalization as well as 3-month functional outcomes and mortality rates.

Results

Among 68 patients, 36 were treated with EVT, with successful recanalization in 55.6%. The low D-dimer group showed a higher rate of successful recanalization and favorable outcome than the high D-dimer group. The mortality rate was higher in the high D-dimer group. No EVT and high D-dimer level were independent predictors of mortality, whereas lesion volume and low D-dimer level were independently associated with favorable outcomes.

Conclusions

D-dimer level is a prognostic factor in acute LVO stroke patients with active cancer, and its high value for EVT decisions provisionally supports its testing in this patient population.
Use of Functional MRI in Deep Brain Stimulation in Parkinson's Diseases: A Systematic Review
Authors: Miao Jingya , Tantawi Mohamed , Koa Victoria , Zhang Ashley B. , Zhang Veronica , Sharan Ashwini , Wu Chengyuan , Matias Caio M.
Published: March 2022

Deep brain stimulation (DBS) has been used to modulate aberrant circuits associated with Parkinson's disease (PD) for decades and has shown robust therapeutic benefits. However, the mechanism of action of DBS remains incompletely understood. With technological advances, there is an emerging use of functional magnetic resonance imaging (fMRI) after DBS implantation to explore the effects of stimulation on brain networks in PD. This systematic review was designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to summarize peer-reviewed articles published within the past 10 years in which fMRI was employed on patients with PD-DBS. Search in PubMed database provided 353 references, and screenings resulted in a total of 19 studies for qualitative synthesis regarding study designs (fMRI scan timepoints and paradigm), methodology, and PD subtypes. This review concluded that fMRI may be used in patients with PD-DBS after proper safety test; resting-state and block-based fMRI designs have been employed to explore the effects of DBS on brain networks and the mechanism of action of the DBS, respectively. With further validation of safety use of fMRI and advances in imaging techniques, fMRI may play an increasingly important role in better understanding of the mechanism of stimulation as well as in improving clinical care to provide subject-specific neuromodulation treatments.
The Relationship Between Affective Visual Mismatch Negativity and Interpersonal Difficulties Across Autism and Schizotypal Traits
Authors: Ford Talitha C. , Hugrass Laila E. , Jack Bradley N.
Published: March 2022

Sensory deficits are a feature of autism and schizophrenia, as well as the upper end of their non-clinical spectra. The mismatch negativity (MMN), an index of pre-attentive auditory processing, is particularly sensitive in detecting such deficits; however, little is known about the relationship between the visual MMN (vMMN) to facial emotions and autism and schizophrenia spectrum symptom domains. We probed the vMMN to happy, sad, and neutral faces in 61 healthy adults (18–40 years, 32 female), and evaluated their degree of autism and schizophrenia spectrum traits using the Autism Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ). The vMMN to happy faces was significantly larger than the vMMNs to sad and neutral faces. The vMMN to happy faces was associated with interpersonal difficulties as indexed by AQ Communication and Attention to Detail subscales, and SPQ associated with more interpersonal difficulties. These data suggest that pre-attentive processing of positive affect might be more specific to the interpersonal features associated with autism and schizophrenia. These findings add valuable insights into the growing body of literature investigating symptom-specific neurobiological markers of autism and schizophrenia spectrum conditions.
Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients
Authors: Dai Yuwei , Yang Zhuanyi , Guo Jialing , Li Haoyu , Gong Jiaoe , Xie Yuanyuan , Xiao Bo , Wang Hua , Long Lili
Published: March 2022

Aim

De novo DDX3X variants account for 1–3% of unexplained intellectual disability cases in females and very rarely in males. Yet, the clinical and genetic features of DDX3X neurodevelopmental disorder in the Chinese cohort have not been characterized.

Method

A total of 23 Chinese patients (i.e., 22 female and 1 male) with 22 de novo DDX3X deleterious variants were detected among 2,317 probands with unexplained intellectual disability (ID) undertaking whole exome sequencing (WES). The age, sex, genetic data, feeding situation, growth, developmental conditions, and auxiliary examinations of the cohort were collected. The Chinese version of the Gesell Development Diagnosis Scale (GDDS-C) was used to evaluate neurodevelopment of DDX3X patients. The Social Communication Questionnaire (SCQ)-Lifetime version was applied as a primary screener to assess risk for autism spectrum disorder (ASD).

Result

A total of 17 DDX3X variants were novel and 22 were de novo. Missense variants overall were only slightly more common than loss-of-function variants and were mainly located in two functional subdomains. The average age of this cohort was 2.67 (±1.42) years old. The overlapping phenotypic spectrum between this cohort and previously described reports includes intellectual disability (23/23, 100%) with varying degrees of severity, muscle tone abnormalities (17/23, 73.9%), feeding difficulties (13/23, 56.5%), ophthalmologic problems (11/23, 47.8%), and seizures (6/23, 26.1%). A total of 15 individuals had notable brain anatomical disruption (15/23, 65.2%), including lateral ventricle enlargement, corpus callosum abnormalities, and delayed myelination. Furthermore, 9 patients showed abnormal electroencephalogram results (9/23, 39.1%). Hypothyroidism was first noted as a novel clinical feature (6/23, 26.1%). The five primary neurodevelopmental domains of GDDS-C in 21 patients were impaired severely, and 13 individuals were above the “at-risk” threshold for ASD.

Interpretation

Although a certain degree of phenotypic overlap with previously reported cohorts, our study described the phenotypic and variation spectrum of 23 additional individuals carrying DDX3X variants in the Chinese population, adding hypothyroidism as a novel finding. We confirmed the importance of DDX3X as a pathogenic gene in unexplained intellectual disability, supporting the necessity of the application of WES in patients with unexplained intellectual disability.
Urine- and Blood-Based Molecular Profiling of Human Prostate Cancer
Authors: Chen Gang , Jia Guojin , Chao Fan , Xie Feng , Zhang Yue , Hou Chuansheng , Huang Yong , Tang Haoran , Yu Jianjun , Zhang Jihong , Jia Shidong , Xu Guoxiong
Published: March 2022

Objective

Prostate cancer (PCa) is one of the most common malignant tumors, accounting for 20% of total tumors ranked first in males. PCa is usually asymptomatic at the early stage and the specificity of the current biomarkers for the detection of PCa is low. The present study evaluates circulating tumor DNA (ctDNA) in blood or urine, which can be used as biomarkers of PCa and the combination of these markers may increase the sensitivity and specificity of the detection of PCa.

Methods

Tissue, blood, and urine samples were collected from patients with PCa. All prostate tissue specimens underwent pathological examination. A hybrid-capture-based next-generation sequencing assay was used for plasma and urinary ctDNA profiling. Sequencing data were analyzed by an in-house pipeline for mutation calling. Mutational profiles of PCa and BPH were compared in both plasma and urine samples. Associations of detected mutations and clinical characteristics were statistically analyzed.

Results

A significant association of mutation allele frequencies (MAFs) in the blood samples with patients with metastatic PCa rather than patients with primary PCa, and MAFs are changed after treatment in patients with PCa. Further, the number of mutations in urine is not associated with clinical characteristics of PCa patients, but the frequencies of mutation alleles in the urine are associated with patient age. Comparison of cfDNA aberration profiles between urine and blood reveals more alterations in urine than in blood, including TP53, AR, ATM, MYC, and SPOP mutations.

Conclusion

This work provides the potential clinical application of urine, in addition to blood, as a powerful and convenient non-invasive approach in personalized medicine for patients with PCa.
Interplay Between Non-Coding RNAs and Programmed Cell Death Proteins
Authors: Ghafouri-Fard Soudeh , Hussen Bashdar Mahmud , Mohaqiq Mahdi , Shoorei Hamed , Baniahmad Aria , Taheri Mohammad , Jamali Elena
Published: March 2022

Programmed cell death (PDCD) family of proteins includes at least 12 members, function of seven of them being more investigated. These members are PDCD1, PDCD2, PDCD4, PDCD5, PDCD6, PDCD7 and PDCD10. Consistent with the important roles of these proteins in the regulation of apoptosis, dysregulation of PDCDs is associated with diverse disorders ranging from intervertebral disc degeneration, amyotrophic lateral sclerosis, immune thrombocytopenia, type 1 diabetes, congenital hypothyroidism, Alzheimer’s disease to different types of cancers. More recently, the interaction between non-coding RNAs and different members of PDCD family is being discovered. In the current study, we described the functional interactions between PDCDs and two classes of non-coding RNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miR-21 and miR-183 are two miRNAs whose interactions with PDCDs have been assessed in different contexts. The lncRNAs interaction with PDCDs is mainly assessed in the context of neoplasia indicating the role of MALAT1, MEG3, SNHG14 and LINC00473 in this process.
PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas
Authors: Ohba Shigeo , Tang Yongjian , Johannessen Tor-Christian Aase , Mukherjee Joydeep
Published: March 2022

PKM2 is a phosphotyrosine-binding glycolytic enzyme upregulated in many cancers, including glioma, and contributes to tumor growth by regulating cell cycle progression. We noted, however, that in multiple glioma cell lines, PKM2 knock-down resulted in an accumulation of cells in G2-M phase. Moreover, PKM2 knock-down decreased Cdk1 activity while introducing a constitutively active Cdk1 reversed the effects of PKM2 knock-down on cell cycle progression. The means by which PKM2 increases Cdk1 activity have not been described. Transient interaction of T14/Y15-phosphorylated Cdk1 with cyclin B allows Cdk7-mediated pT161 Cdk1 phosphorylation followed by cdc25C-mediated removal of pT14/Y15 and activation of Cdk1 in cycling cells. In the present course of investigation, PKM2 modulation did not influence Cdk7 activity, but phosphotyrosine binding forms of PKM2 co-immunoprecipitated with pY15-containing Cdk1-cyclinB and enhanced formation of active pT161 Cdk1-cyclin B complexes. Moreover, exogenous expression of phosphotyrosine binding forms of PKM2 reversed the effects of PKM2 knock-down on G2-M arrest. We here show that PKM2 binds and stabilize otherwise transient pY15-containing Cdk1-cyclinB complexes that in turn facilitate Cdk1-cyclin B activation and entry of cells into mitosis. These results, therefore, establish metabolic enzyme PKM2 as a direct interactor and activator of Cdk1-cyclin B complex and thereby directly controls mitotic progression and the growth of brain tumor cells.
Multimorbidity Is Associated With Pain Over 6 Years Among Community-Dwelling Mexican Americans Aged 80 and Older
Authors: Milani Sadaf Arefi , Raji Mukaila A. , Kuo Yong-Fang , Lopez David S. , Markides Kyriakos S. , Al Snih Soham
Published: March 2022

Introduction

Multimorbidity, the co-occurrence of two or more chronic conditions, is common among older adults and is associated with decreased quality of life, greater disability, and increased mortality. Yet, the association of multimorbidity with pain, another significant contributor to decreased quality of life, has not been widely studied. This is especially understudied among very old (aged ≥ 80) Mexican Americans, a fast-growing segment of the United States (US) population.

Objective

To assess the association of multimorbidity with pain in very old Mexican Americans, over six years of follow-up.

Methods

We used data from Waves 7 (2010/2011) to 9 (2015/2016) of the Hispanic Established Populations for the Epidemiologic Study of the Elderly, a longitudinal study of older Mexican Americans residing in the Southwestern US. Multimorbidity was defined as reporting two or more chronic health conditions. Pain was defined as (1) pain on weight-bearing, (2) pain in back, hips, knees, ankles/feet, legs, entire body, or two or more locations, and (3) pain that limits daily activities. We use generalized estimation equations to estimate the odds ratio of pain as a function of multimorbidity over 6 years.

Results

At baseline (n = 841), 77.3% of participants had multimorbidity. Those with multimorbidity had greater odds [2.27, 95% confidence interval (CI): 1.74, 2.95] of reporting pain on weight-bearing over time, compared to those without multimorbidity. Also, those with multimorbidity had 2.12 times the odds of reporting pain that limited their daily activities (95% CI: 1.61, 2.78) compared to those without multimorbidity. Lastly, those with multimorbidity had higher odds of reporting pain in their back, knee, ankles/feet, legs, hips, entire body, or two or more locations, compared to those without multimorbidity.

Conclusions

Those with multimorbidity consistently had higher odds of all types of pain, highlighting the need for early management of pain among those with multiple chronic conditions and complex health needs. This is especially important among very old Mexican Americans, who have a high burden of chronic health conditions.
The Impact of COVID on Adolescent Mental Health, Self-Harm and Suicide: How Can Primary Care Provider Respond? A Position Paper of the European Academy of Pediatrics
Authors: Michaud Pierre-André , Michaud Laurent , Mazur Artur , Hadjipanayis Adamos , Kapp Carole , Ambresin Anne-Emmanuelle
Published: March 2022

Adolescents aged 10 to 19 live a period of their life marked by opportunities and vulnerabilities during which the issue of mental health is of prime importance. Since several decades, and especially since the start of the COVID pandemic, mental health problems and disorders among adolescents have increased around the world. Depression, self-harm and suicidal behavior are common during this period of life, and pediatricians can play a pivotal role in identifying affected or vulnerable youngsters. This article describes risk factors for self-harm and suicidal behavior and reviews how primary care pediatricians and health professionals can respond to such situations. This scoping review is based on existing evidences as well as the authors clinical experience. It suggests concrete actions that can be taken to secure the life of at risk teenagers, and discusses how to organize the transfer to mental health professionals when needed.
Real-World Metastatic Renal Cell Carcinoma Treatment Patterns and Clinical Outcomes in The Netherlands
Authors: van Laar S.A. , Gombert-Handoko K.B. , Groenwold R.H.H. , van der Hulle T. , Visser L.E. , Houtsma D. , Guchelaar H.J. , Zwaveling J.
Published: March 2022

The number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in investigating mRCC treatment efficacy, their external validity can be limited. Therefore, the efficacy of the different treatment options should also be evaluated in clinical practice. We performed a chart review of electronic health records using text mining software to study the current treatment patterns and outcomes. mRCC patients from two large hospitals in the Netherlands, starting treatment between January 2015 and May 2020, were included. Data were collected from electronic health records using a validated text mining tool. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan–Meier method. Most frequent first-line treatments were pazopanib (n = 70), sunitinib (n = 34), and nivolumab with ipilimumab (n = 28). The overall median PFS values for first-line treatment were 15.7 months (95% confidence interval [95%CI], 8.8–20.7), 16.3 months (95%CI, 9.3–not estimable [NE]) for pazopanib, and 6.9 months (95% CI, 4.4–NE) for sunitinib. The overall median OS values were 33.4 months (95%CI, 28.1–50.9 months), 39.3 months (95%CI, 29.5–NE) for pazopanib, and 28.1 months (95%CI, 7.0–NE) for sunitinib. For nivolumab with ipilimumab, median PFS and median OS were not reached. Of the patients who finished first- and second-line treatments, 64 and 62% received follow-up treatments, respectively. With most patients starting on pazopanib and sunitinib, these real-world treatment outcomes were most likely better than in pivotal trials, which may be due to extensive follow-up treatments.
Palmitic Acid, A Critical Metabolite, Aggravates Cellular Senescence Through Reactive Oxygen Species Generation in Kawasaki Disease
Authors: Zhu Qiongjun , Dong Qianqian , Wang Xuliang , Xia Tianhe , Fu Yu , Wang Qiaoyu , Wu Rongzhou , Wu Tingting
Published: March 2022

Coronary artery lesions (CALs) are severe complications of Kawasaki disease (KD), resulting in stenosis and thrombogenesis. Metabolomic profiling of patients’ plasma could assist in elucidating the pathogenesis of CALs and identifying diagnostic biomarkers, which are imperative for clinical treatment. The metabolic profiles between KD patients with CALs and without CALs (non-coronary artery lesion, or NCAL, group) indicated the most significantly differentially expressed metabolite, palmitic acid (PA), showed the most massive fold change at 9.879. Furthermore, PA was proven to aggravate endothelial cellular senescence by increasing the generation of reactive oxygen species (ROS) in KD, and those two phenotypes were confirmed to be enriched among the differentially expressed genes between KD and normal samples from GEO datasets. Collectively, our findings indicate that cellular senescence may be one of the mechanisms of vascular endothelial damage in KD. PA may be a biomarker and potential therapeutic target for predicting the occurrence of CALs in KD patients. All things considered, our findings confirm that plasma metabolomics was able to identify promising biomarkers and potential pathogenesis mechanisms in KD. To conclude, Palmitic acid could be a novel target in future studies of CALs in patients with KD.
Olmesartan Attenuates Single-Lung Ventilation Induced Lung Injury via Regulating Pulmonary Microbiota
Authors: Lu Di , Wang Zhizhi , Chen Zhiming , Fan Jiayang , Zhai Jianxue , Fang Duopei , Cai He , Liu Xiguang , Wu Hua , Cai Kaican
Published: March 2022

Single-lung ventilation (SLV) associated acute lung injury is similar to ischemia reperfusion (IR) injury which is usually occurred during lung surgery. Olmesartan (Olm), a novel angiotensin receptor blocker (ARB), has been reported to ameliorate organ IR injury. Several recent studies have shown that lung microbiota may be involved in pulmonary diseases, but the effect of pulmonary microbiota in SLV-induced lung injury has not been reported. This study aims to determine the mechanism of how Olm attenuates SLV induced lung injury. Our data showed that 7 days Olm treatment before modeling markedly alleviated SLV-induced lung injury by suppressing inflammation and reactive oxygen species. Bronchoalveolar lavage fluid samples from the injured side were collected for 16S rRNA gene-based sequencing analysis and 53 different bacteria at the genus and species levels were identified. Furthermore, the injured lung samples were collected for metabolomics analysis using liquid chromatography-mass spectrometry analyses to explore differential metabolites. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was applied to analyze the correlation between differential metabolites and lung microbiota. A total of 38 pathways were identified according to differential metabolites and 275 relevant pathways were enriched via analyzing the microbial community, 24 pathways were both identified by analyzing either metabolites or microbiota, including pyrimidine metabolism, purine metabolism, aminoacyl-tRNA biosynthesis and ATP-binding cassette transporter. Besides classical blockage of the renin-angiotensin II system, Olm could also alleviate SLV-induced lung injury by rewiring the interaction between pulmonary microbiota and metabolites.
Sirtuin 2 Alleviates Chronic Neuropathic Pain by Suppressing Ferroptosis in Rats
Authors: Zhang Xiaojiao , Song Tao , Zhao Mengnan , Tao Xueshu , Zhang Bohan , Sun Cong , Wang Pinying , Wang Kunpeng , Zhao Lin
Published: March 2022

Neuropathic pain (NP) is chronic and associated with poor effects of general analgesia. It affects patients’ health and quality of life. The apoptotic process of lipid peroxidation caused by iron overload is called ferroptosis, which may be associated with nervous system disease. A recent study has found that sirtuin 2 (SIRT2) achieves a neuroprotective effect by suppressing ferroptosis. Herein, we aimed to examine whether SIRT2 regulated spared nerve injury (SNI)-induced NP by suppressing ferroptosis in rats. A rat model of NP was induced in adult male Sprague-Dawley rats weighing 200–250 g. Mechanical allodynia was observed from the first day after SNI and continued for 14 days. Compared with age-matched control rats, the expression of SIRT2 and ferroportin 1 (FPN1) decreased in the L4-6 spinal cord of the SNI-induced NP rats. In addition, we observed that the levels of both iron and anti-acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) were significantly increased in the spinal cord after SNI, while the expression of glutathione peroxidase 4 (GPX4) was decreased. Furthermore, an intrathecal injection of SIRT2 overexpressed recombinant adenovirus, which upregulated the expression of SIRT2, attenuated mechanical allodynia, enhanced the level of FPN1, inhibited intracellular iron accumulation, and reduced oxidant stress levels, thereby reversing the changes to ACSL4 and GPX4 expression in the SNI rats. This evidence suggests that SIRT2-targeted therapeutics may help relieve the symptoms of chronic NP.
Current Approaches to Vaccine Safety Using Observational Data: A Rationale for the EUMAEUS (Evaluating Use of Methods for Adverse Events Under Surveillance-for Vaccines) Study Design
Authors: Lai Lana YH , Arshad Faaizah , Areia Carlos , Alshammari Thamir M. , Alghoul Heba , Casajust Paula , Li Xintong , Dawoud Dalia , Nyberg Fredrik , Pratt Nicole , Hripcsak George , Suchard Marc A. , Prieto-Alhambra Dani , Ryan Patrick , Schuemie Martijn J.
Published: March 2022

Post-marketing vaccine safety surveillance aims to detect adverse events following immunization in a population. Whether certain methods of surveillance are more precise and unbiased in generating safety signals is unclear. Here, we synthesized information from existing literature to provide an overview of the strengths, weaknesses, and clinical applications of epidemiologic and analytical methods used in vaccine monitoring, focusing on cohort, case-control and self-controlled designs. These designs are proposed to be evaluated in the EUMAEUS (Evaluating Use of Methods for Adverse Event Under Surveillance–for vaccines) study because of their widespread use and potential utility. Over the past decades, there have been an increasing number of epidemiological study designs used for vaccine safety surveillance. While traditional cohort and case-control study designs remain widely used, newer, novel designs such as the self-controlled case series and self-controlled risk intervals have been developed. Each study design comes with its strengths and limitations, and the most appropriate study design will depend on availability of resources, access to records, number and distribution of cases, and availability of population coverage data. Several assumptions have to be made while using the various study designs, and while the goal is to mitigate any biases, violations of these assumptions are often still present to varying degrees. In our review, we discussed some of the potential biases (i.e., selection bias, misclassification bias and confounding bias), and ways to mitigate them. While the types of epidemiological study designs are well established, a comprehensive comparison of the analytical aspects (including method evaluation and performance metrics) of these study designs are relatively less well studied. We summarized the literature, reporting on two simulation studies, which compared the detection time, empirical power, error rate and risk estimate bias across the above-mentioned study designs. While these simulation studies provided insights on the analytic performance of each of the study designs, its applicability to real-world data remains unclear. To bridge that gap, we provided the rationale of the EUMAEUS study, with a brief description of the study design; and how the use of real-world multi-database networks can provide insights into better methods evaluation and vaccine safety surveillance.
A Network-Based Approach to Investigate the Neuroprotective Effects and Mechanisms of Action of Huangqi-Chuanxiong and Sanleng-Ezhu Herb Pairs in the Treatment of Cerebral Ischemic Stroke
Authors: Zhao Lin , Ding Li Dong , Xia Zi Hao , Sheng Peng , Shen Meng Meng , Cai Zhong Ming , Yan Bing Chun
Published: March 2022

Objective: We aimed to investigate the effect and mechanisms of action of two drug pairs [Huangqi-Chuanxiong and Sanleng-Ezhu Herb (HCSE)] on the treatment of ischemic stroke.

Materials and methods: We mined the current literature related to ischemic stroke and formulated a new formulation of Chinese herbs. Then, we identified the main candidate target genes of the new formulation by network pharmacology. Next, we performed enrichment analysis of the target genes to identify the potential mechanism of action of the new formulation in the treatment of ischemic stroke. Next, we experimentally validated the mechanism of action of the new formulation against ischemic stroke. Infarct volume and neurological deficits were evaluated by 2,3,5-triphenyltetrazolium (TTC) staining and Longa’s score, respectively. The predicted pathways of signal-related proteins were detected by western blotting.

Results: We mined the current literature and identified a new formulation of Chinese herbs for the treatment of ischemic stroke. The formulation included Huangqi, Chuanxiong, Sanleng and Ezhu. Next, we used network pharmacological analysis to identify 23 active compounds and 327 target genes for the new formulation. The key target genes were MAPK3, MAPK1, HSP90AA1, STAT3, PIK3R1, PIK3CA and AKT1. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant enrichment of the PI3K/AKT and MAPK/ERK signaling pathways. By performing experiments, we found that the new formulation reduced the infarct volume of middle cerebral artery occlusion (MCAO) induced mice and activated the PI3K/AKT and MAPK/ERK signaling pathways. These findings confirmed that the new formulation has a significant protective effect against ischemic stroke injury by activating the PI3K/AKT and MAPK/ERK signaling pathways.

Conclusion: We identified a new treatment formulation for ischemic stroke by data mining and network pharmacological target prediction. The beneficial effects of the new formulation act by regulating multiple target genes and pathways. The mechanism of action of the new formulation may be related to the AKT and ERK signaling pathways. Our findings provide a theoretical basis for the effects of the new formulation on ischemic stroke injury.
Exploring the Potential Toxicological Mechanisms of Vine Tea on the Liver Based on Network Toxicology and Transcriptomics
Authors: Xiao Fangyu , Qiu Jihua , Zhao Ying
Published: March 2022

Objective: This study focuses on whether vine tea contains potentially toxic components that trigger hepatotoxicity as a mechanism of action, which further provides some reference for the consumption and guides future product development of vine tea.

Methods: The chemical components of vine tea were collected from the reported literature and the toxicological information matched with the CTD database was collected, and the dataset of potential toxic components was established. The toxic components were submitted to the PharmMapper server to obtain potential targets. At the same time, the relevant targets were searched in the CTD database and GeneCards database with keywords such as “Hepatic Toxicity,” “Liver Damage,” and “Drug-induced liver injury.” After intersection, the potential hepatotoxic targets of vine tea were obtained. The protein interactions of potential hepatotoxic targets of vine tea were analyzed by the STRING database. Protein–protein interaction (PPI) networks were constructed by Cytoscape3.6.1 software. The GO molecular function and KEGG pathway of hepatotoxic targets were enriched by the R package to screen the key targets. The role of the components and key targets was analyzed by the LEDOCK program. The data from GEO database were mined for the functional correlation characterized by cell transcriptional expression caused by vine tea as a disturbance factor.

Results: This study has searched 34 potential toxic components and 57 potential hepatotoxic targets of vine tea, and the result showed that these targets were mainly involved in oxidative stress, cell metabolism, and apoptosis to affect the liver.

Conclusion: Vine tea has the interrelationship of multi-components, multi-targets, and multi-pathways. At the cellular level, the toxic components of vine tea, mainly flavonoids, may promote oxidative stress, promote oxidation to produce free radicals, guide apoptosis, and affect cell metabolism and other cytotoxic mechanisms. However, this hepatotoxicity is related to the dose, duration of vine tea, and individual differences. This study revealed the potential hepatotoxic components of vine tea and provides a reference for further research and development of related functional products.
A Novel Small Molecular Inhibitor of DNMT1 Enhances the Antitumor Effect of Radiofrequency Ablation in Lung Squamous Cell Carcinoma Cells
Authors: Liu Yuan-Yuan , Ding Cheng-Zhi , Chen Jia-Ling , Wang Zheng-Shuai , Yang Bin , Wu Xiao-Ming
Published: March 2022

Radiofrequency ablation (RFA) is a relatively new and effective therapeutic strategy for treating lung squamous cell carcinomas (LSCCs). However, RFA is rarely used in the clinic for LSCC which still suffers from a lack of effective comprehensive treatment strategies. In the present work, we investigate iDNMT, a novel small molecular inhibitor of DNMT1 with a unique structure. In clinical LSCC specimens, endogenous DNMT1 was positively associated with methylation rates of miR-27-3p′s promoter. Moreover, endogenous DNMT1 was negatively correlated with miR-27-3p expression which targets PSEN-1, the catalytic subunit of γ-secretase, which mediates the cleavage and activation of the Notch pathway. We found that DNMT1 increased activation of the Notch pathway in clinical LSCC samples while downregulating miR-27-3p expression and hypermethylation of miR-27-3p′s promoter. In addition of inhibiting activation of the Notch pathway by repressing methylation of the miR-27-3p promoter, treatment of LSCC cells with iDNMT1 also enhanced the sensitivity of LSCC tumor tissues to RFA treatment. These data suggest that iDNMT-induced inhibition of DNMT-1 enhances miR-27-3p expression in LSCC to inhibit activation of the Notch pathway. Furthermore, the combination of iDNMT and RFA may be a promising therapeutic strategy for LSCC.
GATA6+ Peritoneal Resident Macrophage: The Immune Custodian in the Peritoneal Cavity
Authors: Jayakumar Preethi , Laganson Andrea , Deng Meihong
Published: March 2022

Peritoneal resident macrophages (PRMs) have been a prominent topic in the research field of immunology due to their critical roles in immune surveillance in the peritoneal cavity. PRMs initially develop from embryonic progenitor cells and are replenished by bone marrow origin monocytes during inflammation and aging. Furthermore, PRMs have been shown to crosstalk with other cells in the peritoneal cavity to control the immune response during infection, injury, and tumorigenesis. With the advance in genetic studies, GATA-binding factor 6 (GATA6) has been identified as a lineage determining transcription factor of PRMs controlling the phenotypic and functional features of PRMs. Here, we review recent advances in the developmental origin, the phenotypic identity, and functions of PRMs, emphasizing the role of GATA6 in the pathobiology of PRMs in host defense, tissue repairing, and peritoneal tumorigenesis.