bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Genomic Analysis of the Lettuce Bacterial Leaf Spot Pathogen, Xanthomonas hortorum pv. vitians, to Investigate Race Specificity
Authors: Rosenthal Emma , Potnis Neha , Bull Carolee T.
Published: April 2022

Bacterial leaf spot (BLS) of lettuce caused by Xanthomonas hortorum pv. vitians (Xhv) was first described over 100 years ago and remains a significant threat to lettuce cultivation today. This study investigated the genetic relatedness of the Xhv strains and the possible genetic sources of this race-specific pathogenicity. Whole genome sequences of eighteen Xhv strains representing the three races, along with eight related Xanthomonas strains, were included in the analysis. A maximum likelihood phylogeny based on concatenated whole genome SNPs confirmed previous results describing two major lineages of Xhv strains. Gene clusters encoding secretion systems, secondary metabolites, and bacteriocins were assessed to identify putative virulence factors that distinguish the Xhv races. Genome sequences were mined for effector genes, which have been shown to be involved in race specificity in other systems. Two effectors identified in this study, xopAQ and the novel variant xopAF2, were revealed as possible mediators of a gene-for-gene interaction between Xhv race 1 and 3 strains and wild lettuce Lactuca serriola ARM-09-161-10-1. Transposase sequence identified downstream of xopAF2 and prophage sequence found nearby within Xhv race 1 and 3 insertion sequences suggest that this gene may have been acquired through phage-mediated gene transfer. No other factors were identified from these analyses that distinguish the Xhv races.
Interactome and Ubiquitinome Analyses Identify Functional Targets of Herpes Simplex Virus 1 Infected Cell Protein 0
Authors: Hou Fujun , Sun Zeyu , Deng Yue , Chen Siyu , Yang Xiyuan , Ji Feiyang , Zhou Menghao , Ren Keyi , Pan Dongli
Published: April 2022

Herpes simplex virus 1 (HSV-1) can productively infect multiple cell types and establish latent infection in neurons. Infected cell protein 0 (ICP0) is an HSV-1 E3 ubiquitin ligase crucial for productive infection and reactivation from latency. However, our knowledge about its targets especially in neuronal cells is limited. We confirmed that, like in non-neuronal cells, ICP0-null virus exhibited major replication defects in primary mouse neurons and Neuro-2a cells. We identified many ICP0-interacting proteins in Neuro-2a cells, 293T cells, and human foreskin fibroblasts by mass spectrometry–based interactome analysis. Co-immunoprecipitation assays validated ICP0 interactions with acyl-coenzyme A thioesterase 8 (ACOT8), complement C1q binding protein (C1QBP), ovarian tumour domain-containing protein 4 (OTUD4), sorting nexin 9 (SNX9), and vimentin (VIM) in both Neuro-2a and 293T cells. Overexpression and knockdown experiments showed that SNX9 restricted replication of an ICP0-null but not wild-type virus in Neuro-2a cells. Ubiquitinome analysis by immunoprecipitating the trypsin-digested ubiquitin reminant followed by mass spectrometry identified numerous candidate ubiquitination substrates of ICP0 in infected Neuro-2a cells, among which OTUD4 and VIM were novel substrates confirmed to be ubiquitinated by transfected ICP0 in Neuro-2a cells despite no evidence of their degradation by ICP0. Expression of OTUD4 was induced independently of ICP0 during HSV-1 infection. Overexpressed OTUD4 enhanced type I interferon expression during infection with the ICP0-null but not wild-type virus. In summary, by combining two proteomic approaches followed by confirmatory and functional experiments, we identified and validated multiple novel targets of ICP0 and revealed potential restrictive activities of SNX9 and OTUD4 in neuronal cells.
A Cecropin-4 Derived Peptide C18 Inhibits Candida albicans by Disturbing Mitochondrial Function
Authors: Sun Chao-Qin , Peng Jian , Yang Long-Bing , Jiao Zheng-Long , Zhou Luo-Xiong , Tao Ru-Yu , Zhu Li-Juan , Tian Zhu-Qing , Huang Ming-Jiao , Guo Guo
Published: April 2022

Global burden of fungal infections and related health risk has accelerated at an incredible pace, and multidrug resistance emergency aggravates the need for the development of new effective strategies. Candida albicans is clinically the most ubiquitous pathogenic fungus that leads to high incidence and mortality in immunocompromised patients. Antimicrobial peptides (AMPs), in this context, represent promising alternatives having potential to be exploited for improving human health. In our previous studies, a Cecropin-4-derived peptide named C18 was found to possess a broader antibacterial spectrum after modification and exhibit significant antifungal activity against C. albicans. In this study, C18 shows antifungal activity against C. albicans or non-albicans Candida species with a minimum inhibitory concentration (MIC) at 4∼32 μg/ml, and clinical isolates of fluconazole (FLZ)-resistance C. tropicalis were highly susceptible to C18 with MIC value of 8 or 16 μg/ml. Additionally, C18 is superior to FLZ for killing planktonic C. albicans from inhibitory and killing kinetic curves. Moreover, C18 could attenuate the virulence of C. albicans, which includes damaging the cell structure, retarding hyphae transition, and inhibiting biofilm formation. Intriguingly, in the Galleria mellonella model with C. albicans infection, C18 could improve the survival rate of G. mellonella larvae to 70% and reduce C. albicans load from 5.01 × 107 to 5.62 × 104 CFU. For mechanistic action of C18, the level of reactive oxygen species (ROS) generation and cytosolic Ca2 + increased in the presence of C18, which is closely associated with mitochondrial dysfunction. Meanwhile, mitochondrial membrane potential (△Ψm) loss and ATP depletion of C. albicans occurred with the treatment of C18. We hypothesized that C18 might inhibit C. albicans via triggering mitochondrial dysfunction driven by ROS generation and Ca2 + accumulation. Our observation provides a basis for future research to explore the antifungal strategies and presents C18 as an attractive therapeutic candidate to be developed to treat candidiasis.
Combining Coarse-Grained Simulations and Single Molecule Analysis Reveals a Three-State Folding Model of the Guanidine-II Riboswitch
Authors: Fuks Christin , Falkner Sebastian , Schwierz Nadine , Hengesbach Martin
Published: April 2022

Riboswitch RNAs regulate gene expression by conformational changes induced by environmental conditions and specific ligand binding. The guanidine-II riboswitch is proposed to bind the small molecule guanidinium and to subsequently form a kissing loop interaction between the P1 and P2 hairpins. While an interaction was shown for isolated hairpins in crystallization and electron paramagnetic resonance experiments, an intrastrand kissing loop formation has not been demonstrated. Here, we report the first evidence of this interaction in cis in a ligand and Mg2+ dependent manner. Using single-molecule FRET spectroscopy and detailed structural information from coarse-grained simulations, we observe and characterize three interconvertible states representing an open and kissing loop conformation as well as a novel Mg2+ dependent state for the guanidine-II riboswitch from E. coli. The results further substantiate the proposed switching mechanism and provide detailed insight into the regulation mechanism for the guanidine-II riboswitch class. Combining single molecule experiments and coarse-grained simulations therefore provides a promising perspective in resolving the conformational changes induced by environmental conditions and to yield molecular insights into RNA regulation.
Metabolic Pathway of Cardiospecific Troponins: From Fundamental Aspects to Diagnostic Role (Comprehensive Review)
Authors: Chaulin Aleksey M.
Published: April 2022

Many molecules of the human body perform key regulatory functions and are widely used as targets for the development of therapeutic drugs or as specific diagnostic markers. These molecules undergo a significant metabolic pathway, during which they are influenced by a number of factors (biological characteristics, hormones, enzymes, etc.) that can affect molecular metabolism and, as a consequence, the serum concentration or activity of these molecules. Among the most important molecules in the field of cardiology are the molecules of cardiospecific troponins (Tns), which regulate the processes of myocardial contraction/relaxation and are used as markers for the early diagnosis of ischemic necrosis of cardiomyocytes (CMC) in myocardial infarction (MI). The diagnostic value and diagnostic capabilities of cardiospecific Tns have changed significantly after the advent of new (highly sensitive (HS)) detection methods. Thus, early diagnostic algorithms of MI were approved for clinical practice, thanks to which the possibility of rapid diagnosis and determination of optimal tactics for managing patients with MI was opened. Relatively recently, promising directions have also been opened for the use of cardiospecific Tns as prognostic markers both at the early stages of the development of cardiovascular diseases (CVD) (arterial hypertension (AH), heart failure (HF), coronary heart disease (CHD), etc.), and in non-ischemic extra-cardiac pathologies that can negatively affect CMC (for example, sepsis, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), etc.). Recent studies have also shown that cardiospecific Tns are present not only in blood serum, but also in other biological fluids (urine, oral fluid, pericardial fluid, amniotic fluid). Thus, cardiospecific Tns have additional diagnostic capabilities. However, the fundamental aspects of the metabolic pathway of cardiospecific Tns are definitively unknown, in particular, specific mechanisms of release of Tns from CMC in non-ischemic extra-cardiac pathologies, mechanisms of circulation and elimination of Tns from the human body, mechanisms of transport of Tns to other biological fluids and factors that may affect these processes have not been established. In this comprehensive manuscript, all stages of the metabolic pathway are consistently and in detail considered, starting from release from CMC and ending with excretion (removal) from the human body. In addition, the possible diagnostic role of individual stages and mechanisms, influencing factors is analyzed and directions for further research in this area are noted.
Identification of Tumor Microenvironment and DNA Methylation-Related Prognostic Signature for Predicting Clinical Outcomes and Therapeutic Responses in Cervical Cancer
Authors: Liu Bangquan , Zhai Jiabao , Wang Wanyu , Liu Tianyu , Liu Chang , Zhu Xiaojie , Wang Qi , Tian Wenjing , Zhang Fubin
Published: April 2022

Background: Tumor microenvironment (TME) has been reported to have a strong association with tumor progression and therapeutic outcome, and epigenetic modifications such as DNA methylation can affect TMB and play an indispensable role in tumorigenesis. However, the potential mechanisms of TME and DNA methylation remain unclear in cervical cancer (CC).

Methods: The immune and stromal scores of TME were generated by the ESTIMATE algorithm for CC patients in The Cancer Genome Atlas (TCGA) database. The TME and DNA methylation-related genes were identified by the integrative analysis of DNA promoter methylation and gene expression. The least absolute shrinkage and selection operator (LASSO) Cox regression was performed 1,000 times to further identify a nine-gene TME and DNA methylation-related prognostic signature. The signature was further validated in Gene Expression Omnibus (GEO) dataset. Then, the identified signature was integrated with the Federation International of Gynecology and Obstetrics (FIGO) stage to establish a composite prognostic nomogram.

Results: CC patients with high immunity levels have better survival than those with low immunity levels. Both in the training and validation datasets, the risk score of the signature was an independent prognosis factor. The composite nomogram showed higher accuracy of prognosis and greater net benefits than the FIGO stage and the signature. The high-risk group had a significantly higher fraction of genome altered than the low-risk group. Eleven genes were significantly different in mutation frequencies between the high- and low-risk groups. Interestingly, patients with mutant TTN had better overall survival (OS) than those with wild type. Patients in the low-risk group had significantly higher tumor mutational burden (TMB) than those in the high-risk group. Taken together, the results of TMB, immunophenoscore (IPS), and tumor immune dysfunction and exclusion (TIDE) score suggested that patients in the low-risk group may have greater immunotherapy benefits. Finally, four drugs (panobinostat, lenvatinib, everolimus, and temsirolimus) were found to have potential therapeutic implications for patients with a high-risk score.

Conclusions: Our findings highlight that the TME and DNA methylation-related prognostic signature can accurately predict the prognosis of CC and may be important for stratified management of patients and precision targeted therapy.
The Neuromodulatory Basis of Aggression: Lessons From the Humble Fruit Fly
Authors: Palavicino-Maggio Caroline B. , Sengupta Saheli
Published: April 2022

Aggression is an intrinsic trait that organisms of almost all species, humans included, use to get access to food, shelter, and mating partners. To maximize fitness in the wild, an organism must vary the intensity of aggression toward the same or different stimuli. How much of this variation is genetic and how much is externally induced, is largely unknown but is likely to be a combination of both. Irrespective of the source, one of the principal physiological mechanisms altering the aggression intensity involves neuromodulation. Any change or variation in aggression intensity is most likely governed by a complex interaction of several neuromodulators acting via a meshwork of neural circuits. Resolving aggression-specific neural circuits in a mammalian model has proven challenging due to the highly complex nature of the mammalian brain. In that regard, the fruit fly model Drosophila melanogaster has provided insights into the circuit-driven mechanisms of aggression regulation and its underlying neuromodulatory basis. Despite morphological dissimilarities, the fly brain shares striking similarities with the mammalian brain in genes, neuromodulatory systems, and circuit-organization, making the findings from the fly model extremely valuable for understanding the fundamental circuit logic of human aggression. This review discusses our current understanding of how neuromodulators regulate aggression based on findings from the fruit fly model. We specifically focus on the roles of Serotonin (5-HT), Dopamine (DA), Octopamine (OA), Acetylcholine (ACTH), Sex Peptides (SP), Tachykinin (TK), Neuropeptide F (NPF), and Drosulfakinin (Dsk) in fruit fly male and female aggression.
The Role of Exosomes and Exosomal Noncoding RNAs From Different Cell Sources in Spinal Cord Injury
Authors: Yang Zhe-Lun , Rao Jian , Lin Fa-Bin , Liang Ze-Yan , Xu Xiong-Jie , Lin Yi-Ke , Chen Xin-Yao , Wang Chun-Hua , Chen Chun-Mei
Published: April 2022

Spinal cord injury (SCI) not only affects the quality of life of patients but also poses a heavy burden on their families. Therefore, it is essential to prevent the occurrence of SCI; for unpreventable SCI, it is critical to develop effective treatments. In recent years, various major breakthroughs have been made in cell therapy to protect and regenerate the damaged spinal cord via various mechanisms such as immune regulation, paracrine signaling, extracellular matrix (ECM) modification, and lost cell replacement. Nevertheless, many recent studies have shown that the cell therapy has many disadvantages, such as tumorigenicity, low survival rate, and immune rejection. Because of these disadvantages, the clinical application of cell therapy is limited. In recent years, the role of exosomes in various diseases and their therapeutic potential have attracted much attention. The same is true for exosomal noncoding RNAs (ncRNAs), which do not encode proteins but affect transcriptional and translational processes by targeting specific mRNAs. This review focuses on the mechanism of action of exosomes obtained from different cell sources in the treatment of SCI and the regulatory role and therapeutic potential of exosomal ncRNAs. This review also discusses the future opportunities and challenges, proposing that exosomes and exosomal ncRNAs might be promising tools for the treatment of SCI.
Pathogenic Mechanisms Underlying Cirrhotic Cardiomyopathy
Authors: Liu Hongqun , Nguyen Henry H. , Yoon Ki Tae , Lee Samuel S.
Published: April 2022

Cardiac dysfunction associated with cirrhosis in the absence of preexisting heart disease is a condition known as cirrhotic cardiomyopathy (CCM). Cardiac abnormalities consist of enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM may contribute to cardiovascular morbidity and mortality after liver transplantation and other major surgeries, and also to the pathogenesis of hepatorenal syndrome. The underlying mechanisms of CCM are poorly understood and as such medical therapy is an area of unmet medical need. The present review focuses on the pathogenic mechanisms responsible for development of CCM. The two major concurrent mechanistic pathways are the inflammatory phenotype due to portal hypertension, and protein/lipid synthetic/metabolic defects due to cirrhosis and liver insufficiency. The inflammatory phenotype arises from intestinal congestion due to portal hypertension, resulting in bacteria/endotoxin translocation into the systemic circulation. The cytokine storm associated with inflammation, particularly TNFα acting via NFκB depresses cardiac function. They also stimulate two evanescent gases, nitric oxide and carbon monoxide which produce cardiodepression by cGMP. Inflammation also stimulates the endocannabinoid CB-1 pathway. These systems inhibit the stimulatory beta-adrenergic contractile pathway. The liver insufficiency of cirrhosis is associated with defective synthesis or metabolism of several substances including proteins and lipids/lipoproteins. The protein defects including titin and collagen contribute to diastolic dysfunction. Other protein abnormalities such as a switch of myosin heavy chain isoforms result in systolic dysfunction. Lipid biochemical changes at the cardiac sarcolemmal plasma membrane result in increased cholesterol:phospholipid ratio and decreased membrane fluidity. Final common pathway changes involve abnormal cardiomyocyte intracellular ion kinetics, particularly calcium. In conclusion, cirrhotic cardiomyopathy is caused by two pathways of cellular and molecular dysfunction/damage due to hepatic insufficiency and portal hypertension.
Long-Lasting Desynchronization of Plastic Neuronal Networks by Double-Random Coordinated Reset Stimulation
Authors: Khaledi-Nasab Ali , Kromer Justus A. , Tass Peter A.
Published: April 2022

Hypersynchrony of neuronal activity is associated with several neurological disorders, including essential tremor and Parkinson’s disease (PD). Chronic high-frequency deep brain stimulation (HF DBS) is the standard of care for medically refractory PD. Symptoms may effectively be suppressed by HF DBS, but return shortly after cessation of stimulation. Coordinated reset (CR) stimulation is a theory-based stimulation technique that was designed to specifically counteract neuronal synchrony by desynchronization. During CR, phase-shifted stimuli are delivered to multiple neuronal subpopulations. Computational studies on CR stimulation of plastic neuronal networks revealed long-lasting desynchronization effects obtained by down-regulating abnormal synaptic connectivity. This way, networks are moved into attractors of stable desynchronized states such that stimulation-induced desynchronization persists after cessation of stimulation. Preclinical and clinical studies confirmed corresponding long-lasting therapeutic and desynchronizing effects in PD. As PD symptoms are associated with different pathological synchronous rhythms, stimulation-induced long-lasting desynchronization effects should favorably be robust to variations of the stimulation frequency. Recent computational studies suggested that this robustness can be improved by randomizing the timings of stimulus deliveries. We study the long-lasting effects of CR stimulation with randomized stimulus amplitudes and/or randomized stimulus timing in networks of leaky integrate-and-fire (LIF) neurons with spike-timing-dependent plasticity. Performing computer simulations and analytical calculations, we study long-lasting desynchronization effects of CR with and without randomization of stimulus amplitudes alone, randomization of stimulus times alone as well as the combination of both. Varying the CR stimulation frequency (with respect to the frequency of abnormal target rhythm) and the number of separately stimulated neuronal subpopulations, we reveal parameter regions and related mechanisms where the two qualitatively different randomization mechanisms improve the robustness of long-lasting desynchronization effects of CR. In particular, for clinically relevant parameter ranges double-random CR stimulation, i.e., CR stimulation with the specific combination of stimulus amplitude randomization and stimulus time randomization, may outperform regular CR stimulation with respect to long-lasting desynchronization. In addition, our results provide the first evidence that an effective reduction of the overall stimulation current by stimulus amplitude randomization may improve the frequency robustness of long-lasting therapeutic effects of brain stimulation.
Brain Gray Matter Alterations in Hepatic Encephalopathy: A Voxel-Based Meta-Analysis of Whole-Brain Studies
Authors: Zhu Licheng , Zhang Weihua , Chen Lei , Ren Yanqiao , Cao Yanyan , Sun Tao , Sun Bo , Liu Jia , Wang Jing , Zheng Chuansheng
Published: April 2022

Background

Previous studies on voxel-based morphometry (VBM) have found that there were gray matter alterations in patients with hepatic encephalopathy (HE). However, the reported results were inconsistent and lack a quantitative review. Therefore, this study aims for a quantitative meta-analysis of VBM analysis on patients with HE.

Methods

The studies in our meta-analysis were collected from Pubmed, Web of Science, and Embase, which were published from January 1947 to October 2021. The seed-based d mapping (SDM) method was applied to quantitatively estimate the regional gray matter abnormalities in patients with HE. A meta-regression analysis was applied to evaluate the relationship between plasma ammonia and gray matter alteration.

Results

There were nine studies, with sixteen datasets consisting of 333 participants with HE and 429 healthy controls. The pooled and subgroup meta-analyses showed an increase in gray matter volume (GMV) in the bilateral thalamus and the calcarine fissure but a decrease in the GMV in the bilateral insula, the basal ganglia, the anterior cingulate gyrus, and the cerebellum. The meta-regression showed that plasma ammonia was positively associated with the GMV in the left thalamus but was negatively associated with the GMV in the cerebellum and the bilateral striatum.

Conclusion

Gray matter volume in patients with HE largely varied and could be affected by plasma ammonia. The findings of this study could help us to better understand the pathophysiology of cognitive dysfunction in patients with HE.
Multiframe Evolving Dynamic Functional Connectivity (EVOdFNC): A Method for Constructing and Investigating Functional Brain Motifs
Authors: Miller Robyn L. , Vergara Victor M. , Pearlson Godfrey D. , Calhoun Vince D.
Published: April 2022

The study of brain network connectivity as a time-varying property began relatively recently and, to date, has remained primarily concerned with capturing a handful of discrete static states that characterize connectivity as measured on a timescale shorter than that of the full scan. Capturing group-level representations of temporally evolving patterns of connectivity is a challenging and important next step in fully leveraging the information available in large resting state functional magnetic resonance imaging (rs-fMRI) studies. We introduce a flexible, extensible data-driven framework for the stable identification of group-level multiframe (movie-style) dynamic functional network connectivity (dFNC) states. Our approach employs uniform manifold approximation and embedding (UMAP) to produce a continuity-preserving planar embedding of high-dimensional time-varying measurements of whole-brain functional network connectivity. Planar linear exemplars summarizing dominant dynamic trends across the population are computed from local linear approximations to the two-dimensional 2D embedded trajectories. A high-dimensional representation of each 2D exemplar segment is obtained by averaging the dFNC observations corresponding to the n planar nearest neighbors of τ evenly spaced points along the 2D line segment representation (where n is the UMAP number-of-neighbors parameter and τ is the temporal duration of trajectory segments being approximated). Each of the 2D exemplars thus “lifts” to a multiframe high-dimensional dFNC trajectory of length τ. The collection of high-dimensional temporally evolving dFNC representations (EVOdFNCs) derived in this manner are employed as dynamic basis objects with which to characterize observed high-dimensional dFNC trajectories, which are then expressed as weighted combination of these basis objects. Our approach yields new insights into anomalous patterns of fluidly varying whole-brain connectivity that are significantly associated with schizophrenia as a broad diagnosis as well as with certain symptoms of this serious disorder. Importantly, we show that relative to conventional hidden Markov modeling with single-frame unvarying dFNC summary states, EVOdFNCs are more sensitive to positive symptoms of schizophrenia including hallucinations and delusions, suggesting that a more dynamic characterization is needed to help illuminate such a complex brain disorder.
A Multi-Scale Computational Model of Levodopa-Induced Toxicity in Parkinson's Disease
Authors: Muddapu Vignayanandam Ravindernath-Jayashree , Vijayakumar Karthik , Ramakrishnan Keerthiga , Chakravarthy V. Srinivasa
Published: April 2022

Parkinson's disease (PD) is caused by the progressive loss of dopaminergic cells in substantia nigra pars compacta (SNc). The root cause of this cell loss in PD is still not decisively elucidated. A recent line of thinking has traced the cause of PD neurodegeneration to metabolic deficiency. Levodopa (L-DOPA), a precursor of dopamine, used as a symptom-relieving treatment for PD, leads to positive and negative outcomes. Several researchers inferred that L-DOPA might be harmful to SNc cells due to oxidative stress. The role of L-DOPA in the course of the PD pathogenesis is still debatable. We hypothesize that energy deficiency can lead to L-DOPA-induced toxicity in two ways: by promoting dopamine-induced oxidative stress and by exacerbating excitotoxicity in SNc. We present a systems-level computational model of SNc-striatum, which will help us understand the mechanism behind neurodegeneration postulated above and provide insights into developing disease-modifying therapeutics. It was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During L-DOPA therapy, it was observed that higher L-DOPA dosage results in increased loss of terminals in SNc. It was also observed that co-administration of L-DOPA and glutathione (antioxidant) evades L-DOPA-induced toxicity in SNc neurons. Our proposed model of the SNc-striatum system is the first of its kind, where SNc neurons were modeled at a biophysical level, and striatal neurons were modeled at a spiking level. We show that our proposed model was able to capture L-DOPA-induced toxicity in SNc, caused by energy deficiency.
Sleep During Oncological Treatment – A Systematic Review and Meta-Analysis of Associations With Treatment Response, Time to Progression and Survival
Authors: Strøm Louise , Danielsen Josefine T. , Amidi Ali , Cardenas Egusquiza Ana Lucia , Wu Lisa Maria , Zachariae Robert
Published: April 2022

Introduction

Disrupted sleep and sleep-wake activity are frequently observed in cancer patients undergoing oncological treatment. These disruptions are often associated with aggravated symptom burden and diminished health-related quality of life that in turn may compromise treatment adherence and, thus, effectiveness. In addition, disrupted sleep has been linked to carcinogenic processes, which ultimately could result in worse prognostic outcomes.

Aims

Our aim was to systematically review and conduct a meta-analysis of studies examining the associations between sleep and sleep-wake activity and prognostic outcomes in cancer patients undergoing oncological treatment.

Methods

A comprehensive systematic search of English language papers was undertaken in June 2020 using PubMed, The Cochrane Library, and CINAHL. Two reviewers independently screened 4,879 abstracts. A total of 26 papers were included in the narrative review. Thirteen papers reporting hazard ratios reflecting associations between a dichotomized predictor variable (sleep) and prognostic outcomes were subjected to meta-analysis.

Results

Nineteen of the 26 eligible studies on a total of 7,092 cancer patients reported associations between poorer sleep and poorer response to treatment, shorter time to progression, and/or reduced overall survival, but were highly heterogeneous with respect to the sleep and outcome parameters investigated. Meta-analysis revealed statistically significant associations between poor self-reported sleep and reduced overall survival (HR = 1.33 [95% CI 1.09–1.62], k = 11), and shorter time to progression (HR = 1.40 [95% CI 1.23–1.59], k = 3) and between poor objectively assessed sleep and reduced overall survival (HR = 1.74 [95% CI 1.05–2.88], k = 4).

Conclusion

The current findings indicate that disturbed sleep during treatment may be a relevant behavioral marker of poor cancer prognosis. The limited number of studies, the common use of single item sleep measures, and potential publication bias highlight the need for further high quality and longitudinal studies.
Inhalation of Atmospheric-Pressure Gas Plasma Attenuates Brain Infarction in Rats With Experimental Ischemic Stroke
Authors: Chen Ye , Yang Bingyan , Xu Lixin , Shi Zhongfang , Han Ruoyu , Yuan Fang , Ouyang Jiting , Yan Xu , Ostrikov Kostya Ken
Published: April 2022

Previous studies suggest the potential efficacy of neuroprotective effects of gaseous atmospheric-pressure plasma (APP) treatment on neuronal cells. However, it remains unclear if the neuroprotective properties of the gas plasmas benefit the ischemic stroke treatment, and how to use the plasmas in the in vivo ischemic stroke models. Rats were subjected to 90 min middle cerebral artery occlusion (MCAO) to establish the ischemic stroke model and then intermittently inhaled the plasma for 2 min at 60 min MCAO. The regional cerebral blood flow (CBF) was monitored. Animal behavior scoring, magnetic resonance imaging (MRI), 2,3,5-triphenyltetrazolium chloride (TTC) staining, and hematoxylin and eosin (HE) staining were performed to evaluate the therapeutic efficacy of the gas plasma inhalation on MCAO rats. Intermittent gas plasma inhalation by rats with experimental ischemic stroke could improve neurological function, increase regional CBF, and decrease brain infarction. Further MRI tests showed that the gas plasma inhalation could limit the ischemic lesion progression, which was beneficial to improve the outcomes of the MCAO rats. Post-stroke treatment with intermittent gas plasma inhalation could reduce the ischemic lesion progression and decrease cerebral infarction volume, which might provide a new promising strategy for ischemic stroke treatment.
Animal Models of Neurodegenerative Disease: Recent Advances in Fly Highlight Innovative Approaches to Drug Discovery
Authors: Tello Judith A. , Williams Haley E. , Eppler Robert M. , Steinhilb Michelle L. , Khanna May
Published: April 2022

Neurodegenerative diseases represent a formidable challenge to global health. As advances in other areas of medicine grant healthy living into later decades of life, aging diseases such as Alzheimer's disease (AD) and other neurodegenerative disorders can diminish the quality of these additional years, owed largely to the lack of efficacious treatments and the absence of durable cures. Alzheimer's disease prevalence is predicted to more than double in the next 30 years, affecting nearly 15 million Americans, with AD-associated costs exceeding $1 billion by 2050. Delaying onset of AD and other neurodegenerative diseases is critical to improving the quality of life for patients and reducing the burden of disease on caregivers and healthcare systems. Significant progress has been made to model disease pathogenesis and identify points of therapeutic intervention. While some researchers have contributed to our understanding of the proteins and pathways that drive biological dysfunction in disease using in vitro and in vivo models, others have provided mathematical, biophysical, and computational technologies to identify potential therapeutic compounds using in silico modeling. The most exciting phase of the drug discovery process is now: by applying a target-directed approach that leverages the strengths of multiple techniques and validates lead hits using Drosophila as an animal model of disease, we are on the fast-track to identifying novel therapeutics to restore health to those impacted by neurodegenerative disease.
Cognitive Performances: The Role of Digit Ratio (D2:D4) With a Protective Factor for Anxiety
Authors: Rinella Sergio , Massimino Simona , Sorbello Alessia , Perciavalle Vincenzo , Coco Marinella
Published: April 2022

This study aimed to identify a possible correlation between the D2:D4 ratio and state and/or trait anxiety in adult healthy subjects and, if so, whether it exists any difference between men and women. In addition, we also wanted to observe whether there is a relationship between participants' age and state and/or trait anxiety. The research involved 125 subjects of both sexes, who were calculated the D2:D4 ratio and were administered the self-assessment questionnaire State-Trait Anxiety Inventory (STAI-Y). Results show that there are positive significant correlations between the D2:D4 ratio and score at state anxiety and trait anxiety, in the total sample. However, if men are examined separately from women, it can be observed that only men have a statistically significant relationship between D2:D4 ratios and state anxiety and trait anxiety. Moreover, about possible relations between the age of participants and state and trait anxiety, a significant negative relationship was observed, without differences between men and women. However, only subjects with a D2:D4 ratio ≥ 1, without differences between men and women, showed a statistically significant negative linear correlation between their age and their state and trait anxiety. The present data allow us to conclude that a low D2:D4 ratio (<1) represents a protective factor against anxiety in both men and women and that this protection seems likely to act throughout life.
Stressor-Specific Microbiota Intervention
Authors: Chuang Jie-Yu
Published: April 2022

To date, mental disorders are diagnosed and treated by the subjective judgment of psychiatrists based on diagnostic criteria and treatment guidelines, respectively. Mental disorders are heterogeneous illnesses with a substantial treatment-refractory rate. Thus, there is a great need for novel treatment approaches. This article proposes a treatment approach centered on the concept of the gut–brain axis. There is mounting evidence indicating an association between stressors, microbiota, microglia, and mental disorders. Stressors might facilitate dysbiosis, inflammation, and the occurrence of mental disorders. This novel treatment approach is based on the idea that stressor types instead of the heterogeneous psychiatric diagnosis might be closer to the neurobiological underpinnings of mental disorders. First of all, patients with treatment-resistant mental disorders will be asked to describe their major stressors. Then, clinicians will calculate the total threat score and the total deprivation score. Subsequently, treatment tailored to the major stressor type will be administered to restore a healthy gut microbiome. Presumably, treatment will be aimed at increasing microbiota diversity in those who mainly have deprivation stressors and boostingActinobacteriain those who have mainly threat stressors. Large-scale clinical trials are warranted to test this hypothetical approach.
The Basis and Advances in Clinical Application of Cytomegalovirus-Specific Cytotoxic T Cell Immunotherapy for Glioblastoma Multiforme
Authors: Daei Sorkhabi Amin , Sarkesh Aila , Saeedi Hossein , Marofi Faroogh , Ghaebi Mahnaz , Silvestris Nicola , Baradaran Behzad , Brunetti Oronzo
Published: April 2022

A high percentage of malignant gliomas are infected by human cytomegalovirus (HCMV), and the endogenous expression of HCMV genes and their products are found in these tumors. HCMV antigen expression and its implications in gliomagenesis have emerged as a promising target for adoptive cellular immunotherapy (ACT) strategies in glioblastoma multiforme (GB) patients. Since antigen-specific T cells in the tumor microenvironments lack efficient anti-tumor immune response due to the immunosuppressive nature of glioblastoma, CMV-specific ACT relies on in vitro expansion of CMV-specific CD8+ T cells employing immunodominant HCMV antigens. Given the fact that several hurdles remain to be conquered, recent clinical trials have outlined the feasibility of CMV-specific ACT prior to tumor recurrence with minimal adverse effects and a substantial improvement in median overall survival and progression-free survival. This review discusses the role of HCMV in gliomagenesis, disease prognosis, and recent breakthroughs in harnessing HCMV-induced immunogenicity in the GB tumor microenvironment to develop effective CMV-specific ACT.
Treatment Advances in EBV Related Lymphoproliferative Diseases
Authors: Lv Kebing , Yin Ting , Yu Min , Chen Zhiwei , Zhou Yulan , Li Fei
Published: April 2022

Epstein Barr virus (EBV) can affect 90% of the human population. It can invade B lymphocytes, T lymphocytes and natural killer cells of the host and remain in the host for life. The long latency and reactivation of EBV can cause malignant transformation, leading to various lymphoproliferative diseases (LPDs), including EBV-related B-cell lymphoproliferative diseases (EBV-B-LPDs) (for example, Burkitt lymphoma (BL), classic Hodgkin’s lymphoma (cHL), and posttransplantation and HIV-related lymphoproliferative diseases) and EBV-related T-cell lymphoproliferative diseases (EBV-T/NK-LPDs) (for example, extranodal nasal type natural killer/T-cell lymphoma (ENKTCL), aggressive NK cell leukaemia (ANKL), and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). EBV-LPDs are heterogeneous with different clinical features and prognoses. The treatment of EBV-LPDs is usually similar to that of EBV-negative lymphoma with the same histology and can include chemotherapy, radiotherapy, and hematopoietic stem cell transplant (HSCT). However, problems such as serious toxicity and drug resistance worsen the survival prognosis of patients. EBV expresses a variety of viral and lytic proteins that regulate cell cycle and death processes and promote the survival of tumour cells. Based on these characteristics, a series of treatment strategies for EBV in related malignant tumours have been developed, such as monoclonal antibodies, immune checkpoint inhibitors, cytotoxic T lymphocytes (CTLs) and epigenetic therapy. These new individualized therapies can produce highly specific killing effects on tumour cells, and nontumour cells can be protected from toxicity. This paper will focus on the latest progress in the treatment of EBV-LPDs based on pathological mechanisms.
Bone Marrow-Derived Stem Cell Factor Regulates Prostate Cancer-Induced Shifts in Pre-Metastatic Niche Composition
Authors: Foster Brittni M. , Shi Lihong , Harris Koran S. , Patel Chirayu , Surratt Victoria E. , Langsten Kendall L. , Kerr Bethany A.
Published: April 2022

Skeletal metastasis is the leading cause of morbidity and mortality in prostate cancer, with 80% of advanced prostate cancer patients developing bone metastases. Before metastasis, bone remodeling occurs, stimulating pre-metastatic niche formation and bone turnover, and platelets govern this process. Stem cell factor (SCF, Kit Ligand) is increased in advanced prostate cancer patient platelet releasates. Further, SCF and its receptor, CD117/c-kit, correlate with metastatic prostate cancer severity. We hypothesized that bone-derived SCF plays an important role in prostate cancer tumor communication with the bone inducing pre-metastatic niche formation. We generated two cell-specific SCF knockout mouse models deleting SCF in either mature osteoblasts or megakaryocytes and platelets. Using two syngeneic androgen-insensitive murine prostate cancer cell lines, RM1 (Ras and Myc co-activation) and mPC3 (Pten and Trp53 deletion), we examined the role of bone marrow-derived SCF in primary tumor growth and bone microenvironment alterations. Platelet-derived SCF was required for mPC3, but not RM1, tumor growth, while osteoblast-derived SCF played no role in tumor size in either cell line. While exogenous SCF induced proangiogenic protein secretion by RM1 and mPC3 prostate cancer cells, no significant changes in tumor angiogenesis were measured by immunohistochemistry. Like our previous studies, tumor-induced bone formation occurred in mice bearing RM1 or mPC3 neoplasms, demonstrated by bone histomorphometry. RM1 tumor-bearing osteoblast SCF knockout mice did not display tumor-induced bone formation. Bone stromal cell composition analysis by flow cytometry showed significant shifts in hematopoietic stem cell (HSC), mesenchymal stem cell (MSC), and osteoblast cell percentages in mice bearing RM1 or mPC3 tumors. There were no significant changes in the percentage of macrophages, osteoclasts, or osteocytes. Our study demonstrates that megakaryocyte/platelet-derived SCF regulates primary mPC3 tumor growth, while SCF originating from osteoblasts plays a role in bone marrow-derived progenitor cell composition and pre-metastatic niche formation. Further, we show that both the source of SCF and the genetic profile of prostate cancer determine the effects of SCF. Thus, targeting the SCF/CD117 signaling axis with tyrosine kinase inhibitors could affect primary prostate carcinomas or play a role in reducing bone metastasis dependent on the gene deletions or mutations driving the patients’ prostate cancer.
Knowledge, Attitudes, and Practices of NICU Doctors and Nurses Toward Prevention and Control of Nosocomial Infection With Multidrug Resistant Organism
Authors: Zhou Jinyan , Chen Shuohui
Published: April 2022

Background

Nosocomial infection with multidrug resistant organisms (MDRO) can directly influence the curative effect and the prognosis of neonates, bringing great difficulties to clinical treatment. As direct contacts of neonates, the knowledge, attitudes, and practices (KAP) of doctors and nurses are critical for the prevention and control of MDRO infection in neonatal intensive care units (NICUs).

Purpose

This study describes the KAP of doctors and nurses in NICUs toward the prevention and control of nosocomial infection with MDRO and analyzes its influencing factors.

Methods

This cross-sectional study used convenience sampling to survey 397 doctors and nurses from the NICU of 28 hospitals in 11 cities in Zhejiang Province, China. A univariate analysis and a multiple linear regression were used to analyze the data.

Results

The median scoring rate (interquartile range) of the knowledge, attitude, and practice questionnaire was 0.86 (0.82–0.91), 0.98 (0.91–1.00), and 0.995 (0.97–1.00), respectively. However, the median scoring rate regarding “basic knowledge of MDRO” and “special prevention and control measures” was 0.50 in knowledge. The multiple linear regression showed that the influencing factors of KAP were hospital grade, professional title, gender, regular supervision, and training.

Conclusions

There was still room for improvement in the KAP of NICU doctors and nurses, especially regarding the knowledge. Men, doctors and nurses in Grade II hospitals, and doctors and nurses with primary professional titles had worse KAP. Training and supervision helped improve the KAP.

Relevance to Clinical Practice

To improve the KAP of doctors and nurses to enhance the prevention and control effect for the MDRO infection in NICUs, hospitals and departments should carry out targeted training and strengthen supervision, while Grade II hospitals, men, and doctors and nurses with primary professional titles need more attention.
Anti-Apoptosis of Podocytes and Pro-Apoptosis of Mesangial Cells for Telmisartan in Alleviating Diabetic Kidney Injury
Authors: Wei Xin , Ma Yabin , Li Ya , Zhang Wenzhao , Zhong Yuting , Yu Yue , Zhang Li-Chao , Wang Zhibin , Tu Ye
Published: April 2022

Podocytes damage and mesangial cells expansion are two important pathological manifestations of glomerular injury in early diabetes. Telmisartan, as an angiotensin type 1 (AT1) receptor inhibitor, could improve advanced glycation end (AGE) products or angiotensin Ⅱ (Ang Ⅱ)-induced podocytes injury including detachment or apoptosis. In this current paper, we first confirmed the protective effect of telmisartan on early diabetic kidney injury in type 1 diabetic rats. Telmisartan reduced the loss of podocin and inhibited the expression of α-SMA, reflecting its protective effect on podocyte injury and mesangial proliferation, respectively. More interestingly we observed an opposite effect of telmisartan on the cell viability and apoptosis of podocytes and mesangial cells in a high-glucose environment in vitro. The anti-apoptotic effect of telmisartan on podocytes might be related to its inhibition of swiprosin-1 (a protein can mediate high glucose-induced podocyte apoptosis) expression. While telmisartan induced a high expression of PPARγ in mesangial cells, and GW9662 (a PPARγ antagonist) partially inhibited telmisartan-induced apoptosis and reduced viability of mesangial cells. In addition, high glucose-induced PKCβ1/TGFβ1 expression in mesangial cells could be blocked by telmisartan. These data provide a more precise cellular mechanism for revealing the protective effect of telmisartan in diabetic kidney injury.