bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Carbohydrate Composition in Fermented Total Mixed Ration and Its Effects on in vitro Methane Production and Microbiome
Authors: Li Yang , Lv Jingyi , Wang Jihong , Zhou Shuang , Zhang Guangning , Wei Bingdong , Sun Yukun , Lan Yaxue , Dou Xiujing , Zhang Yonggen
Published: November 2021

The purpose of this experiment was to investigate the changes of carbohydrate composition in fermented total mixed diet and its effects on rumen fermentation, methane production, and rumen microbiome in vitro. The concentrate-to-forage ratio of the total mixed ration (TMR) was 4:6, and TMR was ensiled with lactic acid bacteria and fibrolytic enzymes. The results showed that different TMRs had different carbohydrate compositions and subfractions, fermentation characteristics, and bacterial community diversity. After fermentation, the fermented total mixed ration (FTMR) group had lower contents of neutral detergent fiber, acid detergent fiber, starch, non-fibrous carbohydrates, and carbohydrates. In addition, lactic acid content and relative abundance of Lactobacillus in the FTMR group were higher. Compared with the TMR group, the in vitro ammonia nitrogen and total volatile fatty acid concentrations and the molar proportion of propionate and butyrate were increased in the FTMR group. However, the ruminal pH, molar proportion of acetate, and methane production were significantly decreased in the FTMR group. Notably, we found that the relative abundance of ruminal bacteria was higher in FTMR than in TMR samples, including Prevotella, Coprococcus, and Oscillospira. At the same time, we found that the diversity of methanogens in the FTMR group was lower than that in the TMR group. The relative abundance of Methanobrevibacter significantly decreased, while the relative abundances of Methanoplanus and vadinCA11 increased. The relative abundances of Entodinium and Pichia significantly decreased in the FTMR group compared with the TMR group. These results suggest that FTMR can be used as an environmentally cleaner technology in animal farming due to its ability to improve ruminal fermentation, modulate the rumen microbiome, and reduce methane emissions.
Phylogenetic Analysis Reveals Distinct Evolutionary Trajectories of the Fluoroquinolones-Resistant Escherichia coli ST1193 From Fuzhou, China
Authors: Huang Jiangqing , Zhao Zhichang , Zhang Qianwen , Zhang Shengcen , Zhang Shuyu , Chen Min , Qiu Hongqiang , Cao Yingping , Li Bin
Published: November 2021

Escherichia coli (E. coli) ST1193 is an emerging fluoroquinolones-resistant and virulent lineage. Large gaps remain in our understanding of the evolutionary processes and differences of this lineage. Therefore, we used 76 E. coli ST1193 genomes to detect strain-level genetic diversity and phylogeny of this lineage globally. All E. coli ST1193 possessed fimH64, filCH5, and fumC14. There was 94.7% of isolates classified as O-type O75. There was 9.33% of E. coli ST1193 that possessed K5 capsular, while 90.67% of isolates possessed K1 capsular. The core genome analysis revealed that all isolates were divided into two phylogenetic clades (clade A and B). Clade A included 25 non-Chinese E. coli ST1193, and clade B contained all isolates collected from Fuzhou, China, respectively. The results of comparative genomics indicated Indels were identified in 150 clade-specific genes, which were enriched into the biological process and molecular function. Accessory genome phylogenetic tree showed a high degree of correlation between accessory genome clusters and core genome clades. There was significant difference in antibiotic resistance genes (ARGs) [blaCTX–M–55, blaTEM–1, sul2, tet(B), tet(R), APH(6)-Id, and AAC(3)-IId], virulence factors (cia, neuC, gad, and traT), and plasmid replicon types (IncQ1, Col156, and IncB/O/K/Z) between clade A (non-Chinese isolates) and clade B (Chinese isolates) (p < 0.05). Further analysis of the genetic environments of blaCTX–M–55 demonstrated that the flanking contexts of blaCTX–M–55 were diverse. In conclusion, our results reveal the distinct evolutionary trajectories of the spread of E. coli ST1193 in Fuzhou, China and non-China regions. This supports both global transmission and localized lineage expansion of this lineage following specific introductions into a geographic locality.
In vivo and in silico Virulence Analysis of Leptospira Species Isolated From Environments and Rodents in Leptospirosis Outbreak Areas in Malaysia
Authors: Philip Noraini , Jani Jaeyres , Azhari Nurul Natasya , Sekawi Zamberi , Neela Vasantha Kumari
Published: November 2021

The zoonotic disease leptospirosis is caused by pathogenic species of the genusLeptospira. With the advancement of studies in leptospirosis, several new species are being reported. It has always been a query, whetherLeptospiraspecies, serovars, and strains isolated from different geographical locations contribute to the difference in the disease presentations and severity. In an epidemiological surveillance study performed in Malaysia, we isolated seven novel intermediate and saprophytic species (Leptospira semungkisensis,Leptospira fletcheri,Leptospira langatensis,Leptospira selangorensis,Leptospira jelokensis,Leptospira perdikensis,Leptospira congkakensis) from environments and three pathogenic species from rodents (Leptospira borgpeterseniistrain HP364,Leptospira weiliistrain SC295,Leptospira interrogansstrain HP358) trapped in human leptospirosis outbreak premises. To evaluate the pathogenic potential of these isolates, we performed anin vivoandin silicovirulence analysis. Environmental isolates and strain HP364 did not induce any clinical manifestations in hamsters. Strain SC295 caused inactivity and weight loss with histopathological changes in kidneys, however, all hamsters survived until the end of the experiment. Strain HP358 showed a high virulent phenotype as all infected hamsters died or were moribund within 7 days postinfection. Lungs, liver, and kidneys showed pathological changes with hemorrhage as the main presentation.In silicoanalysis elucidated the genome size of strain HP358 to be larger than strains HP364 and SC295 and containing virulence genes reported inLeptospiraspecies and a high number of specific putative virulence factors. In conclusion,L. interrogansstrain HP358 was highly pathogenic with fatal outcome. The constituent ofLeptospiragenomes may determine the level of disease severity and that needs further investigations.
Analysis and Construction of a Molecular Diagnosis Model of Drug-Resistant Epilepsy Based on Bioinformatics
Authors: Han Tenghui , Wu Zhenyu , Zhu Jun , Kou Yao , Li Jipeng , Deng Yanchun
Published: November 2021

Background: Epilepsy is a complex chronic disease of the nervous system which influences the health of approximately 70 million patients worldwide. In the past few decades, despite the development of novel antiepileptic drugs, around one-third of patients with epilepsy have developed drug-resistant epilepsy. We performed a bioinformatic analysis to explore the underlying diagnostic markers and mechanisms of drug-resistant epilepsy.

Methods: Weighted correlation network analysis (WGCNA) was applied to genes in epilepsy samples downloaded from the Gene Expression Omnibus database to determine key modules. The least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to screen the genes resistant to carbamazepine, phenytoin, and valproate, and sensitivity of the three-class classification SVM model was verified through the receiver operator characteristic (ROC) curve. A protein–protein interaction (PPI) network was utilized to analyze the protein interaction relationship. Finally, ingenuity pathway analysis (IPA) was adopted to conduct disease and function pathway and network analysis.

Results: Through WGCNA, 72 genes stood out from the key modules related to drug resistance and were identified as candidate resistance genes. Intersection analysis of the results of the LASSO and SVM-RFE algorithms selected 11, 4, and 5 drug-resistant genes for carbamazepine, phenytoin, and valproate, respectively. Subsequent union analysis obtained 17 hub resistance genes to construct a three-class classification SVM model. ROC showed that the model could accurately predict patient resistance. Expression of 17 hub resistance genes in healthy subjects and patients was significantly different. The PPI showed that there are six resistance genes (CD247, CTSW, IL2RB, MATK, NKG7, and PRF1) that may play a central role in the resistance of epilepsy patients. Finally, IPA revealed that resistance genes (PRKCH and S1PR5) were involved in “CREB signaling in Neurons.”

Conclusion: We obtained a three-class SVM model that can accurately predict the drug resistance of patients with epilepsy, which provides a new theoretical basis for research and treatment in the field of drug-resistant epilepsy. Moreover, resistance genes PRKCH and S1PR5 may cooperate with other resistance genes to exhibit resistance effects by regulation of the cAMP-response element-binding protein (CREB) signaling pathway.
Immunosuppression Induced by Glutamine Deprivation Occurs via Activating PD-L1 Transcription in Bladder Cancer
Authors: Wang Liping , Xu Ting , Yang Xuecheng , Liang Zhijuan , Zhang Jisheng , Li Dan , Chen Yuanbin , Ma Guofeng , Wang Yonghua , Liang Ye , Niu Haitao
Published: November 2021

Few studies have reported whether nutrients in the tumor microenvironment can regulate the expression of PD-L1. Since tumor cells are often situated in a low-glutamine environment, we investigated PD-L1 expression under glutamine deprivation in bladder cancer cells. PD-L1 expression and the activation of the EGFR/MEK/ERK/c-Jun signaling pathway under glutamine deprivation were investigated by qPCR, Western blot, and immunofluorescence analyses. C-Jun-mediated transcriptional regulation of the PD-L1 gene was assessed by ChIP. PD-L1 expression and activation of the EGFR/MEK/ERK/c-Jun signaling pathway were assessed in T24 cells, TCCSUP cells and BALB/c mice with or without glutamine supplementation. Additionally, the impact of PD-L1 expression under glutamine deprivation on the function of T cells was investigated by ELISA. The expression of PD-L1 and EGFR/MEK/ERK/c-Jun pathway activation were elevated by glutamine deprivation, and c-Jun was enriched in the enhancer region of PD-L1. The expression of PD-L1 was considerably impaired by inhibiting the EGFR/MEK/ERK/c-Jun pathway and was elevated by activating this signaling pathway. In addition, the elevated PD-L1 expression and MEK/ERK/c-Jun signaling pathway activation were reduced by glutamine supplementation in vitro and in vivo. PD-L1 upregulation by glutamine deprivation in bladder cancer cells could reduce IFN-γ production by T cells. The expression of PD-L1 was upregulated under glutamine deprivation through the EGFR/MEK/ERK/c-Jun pathway to impair T cell function.
Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739
Authors: Aledavood Elnaz , Gheeraert Aria , Forte Alessia , Vuillon Laurent , Rivalta Ivan , Luque F. Javier , Estarellas Carolina
Published: November 2021

Adenosine monophosphate-activated protein kinase (AMPK) is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 heterotrimeric complexes, which exhibit notable differences in the sensitivity to direct activators. To comprehend the molecular factors of the activation mechanism of AMPK, we have assessed the changes in the structural and dynamical properties of β1- and β2-containing AMPK complexes formed upon binding to the pan-activator PF-739. The analysis revealed the molecular basis of the PF-739-mediated activation of AMPK and enabled us to identify distinctive features that may justify the slightly higher affinity towards the β1−isoform, such as the β1−Asn111 to β2−Asp111 substitution, which seems to be critical for modulating the dynamical sensitivity of β1- and β2 isoforms. The results are valuable in the design of selective activators to improve the tissue specificity of therapeutic treatment.
Remote Optogenetics Using Up/Down-Conversion Phosphors
Authors: Matsubara Takanori , Yamashita Takayuki
Published: November 2021

Microbial rhodopsins widely used for optogenetics are sensitive to light in the visible spectrum. As visible light is heavily scattered and absorbed by tissue, stimulating light for optogenetic control does not reach deep in the tissue irradiated from outside the subject body. Conventional optogenetics employs fiber optics inserted close to the target, which is highly invasive and poses various problems for researchers. Recent advances in material science integrated with neuroscience have enabled remote optogenetic control of neuronal activities in living animals using up- or down-conversion phosphors. The development of these methodologies has stimulated researchers to test novel strategies for less invasive, wireless control of cellular functions in the brain and other tissues. Here, we review recent reports related to these new technologies and discuss the current limitations and future perspectives toward the establishment of non-invasive optogenetics for clinical applications.
Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington’s Disease?
Authors: Villegas Luisana , Nørremølle Anne , Freude Kristine , Vilhardt Frederik
Published: November 2021

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by neuronal loss and tissue atrophy mainly in the striatum and cortex. In the early stages of the disease, impairment of neuronal function, synaptic dysfunction and white matter loss precedes neuronal death itself. Relative to other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease and Amyotrophic Lateral Sclerosis, where the effects of either microglia or NADPH oxidases (NOXs) are recognized as important contributors to disease pathogenesis and progression, there is a pronounced lack of information in HD. This information void contrasts with evidence from human HD patients where blood monocytes and microglia are activated well before HD clinical symptoms (PET scans), and the clear signs of oxidative stress and inflammation in post mortem HD brain. Habitually, NOX activity and oxidative stress in the central nervous system (CNS) are equated with microglia, but research of the last two decades has carved out important roles for NOX enzyme function in neurons. Here, we will convey recent information about the function of NOX enzymes in neurons, and contemplate on putative roles of neuronal NOX in HD. We will focus on NOX-produced reactive oxygen species (ROS) as redox signaling molecules in/among neurons, and the specific roles of NOXs in important processes such as neurogenesis and lineage specification, neurite outgrowth and growth cone dynamics, and synaptic plasticity where NMDAR-dependent signaling, and long-term depression/potentiation are redox-regulated phenomena. HD animal models and induced pluripotent stem cell (iPSC) studies have made it clear that the very same physiological processes are also affected in HD, and we will speculate on possible roles for NOX in the pathogenesis and development of disease. Finally, we also take into account the limited information on microglia in HD and relate this to any contribution of NOX enzymes.
Regional Cortical Thickness Predicts Top Cognitive Performance in the Elderly
Authors: Dominguez Elena Nicole , Stark Shauna M. , Ren Yueqi , Corrada Maria M. , Kawas Claudia H. , Stark Craig E. L.
Published: November 2021

While aging is typically associated with cognitive decline, some individuals are able to diverge from the characteristic downward slope and maintain very high levels of cognitive performance. Prior studies have found that cortical thickness in the cingulate cortex, a region involved in information processing, memory, and attention, distinguish those with exceptional cognitive abilities when compared to their cognitively more typical elderly peers. Others major areas outside of the cingulate, such as the prefrontal cortex and insula, are also key in successful aging well into late age, suggesting that structural properties across a wide range of areas may better explain differences in cognitive abilities. Here, we aim to assess the role of regional cortical thickness, both in the cingulate and the whole brain, in modeling Top Cognitive Performance (TCP), measured by performance in the top 50th percentile of memory and executive function. Using data from National Alzheimer’s Coordinating Center and The 90 + Study, we examined healthy subjects aged 70–100 years old. We found that, while thickness in cingulate regions can model TCP status with some degree of accuracy, a whole-brain, network-level approach out-performed the localist, cingulate models. These findings suggests a need for more network-style approaches and furthers our understanding of neurobiological factors contributing to preserved cognition.
Alpha-Synuclein Induced Immune Cells Activation and Associated Therapy in Parkinson’s Disease
Authors: Su Ruichen , Zhou Tian
Published: November 2021

Parkinson’s disease (PD) is a neurodegenerative disorder closely related to immunity. An important aspect of the pathogenesis of PD is the interaction between α-synuclein and a series of immune cells. Studies have shown that accumulation of α-synuclein can induce an autoimmune response that accelerates the progression of PD. This study discusses the mechanisms underlying the interaction between α-synuclein and the immune system. During the development of PD, abnormally accumulated α-synuclein becomes an autoimmune antigen that binds to Toll-like receptors (TLRs) that activate microglia, which differentiate into the microglia type 1 (M1) subtype. The microglia activate intracellular inflammatory pathways, induce the release of proinflammatory cytokines, and promote the differentiation of cluster of differentiation 4 + (CD4 +) T cells into proinflammatory T helper type 1 (Th1) and T helper type 17 (Th17) subtypes. Given the important role of α-synuclein in the immune system of the patients with PD, identifying potential targets of immunotherapy related to α-synuclein is critical for slowing disease progression. An enhanced understanding of immune-associated mechanisms in PD can guide the development of associated therapeutic strategies in the future.
Imaging Cognitive Impairment and Impulse Control Disorders in Parkinson's Disease
Authors: Martín-Bastida Antonio , Delgado-Alvarado Manuel , Navalpotro-Gómez Irene , Rodríguez-Oroz María Cruz
Published: November 2021

Dementia and mild forms of cognitive impairment as well as neuropsychiatric symptoms (i. e., impulse control disorders) are frequent and disabling non-motor symptoms of Parkinson's disease (PD). The identification of changes in neuroimaging studies for the early diagnosis and monitoring of the cognitive and neuropsychiatric symptoms associated with Parkinson's disease, as well as their pathophysiological understanding, are critical for the development of an optimal therapeutic approach. In the current literature review, we present an update on the latest structural and functional neuroimaging findings, including high magnetic field resonance and radionuclide imaging, assessing cognitive dysfunction and impulse control disorders in PD.
Association Between the Rate of Treatment Response and Short-Term Outcomes in Childhood Guillain-Barré Syndrome
Authors: Jin Mei , Zhao Libo , Liu Jing , Geng Weijin , Zhao Ziwei , Li Chunzhen , Xue Jingru , Sun Suzhen
Published: November 2021

Introduction: Few studies have examined the association between the rate of treatment response and the outcome of pediatric Guillain-Barré syndrome (GBS). Therefore, our study aimed to identify treatment response in relation to the short-term outcomes of GBS. Further, we investigated its potential predictive value for prognosis.

Methods: Our retrospective study included children diagnosed with GBS in the Pediatric Neurology Department of the Children's Hospital of Hebei Province from 2016 to 2020. According to the rate of response from the standard intravenous immunoglobulin (IVIg) treatment, patients were divided into two groups: rapid-response GBS (initial response within 7 days) and slow-response (initial response within 8–30 days). The GBS disability score (Hughes Functional Grading Scale) was used to assess the children's functional disability at nadir, 1 month, and 6 months after onset.

Results: Among the 36 children included in the study, 18 (50%) and 18 (50%) were rapid and slow responders, respectively. Time from IVIg treatment to the initial response was significantly shorter in the rapid-response group (5 [3–6.25] days vs. 10.5[8.75–15] days in slow-response GBS, p < 0.001). Hughes score at 1 month was worse than the rapid responders (Fisher's exact test, p = 0.006). Survival analysis (Kaplan–Meier) with respect to regaining the ability to walk independently (Hughes Functional Grading Scale of 2) within 1 month after onset was significantly different among the two groups (log-rank test for trend, p = 0.024). The abnormal levels of cerebral spinal fluid proteins and autonomic dysfunction were more frequent in the slow-response group than those in the rapid group (p < 0.05).

Conclusion: The rate of response to IVIg treatment was correlated with short-term outcomes in children with GBS and had predictive value for prognosis. The role of patient's initial responses to treatment could be significantly valuable in developing more effective and efficient treatment options.
Neuronal Oscillatory Signatures of Joint Attention and Intersubjectivity in Arrhythmic Coaction
Authors: Maÿe Alexander , Wang Tiezhi , Engel Andreas K.
Published: November 2021

Hyper-brain studies analyze the brain activity of two or more individuals during some form of interaction. Several studies found signs of inter-subject brain activity coordination, such as power and phase synchronization or information flow. This hyper-brain coordination is frequently studied in paradigms which induce rhythms or even synchronization, e.g., by mirroring movements, turn-based activity in card or economic games, or joint music making. It is therefore interesting to figure out in how far coordinated brain activity may be induced by a rhythmicity in the task and/or the sensory feedback that the partners receive. We therefore studied the EEG brain activity of dyads in a task that required the smooth pursuit of a target and did not involve any extrinsic rhythms. Partners controlled orthogonal axes of the two-dimensional motion of an object that had to be kept on the target. Using several methods for analyzing hyper-brain coupling, we could not detect signs of coordinated brain activity. However, we found several brain regions in which the frequency-specific activity significantly correlated with the objective task performance, the subjective experience thereof, and of the collaboration. Activity in these regions has been linked to motor control, sensorimotor integration, executive control and emotional processing. Our results suggest that neural correlates of intersubjectivity encompass large parts of brain areas that are considered to be involved in sensorimotor control without necessarily coordinating their activity across agents.
Conditional Deletion of Activating Rearranged During Transfection Receptor Tyrosine Kinase Leads to Impairment of Photoreceptor Ribbon Synapses and Disrupted Visual Function in Mice
Authors: Peng Wei-Hao , Liao Meng-Lin , Huang Wan-Chun , Liu Pei-Kang , Levi Sarah R. , Tseng Yun-Ju , Lee Chia-Ying , Yeh Lung-Kun , Chen Kuan-Jen , Chien Chung-Liang , Wang Nan-Kai
Published: November 2021

Purpose: The rearranged during transfection (RET) receptor tyrosine kinase plays a key role in transducing signals related to cell growth and differentiation. Ret mutant mice show abnormal retinal activity and abnormal levels and morphology of bipolar cells, yet die on the 21st day after birth as a result of renal underdevelopment. To extend the observation period, we generated the Ret conditional knockout Chx10-Cre;C-Retlx/lx mouse model and analyzed the retinal function and morphological changes in mature and aging Chx10-Cre;C-Retlx/lx mice.

Methods: Retina-specific depletion of Ret was achieved using mice with floxed alleles of the Ret gene with CHX10-driven Cre recombinase; floxed mice without Cre expression were used as controls. Retinal function was examined using electroretinography (ERG), and 2-, 4-, 12-, and 24-month-old mice were analyzed by hematoxylin staining and immunohistochemistry to evaluate retinal morphological alterations. The ultrastructure of photoreceptor synapses was evaluated using electron microscopy.

Results: The results of the ERG testing showed that b-wave amplitudes were reduced in Chx10-Cre;C-Retlx/lx mice, whereas a-waves were not affected. A histopathological analysis revealed a thinner and disorganized outer plexiform layer at the ages of 12 and 24 months in Chx10-Cre;C-Retlx/lx mice. Moreover, the data provided by immunohistochemistry showed defects in the synapses of photoreceptor cells. This result was confirmed at the ultrastructural level, thus supporting the participation of Ret in the morphological changes of the synaptic ribbon.

Conclusion: Our results provide evidence of the role of Ret in maintaining the function of the retina, which was essential for preserving the structure of the synaptic ribbon and supporting the integrity of the outer plexiform layer.
MeCP2 Epigenetic Silencing of Oprm1 Gene in Primary Sensory Neurons Under Neuropathic Pain Conditions
Authors: Sun Na , Yu Lina , Gao Yibo , Ma Longfei , Ren Jinxuan , Liu Ying , Gao Dave Schwinn , Xie Chen , Wu Ying , Wang Lieju , Hong Juncong , Yan Min
Published: November 2021

Opioids are the last option for the pharmacological treatment of neuropathic pain, but their antinociceptive effects are limited. Decreased mu opioid receptor (MOR) expression in the peripheral nervous system may contribute to this. Here, we showed that nerve injury induced hypermethylation of the Oprm1 gene promoter and an increased expression of methyl-CpG binding protein 2 (MeCP2) in injured dorsal root ganglion (DRG). The downregulation of MOR in the DRG is closely related to the augmentation of MeCP2, an epigenetic repressor, which could recruit HDAC1 and bind to the methylated regions of the Oprm1 gene promoter. MeCP2 knockdown restored the expression of MOR in injured DRG and enhanced the analgesic effect of morphine, while the mimicking of this increase via the intrathecal infusion of viral vector-mediated MeCP2 was sufficient to reduce MOR in the DRG. Moreover, HDAC1 inhibition with suberoylanilide hydroxamic acid, an HDAC inhibitor, also prevented MOR reduction in the DRG of neuropathic pain mice, contributing to the augmentation of morphine analgesia effects. Mechanistically, upregulated MeCP2 promotes the binding of a high level of HDCA1 to hypermethylated regions of the Oprm1 gene promoter, reduces the acetylation of histone H3 (acH3) levels of the Oprm1 gene promoter, and attenuates Oprm1 transcription in injured DRG. Thus, upregulated MeCP2 and HDAC1 in Oprm1 gene promoter sites, negatively regulates MOR expression in injured DRG, mitigating the analgesic effect of the opioids. Targeting MeCP2/HDAC1 may thus provide a new solution for improving the therapeutic effect of opioids in a clinical setting.
Balancing Prediction and Surprise: A Role for Active Sleep at the Dawn of Consciousness?
Authors: Van De Poll Matthew N. , van Swinderen Bruno
Published: November 2021

The brain is a prediction machine. Yet the world is never entirely predictable, for any animal. Unexpected events are surprising, and this typically evokes prediction error signatures in mammalian brains. In humans such mismatched expectations are often associated with an emotional response as well, and emotional dysregulation can lead to cognitive disorders such as depression or schizophrenia. Emotional responses are understood to be important for memory consolidation, suggesting that positive or negative ‘valence’ cues more generally constitute an ancient mechanism designed to potently refine and generalize internal models of the world and thereby minimize prediction errors. On the other hand, abolishing error detection and surprise entirely (as could happen by generalization or habituation) is probably maladaptive, as this might undermine the very mechanism that brains use to become better prediction machines. This paradoxical view of brain function as an ongoing balance between prediction and surprise suggests a compelling approach to study and understand the evolution of consciousness in animals. In particular, this view may provide insight into the function and evolution of ‘active’ sleep. Here, we propose that active sleep – when animals are behaviorally asleep but their brain seems awake – is widespread beyond mammals and birds, and may have evolved as a mechanism for optimizing predictive processing in motile creatures confronted with constantly changing environments. To explore our hypothesis, we progress from humans to invertebrates, investigating how a potential role for rapid eye movement (REM) sleep in emotional regulation in humans could be re-examined as a conserved sleep function that co-evolved alongside selective attention to maintain an adaptive balance between prediction and surprise. This view of active sleep has some interesting implications for the evolution of subjective awareness and consciousness in animals.
Dietary Addition With Clostridium butyricum and Xylo-Oligosaccharides Improves Carcass Trait and Meat Quality of Huanjiang Mini-Pigs
Authors: Cai Qiaoli , Hu Chengjun , Tang Wu , Jiang Huijiao , Geng Meimei , Huang Xingguo , Kong Xiangfeng
Published: November 2021

This study was conducted to investigate the effects of dietary addition with Clostridium butyricum (CB) and xylo-oligosaccharides (XOS) on growth performance, carcass trait, and meat quality of pigs. A total of 128 Huanjiang mini-pigs with an initial body weight of 9.5 ± 0.1 kg were randomly assigned to one of four groups. The pigs in control (Con) group were fed a basal diet and those in the experimental groups were fed the basal diet supplemented with 0.05% CB (CB group), 0.02% XOS (XOS group), or 0.05% CB + 0.02% XOS (CB + XOS group). Eight replicate pens were used per group with four pigs per pen. On days 28, 56, and 84 of the trial, the growth performance, carcass trait, and meat quality were evaluated. The results showed that dietary CB addition decreased (p < 0.05) the average daily gain and increased (p < 0.05) the ratio of feed intake to body weight gain at day 28 of the trial; CB, XOS, and CB + XOS addition increased (p < 0.05) the backfat thickness at day 84 of the trial compared with the Con group. Dietary CB, XOS, and CB + XOS addition increased (p < 0.05) the pH45min, while decreased (p < 0.05) the marbling score at day 28 of the trial compared with the Con group. Dietary CB + XOS addition increased (p < 0.05) the contents of Ala, Arg, Asp, Gly, His, Leu, Lys, Met, Phe, Ser, Thr, Tyr, and Val in muscle at day 56 of the trial. At day 84 of the trial, dietary CB addition increased the contents of nonessential amino acid (NEAA), total amino acid (TAA), and monounsaturated fatty acid (MUFA), while decreased (p < 0.05) the percentage of C20:1 in muscle compared with the Con group. Collectively, dietary addition with 0.05% CB and 0.02% XOS could not alter the growth performance, but increase carcass trait, meat quality, and muscular nutrient contents in Huanjiang mini-pigs.
Establishment of a prognosis Prediction Model Based on Pyroptosis-Related Signatures Associated With the Immune Microenvironment and Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma
Authors: Jiang Aimin , Meng Jialin , Bao Yewei , Wang Anbang , Gong Wenliang , Gan Xinxin , Wang Jie , Bao Yi , Wu Zhenjie , Lu Juan , Liu Bing , Wang Linhui
Published: November 2021

Background

Pyroptosis is essential for tumorigenesis and progression of neoplasm. However, the heterogeneity of pyroptosis and its relationship with the tumor microenvironment (TME) in clear cell renal cell carcinoma (ccRCC) remain unclear. The purpose of the present study was to identify pyroptosis-related subtypes and construct a prognosis prediction model based on pyroptosis signatures.

Methods

First, heterogenous pyroptosis subgroups were explored based on 33 pyroptosis-related genes and ccRCC samples from TCGA, and the model established by LASSO regression was verified by the ICGC database. Then, the clinical significance, functional status, immune infiltration, cell–cell communication, genomic alteration, and drug sensitivity of different subgroups were further analyzed. Finally, the LASSO-Cox algorithm was applied to narrow down the candidate genes to develop a robust and concise prognostic model.

Results

Two heterogenous pyroptosis subgroups were identified: pyroptosis-low immunity-low C1 subtype and pyroptosis-high immunity-high C2 subtype. Compared with C1, C2 was associated with a higher clinical stage or grade and a worse prognosis. More immune cell infiltration was observed in C2 than that in C1, while the response rate in the C2 subgroup was lower than that in the C1 subgroup. Pyroptosis-related genes were mainly expressed in myeloid cells, and T cells and epithelial cells might influence other cell clusters via the pyroptosis-related pathway. In addition, C1 was characterized by MTOR and ATM mutation, while the characteristics of C2 were alterations in SPEN and ROS1 mutation. Finally, a robust and promising pyroptosis-related prediction model for ccRCC was constructed and validated.

Conclusion

Two heterogeneous pyroptosis subtypes were identified and compared in multiple omics levels, and five pyroptosis-related signatures were applied to establish a prognosis prediction model. Our findings may help better understand the role of pyroptosis in ccRCC progression and provide a new perspective in the management of ccRCC patients.
Cancer Stem Cells: Metabolic Characterization for Targeted Cancer Therapy
Authors: Kaur Jasmeet , Bhattacharyya Shalmoli
Published: November 2021

The subpopulation of cancer stem cells (CSCs) within tumor bulk are known for tumor recurrence and metastasis. CSCs show intrinsic resistance to conventional therapies and phenotypic plasticity within the tumor, which make these a difficult target for conventional therapies. CSCs have different metabolic phenotypes based on their needs as compared to the bulk cancer cells. CSCs show metabolic plasticity and constantly alter their metabolic state between glycolysis and oxidative metabolism (OXPHOS) to adapt to scarcity of nutrients and therapeutic stress. The metabolic characteristics of CSCs are distinct compared to non-CSCs and thus provide an opportunity to devise more effective strategies to target CSCs. Mechanism for metabolic switch in CSCs is still unravelled, however existing evidence suggests that tumor microenvironment affects the metabolic phenotype of cancer cells. Understanding CSCs metabolism may help in discovering new and effective clinical targets to prevent cancer relapse and metastasis. This review summarises the current knowledge of CSCs metabolism and highlights the potential targeted treatment strategies.
Current Strategies for Cancer Cell-Derived Extracellular Vesicles for Cancer Therapy
Authors: Lin Weijian , Cai Xing-Dong
Published: November 2021

Cancer cell-derived extracellular vesicles (CEVs), a novel type of therapeutic agent in cancer treatment, can be prepared from the autocrine secretion of various cancer cells, the direct extraction of cancer cells and the combination of cancer cell-derived membranes with advanced materials. With various bioactive molecules, exosomes are produced by cells for intercellular communication. Although cancer cell-derived exosomes are known to inhibit tumor apoptosis and promote the progression of cancer, researchers have developed various innovative strategies to prepare anti-tumor vesicles from cancer cells. With current strategies for anti-tumor vesicles, four different kinds of CEVs are classified including irradiated CEVs, advanced materials combined CEVs, chemotherapeutic drugs loaded CEVs and genetically engineered CEVs. In this way, CEVs can not only be the carriers for anti-tumor drugs to the target tumor area but also act as immune-active agents. Problems raised in the strategies mainly concerned with the preparation, efficacy and application. In this review, we classified and summarized the current strategies for utilizing the anti-tumor potential of CEVs. Additionally, the challenges and the prospects of this novel agent have been discussed.
Landscape of Carbon Ion Radiotherapy in Prostate Cancer: Clinical Application and Translational Research
Authors: Chen Xue , Yu Qi , Li Ping , Fu Shen
Published: November 2021

Carbon ion radiotherapy (CIRT) is a useful and advanced technique for prostate cancer. This study sought to investigate the clinical efficacy and translational research for prostate cancer with carbon ion radiotherapy. We integrated the data from published articles, clinical trials websites, and our data. The efficacy of CIRT for prostate cancer was assessed in terms of overall survival, biochemical recurrence-free survival, and toxicity response. Up to now, clinical treatment of carbon ion radiotherapy has been carried in only five countries. We found that carbon ion radiotherapy induced little genitourinary and gastrointestinal toxicity when used for prostate cancer treatment. To some extent, it led to improved outcomes in overall survival, biochemical recurrence-free survival than conventional radiotherapy, especially for high-risk prostate cancer. Carbon ion radiotherapy brought clinical benefits for prostate cancer patients, and quality of life assessment indicated that CIRT affected patients to a lesser extent. Potential biomarkers from our omics-based study could be used to predict the efficacy of prostate cancer with CIRT. Carbon ion radiotherapy brought clinical benefits for prostate cancer patients. The omics-based translational research may provide insights into individualized therapy.
Dosimetric Comparison of Helical Tomotherapy, Volume-Modulated Arc Therapy, and Fixed-Field Intensity-Modulated Radiation Therapy in Locally Advanced Nasopharyngeal Carcinoma
Authors: Lu Shan , Fan Huiqi , Hu Xueyuan , Li Xin , Kuang Yingying , Yu Deyang , Yang Shanshan
Published: November 2021

Objective

To compare the dosimetric parameters of different radiotherapy plans [helical tomotherapy (HT), volume-modulated arc therapy (VMAT), and fixed-field intensity-modulated radiation therapy (FF-IMRT)] for locally advanced nasopharyngeal carcinoma (NPC).

Methods

A total of 15 patients with locally advanced NPC were chosen for this retrospective analysis and replanned for HT, VMAT, and FF-IMRT. The prescribed planning target volume (PTV) dose for the primary tumor and metastatic lymph nodes was 70 Gy (2.12 Gy/fraction, delivered over 33 fractions). The prescribed PTV dose for the high-risk subclinical region was 59.4 Gy (1.8 Gy/fraction, delivered over 33 fractions). The dosimetric parameters of the PTV and organs at risk (OARs) and the efficiency of radiation delivery were assessed and compared using the paired-samples t-test.

Results

Compared with VMAT and FF-IMRT plans, HT plans significantly improved the mean conformity index (CI) and homogeneity index (HI). The HT plans reduced the maximum doses delivered to OARs, such as the brainstem, spinal cord, and optic nerves, and significantly reduced the volume delivered to the high-dose region, especially when examining the V30 value of the parotid glands. However, VMAT reduced the treatment time and improved the efficiency of radiation delivery compared with HT.

Conclusions

For locally advanced NPC, the results showed that HT and VMAT possessed better target homogeneity and conformity, reducing the dose delivered to OARs compared with conventional FF-IMRT, with HT achieving the best effect. Among the techniques studied, VMAT had the shortest radiation delivery time. The results of this study can provide guidance for the selection of appropriate radiation technologies used to treat patients with locally advanced NPC who are undergoing concurrent chemoradiotherapy.
AQP9 Is a Prognostic Factor for Kidney Cancer and a Promising Indicator for M2 TAM Polarization and CD8+ T-Cell Recruitment
Authors: Jing Jibo , Sun Jin , Wu Yuqing , Zhang Nieke , Liu Chunhui , Chen Saisai , Li Wenchao , Hong Cheng , Xu Bin , Chen Ming
Published: November 2021

Background

It is undeniable that the tumor microenvironment (TME) plays an indispensable role in the progression of kidney renal clear cell carcinoma (KIRC). However, the precise mechanism of activities in TME is still unclear.

Methods and Results

Using the CIBERSORT and ESTIMATE calculation methods, the scores of the two main fractions of tumor-infiltrating immune cells (TICs) from The Cancer Genome Atlas (TCGA) database of 537 KIRC patients were calculated. Subsequently, differentially expressed genes (DEGs) were drawn out by performing an overlap between Cox regression analysis and protein–protein interaction (PPI) network. Aquaporin 9 (AQP9) was identified as a latent predictor through the process. Following research revealed that AQP9 expression was positively correlated with the pathological characteristics (TNM stage) and negatively connected with survival time. Then, by performing gene set enrichment analysis (GSEA), it can be inferred that genes with high expression level of AQP9 were mainly enriched in immune-related activities, while low AQP9 group was associated with functions of cellular metabolism. Further studies have shown that regulatory T cells (Tregs), macrophages M2, macrophages M0, CD4+ T cells, and neutrophils were positively correlated with AQP9 expression. While the levels of mast cells, natural killer (NK) cells, and CD8+ T cells are negatively correlated with AQP9. The result of multiple immunohistochemistry (mIHC) suggests a negative relevance between AQP9 and CD8+ T cells and reveals a trend of consistent change on AQP9 and M2 macrophages.

Conclusion

The expression level of AQP9 may be helpful in predicting the prognosis of patients with KIRC, especially to the TME state transition, the mechanism of which is possibly through lipid metabolism and P53, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways that affect M2 polarization. AQP9 was associated with the expression levels of M2, tumor-associated macrophages (TAMs), and the recruitment of CD8+ T cells in tumor environment. The research result indicates that AQP9 may be an obstacle to maintain the immune activity of TME.
Development and Verification of the Amino Metabolism-Related and Immune-Associated Prognosis Signature in Gliomas
Authors: Xu Yang , Ye Liguo , Geng Rongxin , Hu Ping , Sun Qian , Tong Shiao , Yuan Fanen , Chen Qianxue
Published: November 2021

Aberrant reprogramming of metabolism has been considered a hallmark in various malignant tumors. The metabolic changes of amino acid not only have dramatic effects in cancer cells but also influence their immune-microenvironment in gliomas. However, the features of the amino acid metabolism-related and immune-associated gene set have not been systematically described. The expression level of mRNA was obtained from The Cancer Genome Atlas database and the Chinese Glioma Genome Atlas database, which were used as training set and validation set, respectively. Different bioinformatics and statistical methods were combined to construct a robust amino metabolism-related and immune-associated risk signature for distinguishing prognosis and clinical pathology features. Constructing the nomogram enhanced risk stratification and quantified risk assessment based on our gene model. Besides this, the biological mechanism related to the risk score was investigated by gene set enrichment analysis. Hub genes of risk signature were identified by the protein–protein interaction network. The amino acid metabolism-related and immune-associated gene signature recognized high-risk patients, defined as an independent risk factor for overall survival. The nomogram exhibited a high accuracy in predicting the overall survival rate for glioma patients. Furthermore, the high risk score hinted an immunosuppressive microenvironment and a lower sensitivity of immune checkpoint blockade therapy and also identified PSMC5 and PSMD3 as novel biomarkers in glioma. In conclusion, a novel amino acid metabolism-related and immune-associated risk signature for predicting prognosis in glioma has been constructed and identified as two potential novel biomarkers.
Lack of Effects of the Presence of a Dog on Pain Perception in Healthy Participants—A Randomized Controlled Trial
Authors: Wagner Cora , Gaab Jens , Locher Cosima , Hediger Karin
Published: November 2021

Animal-assisted interventions (AAIs) have been shown to be effective in the treatment of pain. Studies suggest that relationships with animals can have comparable qualities to relationships with humans and that this enables animals to provide social support. Further, the presence of an animal can strengthen the therapeutic alliance between patients and treatment providers. This suggests that the analgesic effects of AAI might be mediated by social support from an animal or by strengthening the alliance between the patient and the treatment provider. To test these assumptions, we examined the effects of the presence of a dog on experimentally induced pain in a pain assessment and a pain therapy context. Hundred thirty-two healthy participants were randomly assigned to the conditions “pain,” “pain + dog,” “pain + placebo,” or “pain + placebo + dog.” We collected baseline and posttreatment measurements of heat-pain tolerance and the heat-pain threshold and of the corresponding subjective ratings of heat-pain intensity and unpleasantness as well as of participants' perceptions of the study investigator. The primary outcome was heat-pain tolerance. The presence of the dog did not influence the primary outcome (“pain” vs. “pain + dog”: difference = 0.04, CI = −0.66 to 0.74, p = 0.905; “pain + placebo” vs. “pain + placebo + dog”: difference = 0.43, CI = −0.02 to 0.88, p = 0.059). Participants did also not perceive the study investigator to be more trustworthy in the presence of the dog (“pain” vs. “pain + dog”: difference = 0.10, CI = −0.67 to 0.87, p = 0.796; “pain + placebo” vs. “pain + placebo + dog”: difference = 0.11, CI = −0.43 to 0.64, p = 0.695). The results indicate that the mere presence of a dog does not contribute to pain reduction and that the analgesic effects of AAI that previous studies have found is not replicated in our study as AAI did not increase perceived social support and had no effect on the alliance between the participant and the treatment provider. We assume that the animal most likely needs to be an integrated and plausible part of the treatment rationale so that participants are able to form a treatment-response expectation toward AAI.

Clinical Trial Registration: This study was preregistered as a clinical trial on www.clinicaltrials.gov (Identifier: NCT0389814).