bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Pannexin1, Connexin32, and Connexin43 in Spotted Sea Bass (Lateolabrax maculatus): They Are Important Neuro-Related Immune Response Genes Involved in Inflammation-Induced ATP Release
Authors: Sun Zhaosheng , Xu Chong , Chen Yuxi , Liu Danjie , Wu Ping , Gao Qian
Published: April 2022

Many immunological diseases can be treated by regulating neurobehavior, in which extracellular ATP is a vital member of endogenous danger-associated molecular pattern signaling molecule that plays a crucial part in innate neuro-related immunity. It is actively released through pannexin (Panx) and connexin (Cx) hemichannels from activated or stressed cells during inflammation, injury, or apoptosis. In addition to participating in ATP release, Panxs and Cxs also have crucial immune functions. In this study, pannexin1, three connexin32 isoforms and connexin43 were identified and characterized in spotted sea bass (Lateolabrax maculatus), which were named LmPanx1, LmCx32.2, LmCx32.3, LmCx32.7, and LmCx43. Their similar topological structures were discovered by sequence analysis: a relatively unconserved C-terminal region and four highly conserved transmembrane (TM) domains, and so on. Each extracellular (ECL) region of Panx1 has two conserved cysteine residues. Unlike Panx1, each ECL region of Cx32 and Cx43 contains three conserved cysteine residues, forming two conserved motifs: CX6CX3C motif in ECL1 and CX4CX5C motif in ECL2. Furthermore, Panx1 and Cx43 share similar genomic organization and synteny with their counterparts in selected vertebrates. Cx32 and CX43 were located in the same locus in fish, but diverged into two loci from amphibian. Moreover, despite varying expression levels, the identified genes were constitutively expressed in all examined tissues. All genes were upregulated by PAMP [lipopolysaccharide and poly(I:C)] stimulation or bacterial infection in vivo and in vitro, but they were downregulated in the brain at 6 or 12 h after stimulation. Especially, the three LmCx32 isoforms and LmCx43 were upregulated by ATP stimulation in primary head kidney leukocytes; however, downregulation of LmCx32.3 and LmCx43 expression were noted at 12 h. Conversely, ATP treatment inhibited the expression of LmPanx1. Importantly, we showed that the spotted sea bass Panx1, Cx43, and Cx32 were localized on the cellular membrane and involved in inflammation-induced ATP release. Taken together, our results demonstrated that Panx1, Cx32, and Cx43 are important neuro-related immune response genes involved in inflammation-induced ATP release.
Successive Site Translocating Inoculation Improved T Cell Responses Elicited by a DNA Vaccine Encoding SARS-CoV-2 S Protein
Authors: Tian Xiangxiang , Zhang Yifan , He Zhangyufan , Li Shaoshuai , Yan Dongmei , Zhu Zhaoqin , Wan Yanmin , Wang Wanhai
Published: April 2022

A variety of methods have been explored to increase delivery efficiencies for DNA vaccine. However, the immunogenicity of DNA vaccines has not been satisfactorily improved. Unlike most of the previous attempts, we provided evidence suggesting that changing the injection site successively (successively site-translocated inoculation, SSTI) could significantly enhance the immunogenicity of DNA vaccines in a previous study. To simplify the strategy and to evaluate its impact on candidate SARS-CoV-2 vaccines, we immunized mice with either a SARS-CoV-2 spike-based DNA vaccine or a spike protein subunit vaccine via three different inoculation strategies. Our data demonstrated that S protein specific antibody responses elicited by the DNA vaccine or the protein subunit vaccine showed no significant difference among different inoculation strategies. Of interest, compared with the conventional site fixed inoculation (SFI), both successive site-translocating inoculation (SSTI) and the simplified translocating inoculation (STI) strategy improved specific T cell responses elicited by the DNA vaccine. More specifically, the SSTI strategy significantly improved both the monofunctional (IFN-γ+IL-2-TNF-α-CD8+) and the multifunctional (IFN-γ+IL-2-TNF-α+CD8+, IFN-γ+IL-2-TNF-α+CD4+, IFN-γ+IL-2+TNF-α+CD4+) T cell responses, while the simplified translocating inoculation (STI) strategy significantly improved the multifunctional CD8+ (IFN-γ+IL-2-TNF-α+CD8+, IFN-γ+IL-2+TNF-α+CD8+) and CD4+ (IFN-γ+IL-2-TNF-α+CD4+, IFN-γ+IL-2+TNF-α+CD4+) T cell responses. The current study confirmed that changing the site of intra muscular injection can significantly improve the immunogenicity of DNA vaccines.
Host-Derived Probiotics Shape the Intestinal Microbial Composition, but not Putative Function in Juvenile Japanese Seabass (Lateolabrax japonicus)
Authors: Yang Hong-Ling , Liu Zi-Yan , Jian Jiu-Ting , Liu Zi-Xin , Ye Ji-Dan , Sun Yun-Zhang
Published: April 2022

A complex and dynamic microbiota exists in the intestine of fish and plays vital roles in host growth and health. However, the interactions between host originated beneficial bacteria/probiotics with gut microbiota are still largely unknown. The aim of the study is to investigate the impact of two host-derived probiotics, Lactococcus petauri LF3 and Bacillus siamensis LF4, on the intestinal microbiota of juvenile Japanese seabass (Lateolabrax japonicus). Fish were fed the control diet (C), L. petauri LF3 (LF3) and B. siamensis LF4 (LF4) supplemented diets for 6 weeks, and the intestinal microbial composition and function were evaluated by using high-throughput sequencing technology. The relative abundances of certain phyla changed significantly in the probiotic-supplemented groups, Fusobacteria and Proteobacteria decreased, while Firmicutes and Bacteroidetes increased apparently in the groups LF3 and LF4. The apparently increased relative abundances of intestinal possible beneficial Christensenellaceae_R-7_group and Lactobacillus were observed in the groups LF3 and LF4, especially in the group LF4. Compared with the control group (C), Chao1, Ace and Shannon indices enhanced remarkably in groups LF3 and LF4. Intestinal microbiota was determined to have more similarity and lower individual differences based on beta diversity analysis including PCoA, NMDS and UPGMA clustering tree in groups LF3 and LF4 compared with the control group (C). Additionally, Firmicutes as a significant biomarker emerged in the groups LF3 and LF4 compared with the control. The intestinal microbial functions (amino acid metabolism, carbohydrate metabolism, energy metabolism, membrane transport, etc.) did not alter among all groups based on level-2 KEGG pathways. In summary, host- derived probiotic L. petauri LF3 and B. siamensis LF4 shape the intestinal microbial composition, but not function in juvenile Japanese seabass (L. japonicus).
Mild NaCl Stress Influences Staphylococcal Enterotoxin C Transcription in a Time-Dependent Manner and Reduces Protein Expression
Authors: Etter Danai , Ukowitz Christina , Eicher Corinne , Tasara Taurai , Johler Sophia
Published: April 2022

Enterotoxins (SEs) produced by Staphylococcus aureus are the cause of serious food intoxications. Staphylococcal enterotoxin C (SEC) is one of the main contributors, as it is often highly expressed. S. aureus possesses a competitive growth advantage over accompanying bacterial flora under stress conditions encountered in foods, such as high NaCl concentrations. However, the influence of NaCl as an external stressor on SEC expression is still unclear. We investigated the influence of 4.5% NaCl on sec mRNA and SEC protein levels. A qRT-PCR assay revealed that NaCl stress leads to time-dependently decreased or elevated sec mRNA levels for most strains. SEC protein levels were generally decreased under NaCl stress. Our findings suggest that NaCl stress lowers overall SEC concentration and time-dependently affects sec mRNA levels.
RNA-Binding Macrocyclic Peptides
Authors: Pal Sunit , ‘t Hart Peter
Published: April 2022

Being able to effectively target RNA with potent ligands will open up a large number of potential therapeutic options. The knowledge on how to achieve this is ever expanding but an important question that remains open is what chemical matter is suitable to achieve this goal. The high flexibility of an RNA as well as its more limited chemical diversity and featureless binding sites can be difficult to target selectively but can be addressed by well-designed cyclic peptides. In this review we will provide an overview of reported cyclic peptide ligands for therapeutically relevant RNA targets and discuss the methods used to discover them. We will also provide critical insights into the properties required for potent and selective interaction and suggestions on how to assess these parameters. The use of cyclic peptides to target RNA is still in its infancy but the lessons learned from past examples can be adopted for the development of novel potent and selective ligands.
Variable and Conserved Regions of Secondary Structure in the β-Trefoil Fold: Structure Versus Function
Authors: Blaber Michael
Published: April 2022

β-trefoil proteins exhibit an approximate C3 rotational symmetry. An analysis of the secondary structure for members of this diverse superfamily of proteins indicates that it is comprised of remarkably conserved β-strands and highly-divergent turn regions. A fundamental “minimal” architecture can be identified that is devoid of heterogenous and extended turn regions, and is conserved among all family members. Conversely, the different functional families of β-trefoils can potentially be identified by their unique turn patterns (or turn “signature”). Such analyses provide clues as to the evolution of the β-trefoil family, suggesting a folding/stability role for the β-strands and a functional role for turn regions. This viewpoint can also guide de novo protein design of β-trefoil proteins having novel functionality.
Altered Cholesterol Homeostasis in Huntington’s Disease
Authors: Kacher Radhia , Mounier Coline , Caboche Jocelyne , Betuing Sandrine
Published: April 2022

Huntington’s disease (HD) is an autosomal dominant genetic disorder caused by an expansion of the CAG repeat in the first exon of Huntingtin’s gene. The associated neurodegeneration mainly affects the striatum and the cortex at early stages and progressively spreads to other brain structures. Targeting HD at its earlier stages is under intense investigation. Numerous drugs were tested, with a rate of success of only 3.5% approved molecules used as symptomatic treatment. The restoration of cholesterol metabolism, which is central to the brain homeostasis and strongly altered in HD, could be an interesting disease-modifying strategy. Cholesterol is an essential membrane component in the central nervous system (CNS); alterations of its homeostasis have deleterious consequences on neuronal functions. The levels of several sterols, upstream of cholesterol, are markedly decreased within the striatum of HD mouse model. Transcription of cholesterol biosynthetic genes is reduced in HD cell and mouse models as well as post-mortem striatal and cortical tissues from HD patients. Since the dynamic of brain cholesterol metabolism is complex, it is essential to establish the best method to target it in HD. Cholesterol, which does not cross the blood-brain-barrier, is locally synthesized and renewed within the brain. All cell types in the CNS synthesize cholesterol during development but as they progress through adulthood, neurons down-regulate their cholesterol synthesis and turn to astrocytes for their full supply. Cellular levels of cholesterol reflect the dynamic balance between synthesis, uptake and export, all integrated into the context of the cross talk between neurons and glial cells. In this review, we describe the latest advances regarding the role of cholesterol deregulation in neuronal functions and how this could be a determinant factor in neuronal degeneration and HD progression. The pathways and major mechanisms by which cholesterol and sterols are regulated in the CNS will be described. From this overview, we discuss the main clinical strategies for manipulating cholesterol metabolism in the CNS, and how to reinstate a proper balance in HD.
Enteric Nervous System: The Bridge Between the Gut Microbiota and Neurological Disorders
Authors: Geng Zi-Han , Zhu Yan , Li Quan-Lin , Zhao Chao , Zhou Ping-Hong
Published: April 2022

The gastrointestinal (GI) tract plays an essential role in food digestion, absorption, and the mucosal immune system; it is also inhabited by a huge range of microbes. The GI tract is densely innervated by a network of 200–600 million neurons that comprise the enteric nervous system (ENS). This system cooperates with intestinal microbes, the intestinal immune system, and endocrine systems; it forms a complex network that is required to maintain a stable intestinal microenvironment. Understanding how gut microbes influence the ENS and central nervous system (CNS) has been a significant research subject over the past decade. Moreover, accumulating evidence from animal and clinical studies has revealed that gut microbiota play important roles in various neurological diseases. However, the causal relationship between microbial changes and neurological disorders currently remains unproven. This review aims to summarize the possible contributions of GI microbiota to the ENS and CNS. It also provides new insights into furthering our current understanding of neurological disorders.
Age-Related Changes in Micro Brain Characteristics Based on Relaxed Mean-Field Model
Authors: Zhan Ke , Zheng Yi , Yang Yaqian , Zhen Yi , Tang Shaoting , Zheng Zhiming
Published: April 2022

Brain health is an important research direction of neuroscience. In addition to the effects of diseases, we cannot ignore the negative effect of aging on brain health. There have been many studies on brain aging, but only a few have used dynamic models to analyze differences in micro brain characteristics in healthy people. In this article, we use the relaxed mean-field model (rMFM) to study the effects of normal aging. Two main parameters of this model are the recurrent connection strength and subcortical input strength. The sensitivity of the rMFM to the initial values of the parameters has not been fully discussed in previous research. We examine this issue through repeated numerical experiments and obtain a reasonable initial parameter range for this model. Differences in recurrent connection strength and subcortical input strength due to aging have also not been studied previously. We use statistical methods to find the regions of interest (ROIs) exhibiting significant differences between young and old groups. Further, we carry out a difference analysis on the process of change of these ROIs on a more detailed timescale. We find that even with the same final results, the trends of change in these ROIs are different. This shows that to develop possible methods to prevent or delay brain damage due to aging, more attention needs to be paid to the trends of change of different ROIs, not just the final results.
Possibility of Enlargement in Left Medial Temporal Areas Against Cerebral Amyloid Deposition Observed During Preclinical Stage
Authors: Imabayashi Etsuko , Ishii Kenji , Toyohara Jun , Wagatsuma Kei , Sakata Muneyuki , Tago Tetsuro , Ishibashi Kenji , Kojima Narumi , Kohda Noriyuki , Tokumaru Aya M. , Kim Hunkyung
Published: April 2022

Neurodegenerative changes in the preclinical stage of Alzheimer’s disease (AD) have recently been the focus of attention because they may present a range of treatment opportunities. A total of 134 elderly volunteers who lived in a local community were investigated and grouped into preclinical and mild cognitive impairment stages according to the Clinical Dementia Rating test; we also estimated amyloid deposition in the brain using positron emission tomography (PET). A significant interaction between clinical stage and amyloid PET positivity on cerebral atrophy was observed in the bilateral parietal lobe, parahippocampal gyri, hippocampus, fusiform gyrus, and right superior and middle temporal gyri, as previously reported. Early AD-specific voxel of interest (VOI) analysis was also applied and averaged Z-scores in the right, left, bilateral, and right minus left medial temporal early AD specific area were computed. We defined these averaged Z-scores in the right, left, bilateral, and right minus left early AD specific VOI in medial temporal area as R-MedT-Atrophy-score, L-MedT-Atrophy-score, Bil-MedT-Atrophy-score, and R_L-MedT-Atrophy-score, respectively. It revealed that the R_L-MedT-Atrophy-scores were significantly larger in the amyloid-positive than in the amyloid-negative cognitively normal (CN) elderly group, that is, the right medial temporal areas were smaller than left in amyloid positive CN group and these left-right differences were significantly larger in amyloid positive than amyloid negative CN elderly group. The L-MedT-Atrophy-score was slightly larger (p = 0.073), that is, the left medial temporal area was smaller in the amyloid-negative CN group than in the amyloid-positive CN group. Conclusively, the left medial temporal area could be larger in CN participants with amyloid deposition than in those without amyloid deposition. The area under the receiver operating characteristic curve for differentiating amyloid positivity among CN participants using the R_L-MedT-Atrophy-scores was 0.73; the sensitivity and specificity were 0.828 and 0.606, respectively. Although not significant, a negative correlation was observed between the composite cerebral standardized uptake value ratio in amyloid PET images and L-MedT-Atrophy-score in CN group. The left medial temporal volume might become enlarged because of compensatory effects against AD pathology occurring at the beginning of the amyloid deposition.
Peripheral Pathways to Neurovascular Unit Dysfunction, Cognitive Impairment, and Alzheimer’s Disease
Authors: Nelson Amy R.
Published: April 2022

Alzheimer’s disease (AD) is the most common form of dementia. It was first described more than a century ago, and scientists are acquiring new data and learning novel information about the disease every day. Although there are nuances and details continuously being unraveled, many key players were identified in the early 1900’s by Dr. Oskar Fischer and Dr. Alois Alzheimer, including amyloid-beta (Aβ), tau, vascular abnormalities, gliosis, and a possible role of infections. More recently, there has been growing interest in and appreciation for neurovascular unit dysfunction that occurs early in mild cognitive impairment (MCI) before and independent of Aβ and tau brain accumulation. In the last decade, evidence that Aβ and tau oligomers are antimicrobial peptides generated in response to infection has expanded our knowledge and challenged preconceived notions. The concept that pathogenic germs cause infections generating an innate immune response (e.g., Aβ and tau produced by peripheral organs) that is associated with incident dementia is worthwhile considering in the context of sporadic AD with an unknown root cause. Therefore, the peripheral amyloid hypothesis to cognitive impairment and AD is proposed and remains to be vetted by future research. Meanwhile, humans remain complex variable organisms with individual risk factors that define their immune status, neurovascular function, and neuronal plasticity. In this focused review, the idea that infections and organ dysfunction contribute to Alzheimer’s disease, through the generation of peripheral amyloids and/or neurovascular unit dysfunction will be explored and discussed. Ultimately, many questions remain to be answered and critical areas of future exploration are highlighted.
Understanding Associative Learning Through Higher-Order Conditioning
Authors: Gostolupce Dilara , Lay Belinda P. P. , Maes Etienne J. P. , Iordanova Mihaela D.
Published: April 2022

Associative learning is often considered to require the physical presence of stimuli in the environment in order for them to be linked. This, however, is not a necessary condition for learning. Indeed, associative relationships can form between events that are never directly paired. That is, associative learning can occur by integrating information across different phases of training. Higher-order conditioning provides evidence for such learning through two deceptively similar designs – sensory preconditioning and second-order conditioning. In this review, we detail the procedures and factors that influence learning in these designs, describe the associative relationships that can be acquired, and argue for the importance of this knowledge in studying brain function.
Near Infrared Spectroscopy for Poor Grade Aneurysmal Subarachnoid Hemorrhage—A Concise Review
Authors: Francoeur Charles L. , Lauzier François , Brassard Patrice , Turgeon Alexis F.
Published: April 2022

Delayed cerebral ischemia (DCI) disproportionately affects poor grade aneurysmal subarachnoid hemorrhage (aSAH) patients. An unreliable neurological exam and the lack of appropriate monitoring leads to unrecognized DCI, which in turn is associated with severe long-term deficits and higher mortality. Near Infrared Spectroscopy (NIRS) offers simple, continuous, real time, non-invasive cerebral monitoring. It provides regional cerebral oxygen saturation (c-rSO2), which reflects the balance between cerebral oxygen consumption and supply. Reports have demonstrated a good correlation with other cerebral oxygen and blood flow monitoring, and credible cerebrovascular reactivity indices were also derived from NIRS signals. Multiple critical c-rSO2 values have been reported in aSAH patients, based on various thresholds, duration, variation from baseline or cerebrovascular reactivity indices. Some were associated with vasospasm, some with DCI and others with clinical outcomes. However, the poor grade aSAH population has not been specifically studied and no randomized clinical trial has been published. The available literature does not support a specific NIRS-based intervention threshold to guide diagnostic or treatment in aSAH patients. We review herein the fundamental basic concepts behind NIRS technology, relationship of c-rSO2 to other brain monitoring values and their potential clinical interpretation. We follow with a critical evaluation of the use of NIRS in the aSAH population, more specifically its ability to diagnose vasospasm, to predict DCI and its association to outcome. In summary, NIRS might offer significant potential for poor grade aSAH in the future. However, current evidence does not support its use in clinical decision-making, and proper technology evaluation is required.
Nutraceutical Molecules Slow Down Retinal Degeneration, in Tvrm4 Mice a Model of Retinitis Pigmentosa, by Genetic Modulation of Anti-oxidant Pathway
Authors: Piano Ilaria , Corsi Francesca , Polini Beatrice , Gargini Claudia
Published: April 2022

Rhodopsin (RHO) mutations are responsible for 25–40% of the dominant cases of retinitis pigmentosa (RP) with different severity and progression rates. The Tvrm4 mice, heterozygous for an I307N dominant mutation of RHO, display a normal retinal phenotype when raised in ambient light conditions, but undergo photoreceptor degeneration when briefly exposed to strong white light. Here, The Tvrm4 mice is pre-treated with naringenin 100 mg/kg/die, quercetin 100 mg/kg/die, naringenin 50 + quercercetin 100 mg/kg/die or vehicle dimethyl sulfoxide (DMSO 0.025%) in the drinking water for 35 days. On the 30th day, retinal degeneration was induced by exposure for 1 min to the white light of 12,000 lux intensity, and the treatment was repeated for another 5 days. At the end of the protocol retinal functionality was tested by recording an electroretinogram (ERG). The retinal tissue was collected and was used for further analyses, including immunohistochemically, biochemical, and molecular biology assays. The data obtained show that treatment with nutraceutical molecules is effective in counteracting retinal degeneration by preserving the functionality of photoreceptors and increasing the antioxidant and anti-apoptotic pathways of retinal cells. The present data confirm that nutraceutical molecules are effective in slowing photoreceptor degeneration in a mutation-independent way by modulating the antioxidant response of the retina at the gene expression level.
Complex-Amplitude-Modulation Vectorial Excitation Beam for High-Resolution Observation of Deep Regions in Two-Photon Microscopy
Authors: Matsumoto Naoya , Watanabe Koyo , Konno Alu , Inoue Takashi , Okazaki Shigetoshi
Published: April 2022

In two-photon microscopy, aberration correction is an essential technique for realizing high resolution in deep regions. A spatial light modulator (SLM) incorporated into an optical system for two-photon microscopy performs pre-compensation on the wavefront of the excitation beam, restoring the resolution close to the diffraction limit even in the deep region of a biological sample. If a spatial resolution smaller than the diffraction limit can be achieved along with aberration correction, the importance of two-photon microscopy for deep region observation will increase further. In this study, we realize higher resolution observations in the deep region by combining two resolution-enhancement methods and an aberration correction method. Therefore, a z-polarizer is added to the aberration-correction optical system, and the SLM modulates the amplitude and phase of the excitation beam; in other words, complex-amplitude modulation is performed. The lateral resolution is found to be approximately 20% higher than the diffraction limit obtained using a circularly polarized beam. Verification was conducted by simulation and experimentation using model samples and ex vivo biological samples. The proposed method has the potential to be effective for live imaging and photostimulation of the deep region of the sample, although it requires only minor changes to the conventional optical system that performs aberration correction.
Comparison of Prognosis Between Microscopically Positive and Negative Surgical Margins for Primary Gastrointestinal Stromal Tumors: A Systematic Review and Meta-Analysis
Authors: Liu Zhen , Zhang Yichunzi , Yin Han , Geng Xiuzhu , Li Sishang , Zhao Jinrong , Zeng Ziyang , Ye Xin , Yu Jianchun , Feng Fan , Kang Weiming
Published: April 2022

Background

This meta-analysis aimed to determine the prognostic impact of microscopically positive margins (R1) on primary gastrointestinal stromal tumors.

Methods

A literature search was performed using PubMed, Embase, Web of Science, and Cochrane Library for studies up to 23 November 2020. The pooled disease-free survival (DFS) and overall survival (OS) between R1 and negative margins (R0) were estimated using a random-effects model.

Results

Twenty studies with 6,465 patients were included. Compared with R0 resection, R1 was associated with poor DFS in patients who did not receive adjuvant Imatinib (HR: 1.62, 95% CI: 1.26–2.09; P = 0.48, I2 = 0%; reference: R0). This negative impact of R1 disappeared with the use of adjuvant Imatinib (HR: 1.23, 95% CI: 0.95–1.60; P = 0.38, I2 = 6%; reference: R0). R1 was related to poor DFS in gastric GISTs (HR: 2.15, 95% CI: 1.15–5.02, I2 = 0%; reference: R0), which was attenuated in the subgroup of adjuvant Imatinib (HR: 2.24, 95% CI: 0.32–15.60; P = 0.84, I2 = 0%; reference: R0). Rectal GIST with R1 margin who even received adjuvant Imatinib still had poor DFS (HR: 3.79, 95% CI: 1.27–11.31; P = 0.54, I2 = 0%; reference: R0). Patients who underwent R1 resection had similar OS compared with those underwent R0 resection regardless of the use of adjuvant Imatinib.

Conclusion

R1 was associated with poor DFS for primary GISTs, which was attenuated by adjuvant therapy with Imatinib. Similar result was observed in the gastric GISTs subgroup. Rectal GIST patients with R1 resection had poor DFS even when they received adjuvant Imatinib. The R1 margin did not influence the OS of GISTs.
Brain Tumor Infodemiology: Worldwide Online Health-Seeking Behavior Using Google Trends and Wikipedia Pageviews
Authors: Mondia Mark Willy L. , Espiritu Adrian I. , Jamora Roland Dominic G.
Published: April 2022

Background

Searching the internet for information on common neurologic symptoms and diseases has been increasing in recent times. It is postulated that online search volume data could be utilized to gauge public awareness and real-world epidemiological data regarding brain tumors.

Objectives

The goal of this study was to describe the pattern of online search queries of keywords related to neoplasms of the central nervous system (CNS).

Methods

Using Google Trends, search activity from January 2004 – January 2021 was quantified using relative search volume (RSV). The average RSV for the first 3 years was compared with the final 3 years to account for percent change. Wikipedia article views from July 2007 – January 2021 were generated using Pageviews. Peaks in RSV and page views were then matched for related news.

Results

“Brain tumor”, “brain cancer”, “glioblastoma”, and “glioma” had the highest search volume. RSV from Google Trends and views of Wikipedia pages reflected comparable data in terms of known prevalence rankings of tumor subtypes. There were no observable trends that could correlate to the rising numbers of brain tumor cases worldwide. However, headlines of personalities being diagnosed with glioblastomas were mostly responsible for temporary increases in public interest.

Conclusions

Transient rises in online search volume mirror public awareness of more aggressive CNS neoplasms that have a high burden of disease. Worldwide interest in brain tumors may not necessarily correspond to clinical occurrence, but may signify an unmet gap in providing accurate online information to neuro-oncologic patients.
PD-1/PD-L1 Inhibitor-Associated Myocarditis: Epidemiology, Characteristics, Diagnosis, Treatment, and Potential Mechanism
Authors: Dong Hao , Qi Yihang , Kong Xiangyi , Wang Zhongzhao , Fang Yi , Wang Jing
Published: April 2022

Immune checkpoint inhibitors (ICIs) induce T-cell activation against cancer cells, and due to their anti-tumor function in multiple cancers, ICIs have been considered an important option for oncotherapy. PD-1/PD-L1 inhibitors are now widely used as ICIs for many types of cancers in clinical practices. Myocarditis induced by anti-PD-1/PD-L1 agents is uncommon but shows potentially fatal toxicity. In this review, we attempted to conclude the incidence, characteristics, diagnosis, and treatments, as well as illustrate the potential pathogenesis from the perspectives of T-lymphocyte infiltration, disturbance of regulatory T cells, cytokines, macrophage-mediated inflammatory response, and synergistic effect of PD-1/PD-L1 and CTLA4.
Mathematical Modeling of Complement Pathway Dynamics for Target Validation and Selection of Drug Modalities for Complement Therapies
Authors: Bansal Loveleena , Nichols Eva-Maria , Howsmon Daniel P. , Neisen Jessica , Bessant Christina M. , Cunningham Fraser , Petit-Frere Sebastien , Ludbrook Steve , Damian Valeriu
Published: April 2022

Motivation:The complement pathway plays a critical role in innate immune defense against infections. Dysregulation between activation and regulation of the complement pathway is widely known to contribute to several diseases. Nevertheless, very few drugs that target complement proteins have made it to the final regulatory approval because of factors such as high concentrations and dosing requirements for complement proteins and serious side effects from complement inhibition.

Methods:A quantitative systems pharmacology (QSP) model of the complement pathway has been developed to evaluate potential drug targets to inhibit complement activation in autoimmune diseases. The model describes complement activationviathe alternative and terminal pathways as well as the dynamics of several regulatory proteins. The QSP model has been used to evaluate the effect of inhibiting complement targets on reducing pathway activation caused by deficiency in factor H and CD59. The model also informed the feasibility of developing small-molecule or large-molecule antibody drugs by predicting the drug dosing and affinity requirements for potential complement targets.

Results:Inhibition of several complement proteins was predicted to lead to a significant reduction in complement activation and cell lysis. The complement proteins that are present in very high concentrations or have high turnover rates (C3, factor B, factor D, and C6) were predicted to be challenging to engage with feasible doses of large-molecule antibody compounds (≤20 mg/kg). Alternatively, complement fragments that have a short half-life (C3b, C3bB, and C3bBb) were predicted to be challenging or infeasible to engage with small-molecule compounds because of high drug affinity requirements (>1 nM) for the inhibition of downstream processes. The drug affinity requirements for disease severity reduction were predicted to differ more than one to two orders of magnitude than affinities needed for the conventional 90% target engagement (TE) for several proteins. Thus, the QSP model analyses indicate the importance for accounting for TE requirements for achieving reduction in disease severity endpoints during the lead optimization stage.
Uncertainty Relations of Non-Hermitian Operators: Theory and Experimental Scheme
Authors: Zhao Xinzhi , Zhang Chengjie
Published: April 2022

The theoretical framework for the uncertainty relation of Hermitian operators is perfect and has been applied in many fields. At the same time, non-Hermitian operators are also widely used in some other fields. However, the uncertainty relation of non-Hermitian operators remains to be explored. K.W. Bong and his co-workers proposed the theory of unitary uncertainty relation and verified it in the experiment [Phys. Rev. Lett. 120, 230402 (2018)]. In this work, we generalized this unitary uncertainty relation theory and proposed uncertainty relations of non-Hermitian operators. Due to the difficulties in the direct measurement of non-Hermitian operators in the uncertainty relations, we simplified the uncertainty relation of two non-Hermitian operators with pure states and proposed a realizable experimental measurement scheme by using the Mach–Zehnder interferometer. When the two non-Hermitian operators are unitary, our result can reduce to Bong et al.’s result. Furthermore, for two non-Hermitian operators but not unitary, we obtained a generalized and analogous result of theirs.
Autophagy is Involved in Cardiac Remodeling in Response to Environmental Temperature Change
Authors: Ruperez C. , Blasco-Roset A. , Kular D. , Cairo M. , Ferrer-Curriu G. , Villarroya J. , Zamora M. , Crispi F. , Villarroya F. , Planavila A.
Published: April 2022

Objectives: To study the reversibility of cold-induced cardiac hypertrophy and the role of autophagy in this process.

Background: Chronic exposure to cold is known to cause cardiac hypertrophy independent of blood pressure elevation. The reversibility of this process and the molecular mechanisms involved are unknown.

Methods: Studies were performed in two-month-old mice exposed to cold (4°C) for 24 h or 10 days. After exposure, the animals were returned to room temperature (21°C) for 24 h or 1 week.

Results: We found that chronic cold exposure significantly increased the heart weight/tibia length (HW/TL) ratio, the mean area of cardiomyocytes, and the expression of hypertrophy markers, but significantly decreased the expression of genes involved in fatty acid oxidation. Echocardiographic measurements confirmed hypertrophy development after chronic cold exposure. One week of deacclimation for cold-exposed mice fully reverted the morphological, functional, and gene expression indicators of cardiac hypertrophy. Experiments involving injection of leupeptin at 1 h before sacrifice (to block autophagic flux) indicated that cardiac autophagy was repressed under cold exposure and re-activated during the first 24 h after mice were returned to room temperature. Pharmacological blockage of autophagy for 1 week using chloroquine in mice subjected to deacclimation from cold significantly inhibited the reversion of cardiac hypertrophy.

Conclusion: Our data indicate that mice exposed to cold develop a marked cardiac hypertrophy that is reversed after 1 week of deacclimation. We propose that autophagy is a major mechanism underlying the heart remodeling seen in response to cold exposure and its posterior reversion after deacclimation.
Genotype-Driven Pathogenesis of Atrial Fibrillation in Hypertrophic Cardiomyopathy: The Case of Different TNNT2 Mutations
Authors: Pioner Josè Manuel , Vitale Giulia , Gentile Francesca , Scellini Beatrice , Piroddi Nicoletta , Cerbai Elisabetta , Olivotto Iacopo , Tardiff Jil , Coppini Raffaele , Tesi Chiara , Poggesi Corrado , Ferrantini Cecilia
Published: April 2022

Atrial dilation and atrial fibrillation (AF) are common in Hypertrophic CardioMyopathy (HCM) patients and associated with a worsening of prognosis. The pathogenesis of atrial myopathy in HCM remains poorly investigated and no specific association with genotype has been identified. By re-analysis of our cohort of thin-filament HCM patients (Coppini et al. 2014) AF was identified in 10% of patients with sporadic mutations in the cardiac Troponin T gene (TNNT2), while AF occurrence was much higher (25–75%) in patients carrying specific “hot-spot” TNNT2 mutations. To determine the molecular basis of arrhythmia occurrence, two HCM mouse models expressing human TNNT2 variants (a “hot-spot” one, R92Q, and a “sporadic” one, E163R) were selected according to the different pathophysiological pathways previously demonstrated in ventricular tissue. Echocardiography studies showed a significant left atrial dilation in both models, but more pronounced in the R92Q. In E163R atrial trabeculae, in line with what previously observed in ventricular preparations, the energy cost of tension generation was markedly increased. However, no changes of twitch amplitude and kinetics were observed, and there was no atrial arrhythmic propensity. R92Q atrial trabeculae, instead, displayed normal ATP consumption but markedly increased myofilament calcium sensitivity, as previously observed in ventricular preparations. This was associated with reduced inotropic reserve and slower kinetics of twitch contractions and, importantly, with an increased occurrence of spontaneous beats and triggered contractions that represent an intrinsic arrhythmogenic mechanism promoting AF. The association of specific TNNT2 mutations with AF occurrence depends on the mutation-driven pathomechanism (i.e., increased atrial myofilament calcium sensitivity rather than increased myofilament tension cost) and may influence the individual response to treatment.
Seasonal Changes of Growth, Immune Parameters and Liver Function in Wild Chinese Sturgeons Under Indoor Conditions: Implication for Artificial Rearing
Authors: Zheng Yueping , Zhang Yong , Xie Zhe , Shin Paul K. S. , Xu Jianan , Fan Houyong , Zhuang Ping , Hu Menghong , Wang Youji
Published: April 2022

Seasonality has a significant effect on the physiology of fish, especially the effect of water temperature changes. In the present study, the growth, innate immune parameters and liver function indices of two rescued wild adult Chinese sturgeons under captive conditions were monitored for 1 year. The results showed that the total annual weight loss rate of the male was −4.58% and the total weight gain rate of the female was 24.12%, in which the weight of both individuals registered highly significant differences in summer, fall and winter (p < 0.01). The male Chinese sturgeon also exhibited negative specific growth rates (−0.1 to −0.8%) during spring to fall, whereas positive specific growth rates, ranging from 0.03 to 0.11%, were recorded in the female. Seasonality also affected the innate immune parameters of the two Chinese sturgeons, in which leukocytes had been increasing since spring and C-reactive protein (CRP) content was significantly higher (p < 0.05) in summer than fall in both individuals. The CRP level of the male Chinese sturgeon showed a significant increase from fall to winter (p < 0.05), suggesting that it may have contracted infection or inflammation during this study period. With the analysis of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), transaminase (AST:ALT) ratio, alkaline phosphatase, albumin to globulin ratio and triglycerides, it was found that the liver function of the captive Chinese sturgeons was adversely affected along seasonal changes, with the highest degree of liver impairment in winter. In combining observations from growth performance and changes in innate immune and liver function parameters, the present findings deduced that the male Chinese sturgeon under study was more susceptible to seasonal changes than the female. For better indoor culture of adult Chinese sturgeons, monitoring of hematological parameters to detect early signs of inflammation and liver function abnormality should be conducted with routine veterinary care during prolonged captivity.
STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases
Authors: Collins Helen E. , Zhang Dingguo , Chatham John C.
Published: April 2022

Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.
Natural Sources and Anthropogenic Influences on the River Water and Groundwater Chemistry of the Lower Mahanadi Basin: Insights From Radiogenic Sr Isotopes and Major Ion Chemistry
Authors: Acharya Shiba Shankar , Hishamunda Valens , Chakrabarti Ramananda
Published: April 2022

The Mahanadi River ranks second among the rivers in the peninsular India in terms of water potential and flows through a geologically heterogeneous terrain. The present study uses a multiproxy approach, involving concentrations of major ions, and 87Sr/86Sr of the dissolved phases in seasonally collected river water and groundwater samples from the Lower Mahanadi Basin to investigate the sources of ions, the Cl-enrichment in the river water, the influences of the man-made structures like the Naraj Barrage, and the role of fertilizers on the chemistry of the river water. This study also provides the first estimate of the radiogenic Sr-flux of the Mahanadi River to the Bay of Bengal. Both inverse and forward models were used to evaluate the contributions of different sources to the dissolved ions of the Mahanadi River over different seasons. The results suggest that even in the predominantly silicate watershed of the Lower Mahanadi River, the riverine chemistry is modulated primarily by carbonate dissolution farther upstream followed by silicate weathering although, the contributions vary seasonally. The Naraj Barrage, which divides the main channel of the Lower Mahanadi River into several distributaries marks a divide between the less polluted upstream and the more polluted downstream. The radiogenic 87Sr/86Sr of the Mahanadi River water can be explained by mixing of four endmembers: Proterozoic carbonates, Archean silicates, rainwater, and fertilizers. The dominance of agricultural input during monsoon is consistent with high loadings of nitrates and phosphates used as fertilizers in the Mahanadi River basin along with a strong positive relationship between phosphate concentrations and 87Sr/86Sr of the river water samples. The flux-weighted averages of Sr concentration and 87Sr/86Sr to the Bay of Bengal were found to be 1.03 μmol/l and 0.72154, respectively. The groundwater composition of the Lower Mahanadi Basin is modulated by the mixing of four endmembers, viz. weathering of silicate and carbonate rocks, Bay of Bengal seawater, and fertilizer inputs. The groundwater samples of the Mahanadi basin show an average Sr concentration of 5.45 μmol/l and an average 87Sr/86Sr of 0.71772.
Exfoliated Graphite: A Surface Renewed Electrode for Environmental Applications
Authors: Idris Azeez Olayiwola , Orimolade Benjamin O. , Potlako Mafa , Feleni Usisipho , Nkambule Thabo T. I. , Mamba Bhekie B.
Published: April 2022

Exfoliated graphite is a 2D carbon material that has recently received great attention owing to its remarkable analytical merits such as fast electron migration, ease of surface regeneration, high-temperature resistance, ability to withstand high-current density, excellent conductivity, and sensitivity. Due to its excellent analytical signature, an exfoliated graphite electrode has been reportedly used in the construction of sensors and biosensors for various applications. This electrode can be used alone or blended with several nanomaterials/semiconductors for the degradation of various organic pollutants in wastewater. Despite the outstanding results reported in the use of exfoliated graphite electrodes for various analytical applications, very few reports were documented in the literature. Therefore, this review elaborated on the importance of exfoliated graphite electrodes for electrochemical analysis.