A role for P2X7 in microglial proliferation

Microglia, glial cells with an immunocompetent role in the CNS, react to stimuli from the surrounding environment with alterations of their phenotypic response. Amongst other activating signals, the endotoxin lipopolysaccharide (LPS) is widely used as a tool to mimic bacterial infection in the CNS. LPS-activated microglia undergo dramatic changes in cell morphology/activity; in particular, they stop proliferating and differentiate from resting to effector cells. Activated microglia also show modifications of purinoreceptor signalling with a significant decrease in P2X(7) expression. In this study, we demonstrate that the down-regulation of the P2X(7) receptor in activated microglia may play an important role in the antiproliferative effect of LPS. Indeed, chronic blockade of the P2X(7) receptor by antagonists (oxidized ATP, KN62 and Brilliant Blue G), or treatment with the ATP-hydrolase apyrase, severely decreases microglial proliferation, down-regulation of P2X(7) receptor expression by small RNA interference (siRNA) decreases cell proliferation, and the proliferation of P2X(7)-deficient N9 clones and primary microglia, in which P2X(7) expression is down-regulated by siRNA, is unaffected by either LPS or P2X(7) antagonists. Furthermore, flow cytometric analysis indicates that exposure to oxidized ATP or treatment with LPS reversibly decreases cell cycle progression, without increasing the percentage of apoptotic cells. Overall, our data show that the P2X(7) receptor plays an important role in controlling microglial proliferation by supporting cell cycle progression.     

The synergistic effects of interleukin 2 and interleukin 7 on the proliferation and autologous tumor cell lysis of tumor-associated lymphocytes

Interleukin-7 (IL-7) has an ability to stimulate the proliferation of pre-B cells. It has been shown that IL-7 can also activate T lymphocytes. We here demonstrate that IL-7 in combination with interleukin-2 (IL-2) can drive cell proliferation and enhance the autologous tumor cell lysis by peripheral blood mononuclear cells (PBMC) and autologous mixed lymphocyte tumor cell culture (MLTC)-derived effector cells (MLTC cells). These synergistic effects of IL-2 and IL-7 on the proliferation and the augmentation of autologous tumor cell lysis were found for both effector cells. These effects were inhibited by neutralizing antibodies to IL-2 or IL-7, and by a combination of both antibodies, significantly. In terms of phenotypical expression, CD3 positive cells comprised the vast majority of MLTC cells after culture in medium containing IL-2 and IL-7 with an increase of IL-2 receptor positive cells.Abbreviations CD cluster differentiation - IFN interferon - IL interleukin - JRU Japanese Reference Unit - LAK lymphokine activated killer - mAb monoclonal antibody - MLTC mixed lymphocyte tumor cell culture - PBMC peripheral blood mononuclear cells - TILs tumor infiltrating lymphocytes     

The role of DNA methylation in dyslipidaemia: A systematic review

Epigenetic mechanisms, including DNA methylation and histone modifications, might be involved in the regulation of blood lipid concentration variability and may thereby affect cardiovascular health. We aimed to systematically review studies investigating the association between epigenetic marks and plasma concentrations of triacylglycerol, total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Six medical databases were searched until September 3rd 2015, reference lists were screened, and experts in the field were contacted. Of the 757 identified references, 31 articles reporting on 23 unique studies met all inclusion criteria. These studies included data on 8027 unique participants. Overall, no consistent associations were observed between global DNA methylation and blood lipids. Candidate gene and epigenome-wide association studies reported epigenetic regulation of several genes to be related with blood lipids, of which results for ABCG1, CPT1A, TNNT1, MIR33B, SREBF1, and TNIP were replicated. To date, no studies have been performed on histone modification in relation to blood lipids. To conclude, promising results have been reported in the field of epigenetics and dyslipidaemia, however, further rigorous studies are needed to expand our understanding on the role of epigenetics in regulating human's blood lipid levels and its effects on health and disease.     

The role of refuges in biological invasions: A systematic review

Aim

Ecological refuges buffer organisms against stressors and mediate a range of species interactions. However, their role in the context of biological invasions has yet to be synthesized, despite the increasing prevalence and impact of non-native species. To address this, we conducted a systematic review aiming to determine the extent to which refuges are considered explicitly in the invasion literature and to synthesize their function.

Location

Global.

Time period

Present day.

Major taxa studied

All.

Methods

Our search of the literature was conducted using the SCOPUS and Web of Science databases and followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocol. We obtained 315 records of refuge use in biological invasions from 300 studies. From each record, we extracted information relating to the experimental design, species characteristics and refuge type, where available.

Results

Refuges and refuge-mediated processes are widely reported in the invasion literature. Native species commonly use refuges to avoid non-native predation and competition, with spatial complexity and habitat heterogeneity key factors in facilitating their coexistence. Records show that artificial structures safeguard non-natives in their introduced range. However, there were key differences in the use of such structures in marine and terrestrial environments. Moreover, the enhanced structural complexity created by non-native plants and bivalves is often reported to act as a predation refuge for other species.

Main conclusions

The ubiquity of refuge-based processes suggests that refuges can play an important role in affecting the persistence, spread and impacts of non-native species, either through previously described mechanisms (i.e. refuge-mediated apparent competition and the persistent pressure scenario) or through a mechanism we describe (i.e. when non-native species use existing refuges), or both.     

The protein kinases AtMAP3Kepsilon1 and BnMAP3Kepsilon1 are functional homologues of S. pombe cdc7p and may be involved in cell division

We identified an Arabidopsis thaliana gene, AtMAP3Kepsilon1, and a Brassica napus cDNA, BnMAP3Kepsilon1, encoding functional protein serine/threonine kinases closely related to cdc7p and Cdc15p from Schizosaccharomyces pombe and Saccharomyces cerevisiae, respectively. This is the first report of cdc7-related genes in non-fungal eukaryotes; no such genes have as yet been identified in Metazoans. The B. napus protein is able to partially complement a cdc7 loss of function mutation in S. pombe. RT-PCR and in situ hybridisation revealed that the A. thaliana and B. napus genes are expressed in both the sporophytic and the gametophytic tissues of the respective plant species and revealed further that expression is highest in dividing cells. Moreover, AtMAP3Kepsilon1 gene expression is cell cycle-regulated, with higher expression in G2-M phases. Our results strongly suggest that the plant cdc7p-related protein kinases are involved in a signal transduction pathway similar to the SIN pathway, which positively regulates cytokinesis in S. pombe.     

The role of laminin in attachment,growth, and differentiation of cultured cells: a brief review

Laminin, a major structural multidomain protein of basement membranes, has been shown to exert a variety of biological activities. Prominent among those are mediation of cell attachment as well as influences on cellular proliferation, differentiation and motility. Distinct domains of laminin have been identified which carry these activities. The active sites on laminin are recognized by cellular receptors, several of which belong to the integrin class of heterodimeric transmembrane proteins. These are in direct contact with intracellular proteins and mediate signals from the extracellular matrix to the cytoskeleton and possibly to other intracellular regulatory systems. The biological activities of laminin may be used to design optimal conditions for the expression of a differentiated phenotype of cells in culture.     

Mexican native trouts: a review of their history and current systematic and conservation status

While biologists have been aware of theexistence of native Mexican trouts for over acentury, they have received little study. Thefew early studies that did much more thanmention their existence began in the 1930s andcontinued into the early 1960s, focusingprimarily on distributional surveys andtaxonomic analyses. Starting in the 1980s theBaja California rainbow trout became thesubject of more detailed studies, but verylittle remains known of mainland trouts of theSierra Madre Occidental. We review earlierstudies and report on our own collections andobservations made between 1975 and 2000. Wepresent newly discovered historical evidencethat leads us to conclude that a lostcutthroat trout, a lineage not previously knownfrom Mexico, was collected more than a centuryago from headwaters of the Río Conchos (amajor tributary of the Rio Grande (= RíoBravo)), a basin not previously considered toharbor a native trout. We review the lastcentury of regional natural resource managementand discuss our own observations of trouthabitats. Impacts of logging, road building andovergrazing are widespread and expanding. Manystreams suffer from heavy erosion, siltationand contamination, and though long-termhydrologic data are generally not available,there is evidence of decreased discharge inmany streams. These problems appear related toregion-wide land management practices as wellas recent regional drought. Trout cultureoperations using exotic rainbow trout haverapidly proliferated throughout the region,threatening genetic introgression and/orcompetition with native forms and predation onthem. Knowledge of distribution, abundance,relationships and taxonomy, not to mentionecology and population biology, of nativetrouts of the Sierra Madre Occidental remainsinadequate. Vast areas of most mainlanddrainages are still unexplored by fishcollectors, and even rudimentary informationregarding basic biology, ecology and populationstructure of stocks remains lacking.Concentrated exploration, research andmanagement of this long overlooked andundervalued resource are all urgently needed.The history of natural resources exploitationthat placed so many native trouts of thewestern United States on threatened andendangered species lists is repeating itself inthe Sierra Madre Occidental. Without concertedaction and development of region-widesocio-economic solutions for current, largelynon-sustainable resource management practices,native Mexican trout gene pools will soon be ingrave danger of extinction.     

肠道微生物与神经及精神疾病的研究现状

近年来随着微生物16S rRNA、高通量测序以及序列识别技术的成熟,肠道微生物与多种疾病相关性的研究呈蓬勃发展。大量的研究证据表明肠道微生物可通过刺激迷走神经、调节下丘脑‒垂体‒肾上腺轴功能、参与调节机体免疫系统、合成分泌神经递质、产生多种自身代谢产物（如短链脂肪酸、Lipid456、BDNF等小分子物质）机制参与中枢神经系统自身免疫性疾病、癫痫、神经变性疾病、抑郁症、自闭症、精神分裂症的发病过程。研究肠道微生物与中枢神经系统疾病的相互作用,为揭示复杂的中枢神经系统疾病以及精神疾病的发病机制提供科学证据,以期通过调解肠道菌群的微环境治疗神经精神类疾病。     

The role of P2X7 receptors in tissue fibrosis: a brief review

Many previous studies have demonstrated that P2X₇ receptors (P2X₇Rs) have a pleiotropic function in different pathological conditions and could represent a novel target for the treatment of a range of diseases. In particular, recent studies have explored the role of P2X₇R in fibrosis, the pathological outcome of most chronic inflammatory diseases. The aim of this review is to discuss the biological features of P2X₇R and summarize the current knowledge about the putative role of the P2X₇R in triggering fibrosis in a wide spectrum of organs such as the lung, kidney, liver, pancreas, and heart.     

Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis

Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.     

The role of antimicrobial peptides in cardiovascular physiology and disease

Antimicrobial peptides are natural peptide antibiotics, existing ubiquitously in both plant and animal kingdoms. They exhibit broad-spectrum antimicrobial activity and play an important role in host defense against invading microbes. Recently, these peptides have been shown to possess activities unrelated to direct microbial killing and be involved in the complex network of immune responses and inflammation. Thus, their role has now broadened beyond that of endogenous antibiotics. Because of their wide involvement in inflammatory response and the emerging role of inflammation in atherosclerosis, antimicrobial peptides have been proposed to represent an important link between inflammation and the pathogenesis of atherosclerotic cardiovascular diseases. This review highlights recent findings that support a role of these peptides in cardiovascular physiology and disease.     

A single nuclear polymorphism in let-7g binding site affects the doubling time of thyroid nodule by regulating KRAS-induced cell proliferation

As an indicator for the malignancy of thyroid nodules (TN), the doubling time of TN was studied in this study to evaluate the effect of rs712 polymorphism on the progression of TN. In addition, we aimed to study the potential molecular mechanisms underlying the pathological effect of rs712 polymorphism upon TN. A Taqman method was used to genotype the patients according to their rs712 polymorphism. Real-time polymerase chain reaction, western blot, Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay was conducted to study the correlation between KRAS expression and the pathological effect of rs712 polymorphism. In-silicon analysis and luciferase assay were utilized to establish the regulatory relationship between let-7g and KRAS. KRAS messenger RNA (mRNA)/protein levels in the GG group were upregulated with a decreased apoptosis index. KRAS mRNA was validated to be a virtual target of let-7g. In addition, the mRNA/protein level of KRAS as well as cell proliferation index was decreased in primary thyroid cancer cells genotyped as TT/TG and transfected with KRAS small interfering RNA (siRNA)/let-7g precursors. The cell apoptosis index was evidently elevated in the KRAS siRNA/let-7g precursors group compared with that in the scramble controls. Moreover, KRAS mRNA/protein only showed slight reduction when GG-genotyped primary thyroid cancer cells were transfected by let-7g precursors. Additionally, let-7g precursors exhibited no significant effect on cell proliferation index or cell apoptosis in GG cells. Rs712 polymorphism T>G in the 3′-untranslated region of KRAS interrupts the interactions between let-7g and KRAS mRNA, leading to a higher cell proliferation index and reduced doubling time of TN.     

The role of gut microbiota in the gut-brain axis: current challenges and perspectives

Brain and the gastrointestinal (GI) tract are intimately connected to form a bidirectional neurohumoral communication system. The communication between gut and brain, knows as the gut-brain axis, is so well established that the functional status of gut is always related to the condition of brain. The researches on the gut-brain axis were traditionally focused on the psychological status affecting the function of the GI tract. However, recent evidences showed that gut microbiota communicates with the brain via the gut-brain axis to modulate brain development and behavioral phenotypes. These recent fi ndings on the new role of gut microbiota in the gut-brain axis implicate that gut microbiota could associate with brain functions as well as neurological diseases via the gut-brain axis. To elucidate the role of gut microbiota in the gut-brain axis, precise identification of the composition of microbes constituting gut microbiota is an essential step. However, identifi cation of microbes constituting gut microbiota has been the main technological challenge currently due to massive amount of intestinal microbes and the diffi culties in culture of gut microbes. Current methods for identifi cation of microbes constituting gut microbiota are dependent on omics analysis methods by using advanced high tech equipment. Here, we review the association of gut microbiota with the gut-brain axis, including the pros and cons of the current high throughput methods for identifi cation of microbes constituting gut microbiota to elucidate the role of gut microbiota in the gut-brain axis.     

Anchoring skeletal muscle development and disease: the role of ankyrin repeat domain containing proteins in muscle physiology

The ankyrin repeat is a protein module with high affinity for other ankyrin repeats based on strong Van der Waals forces. The resulting dimerization is unusually resistant to both mechanical forces and alkanization, making this module exceedingly useful for meeting the extraordinary demands of muscle physiology. Many aspects of muscle function are controlled by the superfamily ankyrin repeat domain containing proteins, including structural fixation of the contractile apparatus to the muscle membrane by ankyrins, the archetypical member of the family. Additionally, other ankyrin repeat domain containing proteins critically control the various differentiation steps during muscle development, with Notch and developmental stage-specific expression of the members of the Ankyrin repeat and SOCS box (ASB) containing family of proteins controlling compartment size and guiding the various steps of muscle specification. Also, adaptive responses in fully formed muscle require ankyrin repeat containing proteins, with Myotrophin/V-1 ankyrin repeat containing proteins controlling the induction of hypertrophic responses following excessive mechanical load, and muscle ankyrin repeat proteins (MARPs) acting as protective mechanisms of last resort following extreme demands on muscle tissue. Knowledge on mechanisms governing the ordered expression of the various members of superfamily of ankyrin repeat domain containing proteins may prove exceedingly useful for developing novel rational therapy for cardiac disease and muscle dystrophies.     

The role of DDX46 in breast cancer proliferation and invasiveness: A potential therapeutic target

DDX46, a member of DEAD-box (DDX) proteins, is associated with various cancers, while its involvement in the pathogenesis of breast cancer hasn't been reported so far. The study demonstrated the overexpression of DDX46 in human breast cancer cells and tissue samples, and correlated with high histological grade and lymph node metastasis. Downregulation of DDX46 in the breast cancer cell lines inhibited their proliferation and invasiveness in vitro. Furthermore, the growth of MDA-MB-231 xenografts was suppressed in nude mice by DDX46 knockingdown. Taken together, our findings suggest that DDX46 is an oncogenic factor in human breast cancer, and a potential therapeutic target.     

Biological and molecular profile of fracture non‐union tissue: A systematic review and an update on current insights

Fracture non‐union represents a common complication, seen in 5%–10% of all acute fractures. Despite the enhancement in scientific understanding and treatment methods, rates of fracture non‐union remain largely unchanged over the years. This systematic review investigates the biological, molecular and genetic profiles of both (i) non‐union tissue and (ii) non–union‐related tissues, and the genetic predisposition to fracture non‐union. This is crucially important as it could facilitate earlier identification and targeted treatment of high‐risk patients, along with improving our understanding on pathophysiology of fracture non‐union. Since this is an update on our previous systematic review, we searched the literature indexed in PubMed Medline; Ovid Medline; Embase; Scopus; Google Scholar; and the Cochrane Library using Medical Subject Heading (MeSH) or Title/Abstract words (non‐union(s), non‐union(s), human, tissue, bone morphogenic protein(s) (BMPs) and MSCs) from August 2014 (date of our previous publication) to 2 October 2021 for non‐union tissue studies, whereas no date restrictions imposed on non–union‐related tissue studies. Inclusion criteria of this systematic review are human studies investigating the characteristics and properties of non‐union tissue and non–union‐related tissues, available in full‐text English language. Limitations of this systematic review are exclusion of animal studies, the heterogeneity in the definition of non‐union and timing of tissue harvest seen in the included studies, and the search term MSC which may result in the exclusion of studies using historical terms such as ‘osteoprogenitors’ and ‘skeletal stem cells’. A total of 24 studies (non‐union tissue: n = 10; non–union‐related tissues: n = 14) met the inclusion criteria. Soft tissue interposition, bony sclerosis of fracture ends and complete obliteration of medullary canal are commonest macroscopic appearances of non‐unions. Non‐union tissue colour and surrounding fluid are two important characteristics that could be used clinically to distinguish between septic and aseptic non‐unions. Atrophic non‐unions had a predominance of endochondral bone formation and lower cellular density, when compared against hypertrophic non‐unions. Vascular tissues were present in both atrophic and hypertrophic non‐unions, with no difference in vessel density between the two. Studies have found non‐union tissue to contain biologically active MSCs with potential for osteoblastic, chondrogenic and adipogenic differentiation. Proliferative capacity of non‐union tissue MSCs was comparable to that of bone marrow MSCs. Rates of cell senescence of non‐union tissue remain inconclusive and require further investigation. There was a lower BMP expression in non‐union site and absent in the extracellular matrix, with no difference observed between atrophic and hypertrophic non‐unions. The reduced BMP‐7 gene expression and elevated levels of its inhibitors (Chordin, Noggin and Gremlin) could potentially explain impaired bone healing observed in non‐union MSCs. Expression of Dkk‐1 in osteogenic medium was higher in non‐union MSCs. Numerous genetic polymorphisms associated with fracture non‐union have been identified, with some involving the BMP and MMP pathways. Further research is required on determining the sensitivity and specificity of molecular and genetic profiling of relevant tissues as a potential screening biomarker for fracture non‐unions.     

细胞膜转运分子ABCC3和SLC7A7在肠道病毒A71型感染中作用的初步研究

肠道病毒A71型(enterovirus A71,EV-A71)是导致手足口病(hand-foot-mouth disease,HFMD)的主要病原体之一,目前对其治疗尚无特异高效的抗病毒药物.研究表明,细胞膜转运相关分子参与病毒的入侵、复制以及感染性子代病毒颗粒的释放.为寻找宿主中可有效抑制EV-A71感染的细胞膜转...