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Frontiers in Immunology 2020is a member of the human commensal microflora that exists, apparently benignly, at multiple sites on the host. However, as an opportunist pathogen it can also cause a... (Review)
Review
is a member of the human commensal microflora that exists, apparently benignly, at multiple sites on the host. However, as an opportunist pathogen it can also cause a range of serious diseases. This requires an ability to circumvent the innate immune system to establish an infection. Professional phagocytes, primarily macrophages and neutrophils, are key innate immune cells which interact with , acting as gatekeepers to contain and resolve infection. Recent studies have highlighted the important roles of macrophages during infections, using a wide array of killing mechanisms. In defense, has evolved multiple strategies to survive within, manipulate and escape from macrophages, allowing them to not only subvert but also exploit this key element of our immune system. Macrophage- interactions are multifaceted and have direct roles in infection outcome. In depth understanding of these host-pathogen interactions may be useful for future therapeutic developments. This review examines macrophage interactions with throughout all stages of infection, with special emphasis on mechanisms that determine infection outcome.
Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Vaccines; Cations; Cell Death; Chemotaxis; Cytokines; Extracellular Vesicles; Host-Pathogen Interactions; Humans; Hydrogen-Ion Concentration; Immune Evasion; Macrophages; Mice; Nutrients; Phagocytosis; Phagosomes; Reactive Nitrogen Species; Reactive Oxygen Species; Receptors, Complement; Receptors, Fc; Receptors, Scavenger; Staphylococcal Infections; Staphylococcus aureus
PubMed: 33542723
DOI: 10.3389/fimmu.2020.620339 -
Nature Jul 2010The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of...
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Topics: Case-Control Studies; Cell Movement; Child; Child Development Disorders, Pervasive; Cytoprotection; DNA Copy Number Variations; Europe; Gene Dosage; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Signal Transduction; Social Behavior
PubMed: 20531469
DOI: 10.1038/nature09146 -
Cancer Cytopathology Aug 2018An increasing number of renal cell carcinomas (RCCs) require ancillary studies for diagnosis. The majority of renal fine needle aspirates do not require ancillary... (Review)
Review
An increasing number of renal cell carcinomas (RCCs) require ancillary studies for diagnosis. The majority of renal fine needle aspirates do not require ancillary studies. Among the most common useful stains are cytokeratin 7 (separating clear cell RCC [negative] from papillary RCC, clear cell papillary RCC, and multilocular cystic RCC [positive] as well as separating chromophobe RCC [diffusely positive] from oncocytoma [focally positive/negative]) and CD117 (separating chromophobe RCC and oncocytoma [positive] from granular variants of clear cell RCC [negative]). CD68 and keratin are helpful in distinguishing RCC from xanthogranulomatous pyelonephritis. HMB45 is useful in recognizing scant aspirates of angiomyolipoma. Less common subtypes of RCC may benefit from the use of more specialized ancillary studies (succinate dehydrogenase B, fumarate hydratase, tumor suppressor gene INI, OCT3/4). While the majority of renal fine needle aspirates can be accurately diagnosed based on morphology alone, improved subtyping and accuracy can be achieved with the use of immunohistochemical and molecular studies. Cancer Cytopathol 2018;000:000-000. © 2018 American Cancer Society.
Topics: Biomarkers, Tumor; Biopsy, Fine-Needle; Carcinoma, Renal Cell; Cytodiagnosis; Diagnosis, Differential; Humans; Kidney Neoplasms
PubMed: 30156770
DOI: 10.1002/cncy.22029 -
PLoS Pathogens Mar 2021Peptidoglycan is the major structural component of the Staphylococcus aureus cell wall, in which it maintains cellular integrity, is the interface with the host, and its...
Peptidoglycan is the major structural component of the Staphylococcus aureus cell wall, in which it maintains cellular integrity, is the interface with the host, and its synthesis is targeted by some of the most crucial antibiotics developed. Despite this importance, and the wealth of data from in vitro studies, we do not understand the structure and dynamics of peptidoglycan during infection. In this study we have developed methods to harvest bacteria from an active infection in order to purify cell walls for biochemical analysis ex vivo. Isolated ex vivo bacterial cells are smaller than those actively growing in vitro, with thickened cell walls and reduced peptidoglycan crosslinking, similar to that of stationary phase cells. These features suggested a role for specific peptidoglycan homeostatic mechanisms in disease. As S. aureus missing penicillin binding protein 4 (PBP4) has reduced peptidoglycan crosslinking in vitro its role during infection was established. Loss of PBP4 resulted in an increased recovery of S. aureus from the livers of infected mice, which coincided with enhanced fitness within murine and human macrophages. Thicker cell walls correlate with reduced activity of peptidoglycan hydrolases. S. aureus has a family of 4 putative glucosaminidases, that are collectively crucial for growth. Loss of the major enzyme SagB, led to attenuation during murine infection and reduced survival in human macrophages. However, loss of the other three enzymes Atl, SagA and ScaH resulted in clustering dependent attenuation, in a zebrafish embryo, but not a murine, model of infection. A combination of pbp4 and sagB deficiencies resulted in a restoration of parental virulence. Our results, demonstrate the importance of appropriate cell wall structure and dynamics during pathogenesis, providing new insight to the mechanisms of disease.
Topics: Animals; Cell Wall; Host-Pathogen Interactions; Mice; Peptidoglycan; Staphylococcal Infections; Staphylococcus aureus; Virulence; Zebrafish
PubMed: 33788901
DOI: 10.1371/journal.ppat.1009468 -
The Journal of Physiology Oct 2007Renshaw cell properties have been studied extensively for over 50 years, making them a uniquely well-defined class of spinal interneuron. Recent work has revealed novel... (Review)
Review
Renshaw cell properties have been studied extensively for over 50 years, making them a uniquely well-defined class of spinal interneuron. Recent work has revealed novel ways to identify Renshaw cells in situ and this in turn has promoted a range of studies that have determined their ontogeny and organization of synaptic inputs in unprecedented detail. In this review we illustrate how mature Renshaw cell properties and connectivity arise through a combination of activity-dependent and genetically specified mechanisms. These new insights should aid the development of experimental strategies to manipulate Renshaw cells in spinal circuits and clarify their role in modulating motor output.
Topics: Animals; Calcium-Binding Proteins; Interneurons; Synapses
PubMed: 17640932
DOI: 10.1113/jphysiol.2007.136200 -
ACS Nano Jul 2020Mononuclear phagocytes such as monocytes, tissue-specific macrophages, and dendritic cells are primary actors in both innate and adaptive immunity. These professional...
Mononuclear phagocytes such as monocytes, tissue-specific macrophages, and dendritic cells are primary actors in both innate and adaptive immunity. These professional phagocytes can be parasitized by intracellular bacteria, turning them from housekeepers to hiding places and favoring chronic and/or disseminated infection. One of the most infamous is the bacteria that cause tuberculosis (TB), which is the most pandemic and one of the deadliest diseases, with one-third of the world's population infected and an average of 1.8 million deaths/year worldwide. Here we demonstrate the effective targeting and intracellular delivery of antibiotics to infected macrophages both and , using pH-sensitive nanoscopic polymersomes made of PMPC-PDPA block copolymer. Polymersomes showed the ability to significantly enhance the efficacy of the antibiotics killing , , and another established intracellular pathogen, . Moreover, they demonstrated to easily access TB-like granuloma tissues-one of the harshest environments to penetrate-in zebrafish models. We thus successfully exploited this targeting for the effective eradication of several intracellular bacteria, including , the etiological agent of human TB.
Topics: Animals; Humans; Macrophages; Monocytes; Mycobacterium tuberculosis; Tuberculosis; Zebrafish
PubMed: 32515944
DOI: 10.1021/acsnano.0c01870 -
Journal of Neurophysiology May 2018In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial... (Review)
Review
In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial pathogenic factors, motoneuron loss follows a specific pattern: the largest α-motoneurons die before smaller α-motoneurons, and γ-motoneurons are spared. In this article, we examine how homeostatic responses to this orderly progression could lead to local microcircuit dysfunction that in turn propagates motoneuron dysfunction and death. We first review motoneuron diversity and the principle of α-γ coactivation and then discuss two specific spinal motoneuron microcircuits: those involving proprioceptive afferents and those involving Renshaw cells. Next, we propose that the overall homeostatic response of the nervous system is aimed at maintaining force output. Thus motoneuron degeneration would lead to an increase in inputs to motoneurons, and, because of the pattern of neuronal degeneration, would result in an imbalance in local microcircuit activity that would overwhelm initial homeostatic responses. We suggest that this activity would ultimately lead to excitotoxicity of motoneurons, which would hasten the progression of disease. Finally, we propose that should this be the case, new therapies targeted toward microcircuit dysfunction could slow the course of ALS.
Topics: Afferent Pathways; Amyotrophic Lateral Sclerosis; Disease Progression; Humans; Motor Neurons; Muscle Spindles; Proprioception; Renshaw Cells
PubMed: 29384454
DOI: 10.1152/jn.00331.2017 -
Toxicon : Official Journal of the... Jun 2018Botulinum neurotoxin (BoNT) is a widely used therapeutic in part because its mechanism of action is much wider than initially expected. Since BoNT is taken up more... (Review)
Review
Botulinum neurotoxin (BoNT) is a widely used therapeutic in part because its mechanism of action is much wider than initially expected. Since BoNT is taken up more avidly in active presynaptic terminals, there is some selectivity for weakening muscles involved in frequent involuntary movements. BoNT blocks gamma motoneurons as well as alpha motoneurons, hence reducing afferent spindle activity which appears to have a favorable effect. Some BoNT is retrogradely transported in the motor axons, leading at least to reduction in recurrent inhibition mediated by the Renshaw cell. There are also central nervous system changes after BoNT injections and these may be due to brain plasticity.
Topics: Animals; Botulinum Toxins; Humans; Motor Neurons; Neuromuscular Agents
PubMed: 28803760
DOI: 10.1016/j.toxicon.2017.08.011 -
Nature Cell Biology Jan 2023Metastasis involves dissemination of cancer cells away from a primary tumour and colonization at distal sites. During this process, the mechanical properties of the...
Metastasis involves dissemination of cancer cells away from a primary tumour and colonization at distal sites. During this process, the mechanical properties of the nucleus must be tuned since they pose a challenge to the negotiation of physical constraints imposed by the microenvironment and tissue structure. We discovered increased expression of the inner nuclear membrane protein LAP1 in metastatic melanoma cells, at the invasive front of human primary melanoma tumours and in metastases. Human cells express two LAP1 isoforms (LAP1B and LAP1C), which differ in their amino terminus. Here, using in vitro and in vivo models that recapitulate human melanoma progression, we found that expression of the shorter isoform, LAP1C, supports nuclear envelope blebbing, constrained migration and invasion by allowing a weaker coupling between the nuclear envelope and the nuclear lamina. We propose that LAP1 renders the nucleus highly adaptable and contributes to melanoma aggressiveness.
Topics: Humans; Protein Isoforms; Cell Movement; Nuclear Envelope; Melanoma; Tumor Microenvironment
PubMed: 36624187
DOI: 10.1038/s41556-022-01042-3 -
Cell Reports Jun 2023Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH...
Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.
Topics: Animals; Humans; Mice; Bone Neoplasms; Cartilage; Chondroma; Chondrosarcoma; Isocitrate Dehydrogenase; Mutation
PubMed: 37267108
DOI: 10.1016/j.celrep.2023.112578