Intraarticular injection of bone marrow-derived mesenchymal stem cells enhances regeneration in knee osteoarthritis.

PURPOSE: This review aimed to evaluate the efficacy of intra-articular injections of bone marrow derived mesenchymal stem cells (BM-MSCs) for the treatment of knee osteoarthritis (KOA). METHODS: This narrative review evaluates recent English language clinical data and published research articles between 2014 and 2019. Key word search strings of ((("bone marrow-derived mesenchymal stem cell" OR "bone marrow mesenchymal stromal cell" OR "bone marrow stromal cell")) AND ("osteoarthritis" OR "knee osteoarthritis")) AND ("human" OR "clinical"))) AND "intra-articular injection" were used to identify relevant articles using PMC, Cochrane Library, Web Of Science and Scopus databases. RESULTS: Pre-clinical studies have demonstrated successful, safe and encouraging results for articular cartilage repair and regeneration. This is concluded to be due to the multilineage differential potential, immunosuppressive and self-renewal capabilities of BM-MSCs, which have shown to augment pain and improve functional outcomes. Subsequently, clinical applications of intra-articular injections of BM-MSCs are steadily increasing, with most studies demonstrating a decrease in poor cartilage index, improvements in pain, function and Quality of Life (QoL); with moderate-to-high level evidence regarding safety for therapeutic administration. However, low confidence in clinical efficacy remains due to a plethora of heterogenous methodologies utilised, resulting in challenging study comparisons. A moderate number of cells (40 × 106) were identified as most likely to achieve optimal responses in individuals with grade ≥ 2 KOA. Likewise, significant improvements were reported when using lower (24 × 106) and higher (100 × 106) cell numbers, although adverse effects including persistent pain and swelling were a consequence. CONCLUSION: Overall, the benefits of intra-articular injections of BM-MSCs were deemed to outweigh the adverse effects; thus, this treatment be considered as a future therapy strategy. To realise this, long-term large-scale randomised clinical trials are required to enable improved interpretations, to determine the validity of efficacy in future studies. LEVEL OF EVIDENCE: IV

Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Loss of retinal pigment epithelium (RPE) is a major pathological hallmark in AMD with or without pathological neovascularization. Although activation of the immune system is implicated in disease progression, pathological pathways remain diverse and unclear. Here, we report an unexpected protective role of a pro-inflammatory cytokine, interleukin-33 (IL-33) in ocular angiogenesis. IL-33 and its receptor (ST2) are expressed constitutively in human and murine retina and choroid. When RPE was activated, IL-33 expression was markedly elevated in vitro. We found that IL-33 regulated tissue remodelling by attenuating wound-healing responses, including reduction in migration of choroidal fibroblasts and retinal microvascular endothelial cells, and inhibition of collagen gel contraction. In vivo, local administration of recombinant IL-33 inhibited murine choroidal neovascularization (CNV) formation, a surrogate of human neovascular AMD, and this effect was ST2-dependent. Collectively, these data demonstrate IL-33 as a potential immunotherapy and distinguishes pathways for subverting AMD pathology

Vagal sensory neurons drive mucous cell metaplasia

Summary: Airway sensory neuron-produced Substance P heightens allergy-induced goblet cell hyperplasia and hypersecretion of Muc5AC, electrically silencing these overreactive neurons reduced these components of lung type 2 allergic inflammatory response

Listen to genes : dealing with microarray data in the frequency domain

Background: We present a novel and systematic approach to analyze temporal microarray data. The approach includes normalization, clustering and network analysis of genes. Methodology: Genes are normalized using an error model based uniform normalization method aimed at identifying and estimating the sources of variations. The model minimizes the correlation among error terms across replicates. The normalized gene expressions are then clustered in terms of their power spectrum density. The method of complex Granger causality is introduced to reveal interactions between sets of genes. Complex Granger causality along with partial Granger causality is applied in both time and frequency domains to selected as well as all the genes to reveal the interesting networks of interactions. The approach is successfully applied to Arabidopsis leaf microarray data generated from 31,000 genes observed over 22 time points over 22 days. Three circuits: a circadian gene circuit, an ethylene circuit and a new global circuit showing a hierarchical structure to determine the initiators of leaf senescence are analyzed in detail. Conclusions: We use a totally data-driven approach to form biological hypothesis. Clustering using the power-spectrum analysis helps us identify genes of potential interest. Their dynamics can be captured accurately in the time and frequency domain using the methods of complex and partial Granger causality. With the rise in availability of temporal microarray data, such methods can be useful tools in uncovering the hidden biological interactions. We show our method in a step by step manner with help of toy models as well as a real biological dataset. We also analyse three distinct gene circuits of potential interest to Arabidopsis researchers

Hepatic steatosis in people older and younger than fifty who are living with HIV and HIV-negative controls: A cross-sectional study nested within the POPPY cohort

BACKGROUND: Hepatic steatosis is a major cause of chronic liver disease associated with several negative health outcomes. We compared the prevalence of and factors associated with steatosis in people living with and without HIV. METHODS: Older (>50 years) and younger (50 years) underwent liver transient elastography examination with controlled attenuation parameter (steatosis ≥238 dB/m, moderate/severe steatosis ≥280 dB/m, liver fibrosis ≥7.1 kPa). We compared groups using logistic regression/Chi-squared/Fisher's exact/Kruskal–Wallis tests. RESULTS: In total, 317 participants (109 older people with HIV; 101 younger people with HIV; 107 HIV-negative controls) were predominantly white (86%) and male (76%), and 21% were living with obesity (body mass index ≥30 kg/m2). Most (97%) people with HIV had undetectable HIV RNA. The prevalence of fibrosis was 8.4%, 3.0%, and 6.5% in the three groups, respectively (p = 0.26). Fibrosis was predominately (>65%) mild. The prevalence of steatosis was the same in older people with HIV (66.4%) and controls (66.4%) but lower in younger people with HIV (37.4%; p < 0.001). After adjustment, younger people with HIV were less likely to have steatosis (odds ratio [OR] 0.26; 95% confidence interval [CI] 0.14–0.52) than controls, but male sex (OR 2.45; 95% CI 1.20–4.50) and high waist-to-hip ratio (OR 3.04; 95% CI 1.74–5.33) were associated with an increased odds of steatosis. We found no association between steatosis and HIV-related variables. CONCLUSIONS: The prevalence of hepatic steatosis and fibrosis was similar between older participants regardless of HIV status. Age, sex, and abdominal obesity, but not HIV-related variables, were associated with steatosis. Interventions for controlling obesity should be integrated into routine HIV care

Tyrosine Phosphorylation of the E3 Ubiquitin Ligase TRIM21 Positively Regulates Interaction with IRF3 and Hence TRIM21 Activity

Patients suffering from Systemic Lupus Erythematous (SLE) have elevated type I interferon (IFN) levels which correlate with disease activity and severity. TRIM21, an autoantigen associated with SLE, has been identified as an ubiquitin E3 ligase that targets the transcription factor IRF3 in order to turn off and limit type I IFN production following detection of viral and bacterial infection by Toll Like Receptors (TLRs). However, how the activity of TRIM21 is regulated downstream of TLRs is unknown. In this study we demonstrate that TRIM21 is tyrosine phosphorylated following TLR3 and TLR4 stimulation, suggesting that its activity is potentially regulated by tyrosine phosphorylation. Using Netphos, we have identified three key tyrosines that are strongly predicted to be phosphorylated, two of which are conserved between the human and murine forms of TRIM21, at residues 343, 388, and 393, all of which have been mutated from tyrosine to phenylalanine (Y343F, Y388F, and Y393F). We have observed that tyrosine phosphorylation of TRIM21 only occurs in the substrate binding PRY/SPRY domain, and that Y393, and to a lesser extent, Y388 are required for TRIM21 to function as a negative regulator of IFN-β promoter activity. Further studies revealed that mutating Y393 to phenylalanine inhibits the ability of TRIM21 to interact with its substrate, IRF3, thus providing a molecular explanation for the lack of activity of Y393 on the IFN-β promoter. Our data demonstrates a novel role for tyrosine phosphorylation in regulating the activity of TRIM21 downstream of TLR3 and TLR4. Given the pathogenic role of TRIM21 in systemic autoimmunity, these findings have important implications for the development of novel therapeutics

Interpretation of ambiguous situations: evidence for a dissociation between social and physical threat in Williams syndrome

There is increasing evidence that Williams syndrome (WS) is associated with elevated anxiety that is non-social in nature, including generalised anxiety and fears. To date very little research has examined the cognitive processes associated with this anxiety. In the present research, attentional bias for non-social threatening images in WS was examined using a dot-probe paradigm. Participants were 16 individuals with WS aged between 13 and 34 years and two groups of typically developing controls matched to the WS group on chronological age and attentional control ability respectively. The WS group exhibited a significant attention bias towards threatening images. In contrast, no bias was found for group matched on attentional control and a slight bias away from threat was found in the chronological age matched group. The results are contrasted with recent findings suggesting that individuals with WS do not show an attention bias for threatening faces and discussed in relation to neuroimaging research showing elevated amygdala activation in response to threatening non-social scenes in WS

Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

EWS/FLI Mediates Transcriptional Repression via NKX2.2 during Oncogenic Transformation in Ewing's Sarcoma

EWS/FLI is a master regulator of Ewing's sarcoma formation. Gene expression studies in A673 Ewing's sarcoma cells have demonstrated that EWS/FLI downregulates more genes than it upregulates, suggesting that EWS/FLI, and/or its targets, function as transcriptional repressors. One critical EWS/FLI target, NKX2.2, is a transcription factor that contains both transcriptional activation and transcriptional repression domains, raising the possibility that it mediates portions of the EWS/FLI transcriptional signature. We now report that microarray analysis demonstrated that the transcriptional profile of NKX2.2 consists solely of downregulated genes, and overlaps with the EWS/FLI downregulated signature, suggesting that NKX2.2 mediates oncogenic transformation via transcriptional repression. Structure-function analysis revealed that the DNA binding and repressor domains in NKX2.2 are required for oncogenesis in Ewing's sarcoma cells, while the transcriptional activation domain is completely dispensable. Furthermore, blockade of TLE or HDAC function, two protein families thought to mediate the repressive function of NKX2.2, inhibited the transformed phenotype and reversed the NKX2.2 transcriptional profile in Ewing's sarcoma cells. Whole genome localization studies (ChIP-chip) revealed that a significant portion of the NKX2.2-repressed gene expression signature was directly mediated by NKX2.2 binding. These data demonstrate that the transcriptional repressive function of NKX2.2 is necessary, and sufficient, for the oncogenic phenotype of Ewing's sarcoma, and suggest a therapeutic approach to this disease