Species richness and abundance of clinid fish (Teleostei; Clinidae) in intertidal rock pools

Factors affecting species richness and abundance of clinid fish(Fam. Clinidae)in 19 intertidal rock pools near Muizenberg, South Africa, were investigated. Some measure of cover is the most important predictor of clinid species richness, abundance and biomass. Intraspecific partitioning of habitat by Clinus superciliosus was observed, and apparently occurs in C. cottoides as well. Fish were observed to move between pools during high tides, and some individuals showed fidelity to particular pools. There is some evidence for suggesting that C. superciliosus might be a colonizing species

Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease.

TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and engineered to enhance intestinal protease resistance. V565 activity was evaluated in TNFα-TNFα receptor-binding ELISAs as well as TNFα responsive cellular assays and demonstrated neutralisation of both soluble and membrane TNFα with potencies similar to those of adalimumab. Although sensitive to pepsin, V565 retained activity after lengthy incubations with trypsin, chymotrypsin, and pancreatin, as well as mouse small intestinal and human ileal and faecal supernatants. In orally dosed naïve and DSS colitis mice, high V565 concentrations were observed in intestinal contents and faeces and immunostaining revealed V565 localisation in mouse colon tissue. V565 was detected by ELISA in post-dose serum of colitis mice, but not naïve mice, demonstrating penetration of disrupted epithelium. In an ex vivo human IBD tissue culture model, V565 inhibition of tissue phosphoprotein levels and production of inflammatory cytokine biomarkers was similar to infliximab, demonstrating efficacy when present at the disease site. Taken together, results of these studies provide confidence that oral V565 dosing will be therapeutic in IBD patients where the mucosal epithelial barrier is compromised

Oral Anti-Tumour Necrosis Factor Domain Antibody V565 Provides High Intestinal Concentrations, and Reduces Markers of Inflammation in Ulcerative Colitis Patients.

V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following oral administration, ileal recovery of V565 was investigated in four patients with terminal ileostomy. Intestinal and systemic pharmacokinetics were measured in six patients with Crohn's disease and evidence of target engagement assessed in five patients with ulcerative colitis. Following oral administration, V565 was detected at micromolar concentrations in ileal fluid from the ileostomy patients and in stools of the Crohn's patients. In four of the five ulcerative colitis patients, biopsies taken after 7d dosing demonstrated V565 in the lamina propria with co-immunostaining on CD3+ T-lymphocytes and CD14+ macrophages. Phosphorylation of signalling proteins in biopsies taken after 7d oral dosing was decreased by approximately 50%. In conclusion, enteric coating of V565 mini-tablets provided protection in the stomach with gradual release in intestinal regions affected by IBD. Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD

Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine

The variation in antibody response to vaccination likely involves small contributions of numerous genetic variants, such as single-nucleotide polymorphisms (SNPs), which interact in gene networks and pathways. To accumulate the bits of genetic information relevant to the phenotype that are distributed throughout the interaction network, we develop a network eigenvector centrality algorithm (SNPrank) that is sensitive to the weak main effects, gene–gene interactions and small higher-order interactions through hub effects. Analogous to Google PageRank, we interpret the algorithm as the simulation of a random SNP surfer (RSS) that accumulates bits of information in the network through a dynamic probabilistic Markov chain. The transition matrix for the RSS is based on a data-driven genetic association interaction network (GAIN), the nodes of which are SNPs weighted by the main-effect strength and edges weighted by the gene–gene interaction strength. We apply SNPrank to a GAIN analysis of a candidate-gene association study on human immune response to smallpox vaccine. SNPrank implicates a SNP in the retinoid X receptor α (RXRA) gene through a network interaction effect on antibody response. This vitamin A- and D-signaling mediator has been previously implicated in human immune responses, although it would be neglected in a standard analysis because its significance is unremarkable outside the context of its network centrality. This work suggests SNPrank to be a powerful method for identifying network effects in genetic association data and reveals a potential vitamin regulation network association with antibody response

Significant Impact of Sequence Variations in the Nucleoprotein on CD8 T Cell-Mediated Cross-Protection against Influenza A Virus Infections

Background: Memory CD8 T cells to influenza A viruses are widely detectable in healthy human subjects and broadly cross-reactive for serologically distinct influenza A virus subtypes. However, it is not clear to what extent such pre-existing cellular immunity can provide cross-subtype protection against novel emerging influenza A viruses. Methodology/Principal: Findings We show in the mouse model that naturally occurring sequence variations of the conserved nucleoprotein of the virus significantly impact cross-protection against lethal disease in vivo. When priming and challenge viruses shared identical sequences of the immunodominant, protective NP366/Db epitope, strong cross-subtype protection was observed. However, when they did not share complete sequence identity in this epitope, cross-protection was considerably reduced. Contributions of virus-specific antibodies appeared to be minimal under these circumstances. Detailed analysis revealed that the magnitude of the memory CD8 T cell response triggered by the NP366/Db variants was significantly lower than those triggered by the homologous NP366/Db ligand. It appears that strict specificity of a dominant public TCR to the original NP366/Db ligand may limit the expansion of cross-reactive memory CD8 T cells to the NP366/Db variants. Conclusions/Significance: Pre-existing CD8 T cell immunity may provide substantial cross-protection against heterosubtypic influenza A viruses, provided that the priming and the subsequent challenge viruses share the identical sequences of the immunodominant, protective CTL epitopes

Root-Knot Nematodes Exhibit Strain-Specific Clumping Behavior That Is Inherited as a Simple Genetic Trait

Root-knot nematodes are obligate parasites of a wide range of plant species and can feed only on the cytoplasm of living plant cells. In the absence of a suitable plant host, infective juveniles of strain VW9 of the Northern root-knot nematode, Meloidogyne hapla, when dispersed in Pluronic F-127 gel, aggregate into tight, spherical clumps containing thousands of worms. Aggregation or clumping behavior has been observed in diverse genera in the phylum Nematoda spanning free-living species such as Caenorhabditis elegans as well as both plant and animal parasites. Clumping behavior differs between strains of M. hapla and occurs with other species within this genus where strain-specific differences in clumping ability are also apparent. Exposure of M. hapla juveniles to a gradient formed using low levels of cyanide promotes formation of clumps at a preferred cyanide level. Analysis of F2 lines from a cross of M. hapla strains that differ in clump-forming behavior reveals that the behavior segregates as a single, major locus that can be positioned on the genetic map of this nematode. Clumping behavior may be a survival strategy whose importance and function depend on the niche of the nematode strain or species

Oncological considerations of skin-sparing mastectomy

AIM: To review evidence concerning the oncological safety of performing skin-sparing mastectomy (SSM) for invasive breast cancer and ductal carcinoma in situ (DCIS). Furthermore, the evidence concerning RT in relation to SSM and the possibility of nipple preservation was considered. METHODS: Literature review facilitated by Medline and PubMed databases. FINDINGS: Despite the lack of randomised controlled trials, SSM has become an accepted procedure in women undergoing mastectomy and immediate reconstruction for early breast cancer. Compared to non-skin-sparing mastectomy (NSSM), SSM seems to be oncologically safe in patients undergoing mastectomy for invasive tumours smaller than 5 cm, multicentric tumours, DCIS or risk-reduction. However, the technique should be avoided in patients with inflammatory breast cancer or in those with extensive tumour involvement of the skin in view of the high risk of local recurrence. SSM with nipple areola complex (NAC) preservation appears to be oncologically safe, provided the tumour is not close to the nipple and a frozen section protocol for the retro-areolar tissue is followed. Although radiotherapy (RT) does not represent a contraindication to SSM, the latter should be used with caution if postoperative RT is likely, since it detracts from the final cosmetic outcome

Anxiety disorders in children with Williams syndrome, their mothers, and their siblings: Implications for the etiology of anxiety disorders

This study examines the prevalence of anxiety disorders in children with Williams syndrome (WS), their sibling closest in age, and their mothers as well as the predictors of anxiety in these groups. The prevalence of anxiety disorders was assessed and compared to that in the general population. Children with WS had a significantly higher prevalence of specific phobia, generalized anxiety disorder (GAD), and separation anxiety in comparison to children in the general population. While mothers had a higher prevalence of GAD than population controls, the excess was accounted for by mothers who had onset after the birth of their WS child. The siblings had rates similar to the general population. This pattern of findings suggests the presence of a gene in the WS region whose deletion predisposes to anxiety disorders. It is also worthwhile to investigate relations between genes deleted in WS and genes previously implicated in anxiety disorders

Matrix Metalloprotease 9 Mediates Neutrophil Migration into the Airways in Response to Influenza Virus-Induced Toll-Like Receptor Signaling

The early inflammatory response to influenza virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which neutrophils gain entry to the respiratory tract and their role during pathogenesis remain unclear. Here, we report that neutrophils significantly contributed to morbidity in a pathological mouse model of influenza virus infection. Using extensive immunohistochemistry, bone marrow transfers, and depletion studies, we identified neutrophils as the predominant pulmonary cellular source of the gelatinase matrix metalloprotease (MMP) 9, which is capable of digesting the extracellular matrix. Furthermore, infection of MMP9-deficient mice showed that MMP9 was functionally required for neutrophil migration and control of viral replication in the respiratory tract. Although MMP9 release was toll-like receptor (TLR) signaling-dependent, MyD88-mediated signals in non-hematopoietic cells, rather than neutrophil TLRs themselves, were important for neutrophil migration. These results were extended using multiplex analyses of inflammatory mediators to show that neutrophil chemotactic factor, CCL3, and TNFα were reduced in the Myd88−/− airways. Furthermore, TNFα induced MMP9 secretion by neutrophils and blocking TNFα in vivo reduced neutrophil recruitment after infection. Innate recognition of influenza virus therefore provides the mechanisms to induce recruitment of neutrophils through chemokines and to enable their motility within the tissue via MMP9-mediated cleavage of the basement membrane. Our results demonstrate a previously unknown contribution of MMP9 to influenza virus pathogenesis by mediating excessive neutrophil migration into the respiratory tract in response to viral replication that could be exploited for therapeutic purposes