Simplified monomeric VHH-Fc antibodies provide new opportunities for passive immunization

Simplified monomeric monoclonal antibodies consisting of a single-domain VHH, derived from camelid heavy-chain only antibodies, fused with the Fc domain of either IgG (VHH-IgG) or IgA (VHH-IgA) antibodies, are promising therapeutic proteins. These simplified single-gene encoded antibodies are much easier to manufacture and can be produced in plants and in yeast for bulk applications. These merits enable novel passive immunization applications, such as in-feed oral delivery of VHH-IgAs, which have successfully provided protection against a gastrointestinal infection in the piglet model

Antibiotic-induced perturbations are manifested in the dominant intestinal bacterial phyla of atlantic salmon

The intestinal microbiota of certain farmed fish are often exposed to antimicrobial substances, such as antibiotics, that are used to prevent and treat bacterial diseases. Antibiotics that kill or inhibit the growth of harmful microbes can rapidly alter intestinal microbial diversity and composition, with potential effects on the host health. In this study, we have elucidated the impact of two antibiotics, florfenicol and oxolinic acid, by employing a high-throughput 16S rRNA gene amplicon sequencing technique on the distal and mid intestinal microbial communities of Atlantic salmon (Salmo salar). For this, Atlantic salmon were offered diets with or without antibiotics. We then investigated the bacterial communities in the intestinal mucus of the fish. Our results showed that antibiotic exposure shifts the intestinal microbial profile differentially. In addition, the bacterial compositions of the control and antibiotic-fed groups were significantly different. Antibiotic feeding altered the composition and abundance of the dominant bacterial phyla, namely Proteobacteria, Actinobacteria, Firmicutes, Spirochaetes, Bacteroidetes, Tenericutes, and Thermotogae. The bacterial association network analysis also indicated the differential pattern of co-occurrence of bacteria in the three study groups. The results regarding the differences in the structure and association of the intestinal microbiota of Atlantic salmon after florfenicol and oxolinic acid feeding can be employed to attenuate the adverse effects of antibiotic feeding on fishpublishedVersio

Re-aligning Shadow Models can Improve White-box Membership Inference Attacks

Machine learning models have been shown to leak sensitive information about their training datasets. As models are being increasingly used, on devices, to automate tasks and power new applications, there have been concerns that such white-box access to its parameters, as opposed to the black-box setting which only provides query access to the model, increases the attack surface. Directly extending the shadow modelling technique from the black-box to the white-box setting has been shown, in general, not to perform better than black-box only attacks. A key reason is misalignment, a known characteristic of deep neural networks. We here present the first systematic analysis of the causes of misalignment in shadow models and show the use of a different weight initialisation to be the main cause of shadow model misalignment. Second, we extend several re-alignment techniques, previously developed in the model fusion literature, to the shadow modelling context, where the goal is to re-align the layers of a shadow model to those of the target model.We show re-alignment techniques to significantly reduce the measured misalignment between the target and shadow models. Finally, we perform a comprehensive evaluation of white-box membership inference attacks (MIA). Our analysis reveals that (1) MIAs suffer from misalignment between shadow models, but that (2) re-aligning the shadow models improves, sometimes significantly, MIA performance. On the CIFAR10 dataset with a false positive rate of 1\%, white-box MIA using re-aligned shadow models improves the true positive rate by 4.5\%.Taken together, our results highlight that on-device deployment increase the attack surface and that the newly available information can be used by an attacker

Macroalga-derived alginate oligosaccharide alters intestinal bacteria of atlantic salmon

Prebiotics are substrates intended to sculpt gut microbial communities as they are selectively utilized by the microorganisms to exert beneficial health effects on hosts. Macroalga-derived oligosaccharides are candidate prebiotics, and herein, we determined the effects of Laminaria sp.-derived alginate oligosaccharide (AlgOS) on the distal intestinal microbiota of Atlantic salmon (Salmo salar). Using a high-throughput 16S rRNA gene amplicon sequencing technique, we investigated the microbiota harbored in the intestinal content and mucus of the fish offered feeds supplemented with 0.5 and 2.5% AlgOS. We found that the prebiotic shifts the intestinal microbiota profile; alpha diversity was significantly reduced with 2.5% AlgOS while with 0.5% AlgOS the alteration occurred without impacting the bacterial diversity. Beta diversity analysis indicated the significant differences between control and prebiotic-fed groups. The low supplementation level of AlgOS facilitated the dominance of Proteobacteria (including Photobacterium phosphoreum, Aquabacterium parvum, Achromobacter insolitus), and Spirochaetes (Brevinema andersonii) in the content or mucus of the fish, and few of these bacteria (Aliivibrio logei, A. parvum, B. andersonii, A. insolitus) have genes associated with butyrate production. The results indicate that the low inclusion of AlgOS can plausibly induce a prebiotic effect on the distal intestinal microbiota of Atlantic salmon. These findings can generate further interest in the potential of macroalgae-derived oligosaccharides for food and feed applications.publishedVersio

RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress

Mutations in RECQL4 helicase are associated with Rothmund–Thomson syndrome (RTS). A subset of RTS patients is predisposed to cancer and is sensitive to DNA damaging agents. The enhanced sensitivity of cells from RTS patients correlates with the accumulation of transcriptionally active nuclear p53. We found that in untreated normal human cells these two nuclear proteins, p53 and RECQL4, instead colocalize in the mitochondrial nucleoids. RECQL4 accumulates in mitochondria in all phases of the cell cycle except S phase and physically interacts with p53 only in the absence of DNA damage. p53–RECQL4 binding leads to the masking of the nuclear localization signal of p53. The N-terminal 84 amino acids of RECQL4 contain a mitochondrial localization signal, which causes the localization of RECQL4–p53 complex to the mitochondria. RECQL4–p53 interaction is disrupted after stress, allowing p53 translocation to the nucleus. In untreated normal cells RECQL4 optimizes de novo replication of mtDNA, which is consequently decreased in fibroblasts from RTS patients. Wild-type RECQL4-complemented RTS cells show relocalization of both RECQL4 and p53 to the mitochondria, loss of p53 activation, restoration of de novo mtDNA replication and resistance to different types of DNA damage. In cells expressing Δ84 RECQL4, which cannot translocate to mitochondria, all the above functions are compromised. The recruitment of p53 to the sites of de novo mtDNA replication is also regulated by RECQL4. Thus these findings elucidate the mechanism by which p53 is regulated by RECQL4 in unstressed normal cells and also delineates the mitochondrial functions of the helicase

Study protocol on prevalence of non-exudative macular neovascularisation and its contribution to prediction of exudation in fellow eyes with unilateral exudative AMD (EYE-NEON)

PURPOSE: Fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD) are at risk of developing macular neovascularisation (MNV). These eyes may first develop subclinical non-exudative MNV (neMNV) before they leak to form exudative MNV (eMNV). The EYE NEON study is a 2-year study aimed at estimating the prevalence and incidence of neMNV and evaluating its role as a predictor for conversion to neovascular AMD. METHODS: EYE NEON is a multicentre study that will run in retinal clinics across 25 National Health Service with the aim to recruit 800 patients with new onset nAMD in the first eye. The fellow-eye with no evidence of nAMD at baseline will be the study eye. All study eyes will have OCT and OCTA done at first and second year following first anti-VEGF treatment to the first eye (non-study eye), with new onset nAMD. We will estimate the prevalence and incidence of neMNV over 2 years, rate of conversion from neMNV to eMNV and numbers initiated on treatment for neovascular AMD in the study eye will be reported. Predictive models of conversion including neMNV with other demographic and imaging parameters will be developed. CONCLUSION: The study design with proposed target sample size is sufficient to evaluate the retinal imaging characteristics of the study eyes with and without neMNV and develop predictive models to inform risk of conversion to nAMD

Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR) in predicting systemic inflammatory response syndrome (SIRS) and sepsis after percutaneous nephrolithotomy (PNL)

The objective of this prospective observational study was to assess the clinical significance of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR) as potential biomarkers to identify post-PNL SIRS or sepsis. Demographic data and laboratory data including hemoglobin (Hb), total leucocyte count (TLC), serum creatinine, urine microscopy and culture were collected. The NLR, LMR and PLR were calculated by the mathematical division of their absolute values derived from routine complete blood counts from peripheral blood samples. Stone factors were assessed by non-contrast computerized tomography of kidneys, ureter and bladder (NCCT KUB) and included stone burden (Volume = L x W x D x pi x 0.167), location and Hounsfield value and laterality. Intraoperative factors assessed were puncture site, tract size, tract number, operative time, the need for blood transfusion and stone clearance. Of 517 patients evaluated, 56 (10.8%) developed SIRS and 8 (1.5%) developed sepsis. Patients developing SIRS had significantly higher TLC (10.4 +/- 3.5 vs 8.6 +/- 2.6, OR 1.19, 95% CI 1.09-1.3, p = 0.000002), higher NLR (3.6 +/- 2.4 vs 2.5 +/- 1.04, OR 1.3, 95% CI = 1.09-1.5, p = 0.0000001), higher PLR (129.3 +/- 53.8 vs 115.4 +/- 68.9, OR 1.005, 95% CI 1.001-1.008, p = 0.005) and lower LMR (2.5 +/- 1.7 vs 3.2 +/- 1.8, OR 1.18, 95% CI 1.04-1.34, p = 0.006). Staghorn stones (12.8 vs 3.24%, OR 4.361, 95% CI 1.605-11.846, p = 0.008) and long operative times (59.6 +/- 14.01 vs 55.2 +/- 16.02, OR 1.01, 95% CI 1.00-1.03, p = 0.05) had significant association with postoperative SIRS. In conclusion, NLR, PLR and LMR can be useful independent, easily accessible and cost-effective predictors for early identification of post-PNL SIRS/sepsis.Manipal Academy of Higher Education, Manipa

Thawing Versus. Tracker Behaviour: Observational Evidence

Currently there is a variety of scalar field models to explain the late time acceleration of the Universe. This includes the standard canonical and non-canonical scalar field models together with recently proposed Galileon scalar field models. One can divide all these scalar field models into two broad categories, namely the thawing and the tracker class. In this work we investigate the evidence for these models with the presently available observational data using the Bayesian approach. We use the Generalized Chaplygin Gas (GCG) parametrization for dark energy equation of state (EoS) as it gives rise to both the thawing and tracking behaviours for different values of the parameters. Analysis of the observational data does not give any clear evidence for either thawing or tracking behaviour within the context of background cosmology, However, if we consider the evolution of inhomogenities and analyze the data in this context then there is a significant evidence in favour of thawing behaviour.Comment: 6 Pages, three eps figures, new material added, new references added. Conclusion changed. Accepted for publication MNRA

Biocompatibility of chitosan carriers with application in drug delivery

Chitosan is one of the most used polysaccharides in the design of drug delivery strategies for administration of either biomacromolecules or low molecular weight drugs. For these purposes, it is frequently used as matrix forming material in both nano and micron-sized particles. In addition to its interesting physicochemical and biopharmaceutical properties, which include high mucoadhesion and a great capacity to produce drug delivery systems, ensuring the biocompatibility of the drug delivery vehicles is a highly relevant issue. Nevertheless, this subject is not addressed as frequently as desired and even though the application of chitosan carriers has been widely explored, the demonstration of systems biocompatibility is still in its infancy. In this review, addressing the biocompatibility of chitosan carriers with application in drug delivery is discussed and the methods used in vitro and in vivo, exploring the effect of different variables, are described. We further provide a discussion on the pros and cons of used methodologies, as well as on the difficulties arising from the absence of standardization of procedures