THE RELATION BETWEEN REGRESSION COEFFICIENTS IN A MULTIPLE-REGRESSION ANALYSIS

In a multiple-regression analysis it is often necessary to assign a value, different from the least-squares value, to one or more of the regression coefficients. A simple method is described which eliminates the matrix algebra which, in such cases, is usually necessary in order to re-evaluate the remaining coeffcients, together with the associated variances and covariancesThe method is generalized to give an equally simple procedure for testing possible linear relations among the regression coefficients. (auth

Therapeutic efficacy of anti-MMP9 antibody in combination with nab-paclitaxel-based chemotherapy in pre-clinical models of pancreatic cancer

Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti-MMP9 antibody (αMMP9) was evaluated in combination with nab-paclitaxel (NPT)-based standard cytotoxic therapy in pre-clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA-Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2-week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six-week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti-MMP9 antibody increased the levels of tumour-associated IL-28 (1.5-fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti-MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti-MMP9 antibody can exert specific stroma-directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy

Elucidation of the RamA Regulon in Klebsiella pneumoniae Reveals a Role in LPS Regulation

Klebsiella pneumoniae is a significant human pathogen, in part due to high rates of multidrug resistance. RamA is an intrinsic regulator in K. pneumoniae established to be important for the bacterial response to antimicrobial challenge; however, little is known about its possible wider regulatory role in this organism during infection. In this work, we demonstrate that RamA is a global transcriptional regulator that significantly perturbs the transcriptional landscape of K. pneumoniae, resulting in altered microbe-drug or microbe-host response. This is largely due to the direct regulation of 68 genes associated with a myriad of cellular functions. Importantly, RamA directly binds and activates the lpxC, lpxL-2 and lpxO genes associated with lipid A biosynthesis, thus resulting in modifications within the lipid A moiety of the lipopolysaccharide. RamA-mediated alterations decrease susceptibility to colistin E, polymyxin B and human cationic antimicrobial peptide LL-37. Increased RamA levels reduce K. pneumoniae adhesion and uptake into macrophages, which is supported by in vivo infection studies, that demonstrate increased systemic dissemination of ramA overexpressing K. pneumoniae. These data establish that RamA-mediated regulation directly perturbs microbial surface properties, including lipid A biosynthesis, which facilitate evasion from the innate host response. This highlights RamA as a global regulator that confers pathoadaptive phenotypes with implications for our understanding of the pathogenesis of Enterobacter, Salmonella and Citrobacter spp. that express orthologous RamA proteins

Lipid Oxidation and Sensory Characteristics of Grass-Fed Beef: Effect of Duration of Grazing Prior to Slaughter

Beef from cattle produced from grass has a higher concentration of fatty acids considered to be beneficial to human health than beef produced from more intensive production systems and this increase in fatty acid concentration is dependant on the duration at pasture prior to slaughter (Noci et al., 2003). Improvements in the fatty acid composition of beef must not impair other quality characteristics of beef. Little information is available on the pattern of change of quality characteristics in grazing animals. The objective of this study was to determine the shelf-life and eating quality of beef from cattle produced from a standard Irish grass silage/concentrates finishing system but allowed to graze grass for different periods prior to slaughter

Facing Up to Unpalatable Evidence for the Sake of Our Patients

Paul Mullen discusses Seena Fazel and colleagues' paper on the association between violent behavior and having been diagnosed with a schizophrenic disorder, and its implications for care of these individuals

Long-term stability of RNA in post-mortem bovine skeletal muscle, liver and subcutaneous adipose tissues

peer-reviewedBackground: Recovering high quality intact RNA from post-mortem tissue is of major concern for gene expression studies in animals and humans. Since the availability of post-mortem tissue is often associated with substantial delay, it is important that we understand the temporal variation in the stability of total RNA and of individual gene transcripts so as to be able to appropriately interpret the data generated from such studies. Hence, the objective of this experiment was to qualitatively and quantitatively assess the integrity of total and messenger RNA extracted from bovine skeletal muscle, subcutaneous adipose tissue and liver stored at 4°C at a range of time points up to 22 days post-mortem. These conditions were designed to mimic the environment prevailing during the transport of beef from the abattoir to retail outlets. Results: The 28S and 18S rRNA molecules of total RNA were intact for up to 24 h post-mortem in liver and adipose tissues and up to 8 days post-mortem in skeletal muscle. The mRNA of housekeeping genes (GAPDH and ACTB) and two diet-related genes (RBP5 and SCD) were detectable up to 22 days post-mortem in skeletal muscle. While the mRNA stability of the two housekeeping genes was different in skeletal muscle and liver, they were similar to each other in adipose tissue. After 22 days post-mortem, the relative abundance of RBP5 gene was increased in skeletal muscle and in adipose tissue and decreased in liver. During this period, the relative abundance of SCD gene also increased in skeletal muscle whereas it decreased in both adipose tissue and liver. Conclusion: Stability of RNA in three tissues (skeletal muscle, subcutaneous adipose tissue and liver) subjected to long-term post-mortem storage at refrigeration temperature indicated that skeletal muscle can be a suitable tissue for recovering biologically useful RNA for gene expression studies even if the tissue is subjected to post-mortem storage for weeks, whereas adipose tissue and liver should be processed within 24 hours post-mortem.This research was part funded by the Irish Government under the National Development Plan 2000-2006. Support to BB under the Walsh Fellowship Programme of Teagasc is acknowledged

The weak password problem: chaos, criticality, and encrypted p-CAPTCHAs

Vulnerabilities related to weak passwords are a pressing global economic and security issue. We report a novel, simple, and effective approach to address the weak password problem. Building upon chaotic dynamics, criticality at phase transitions, CAPTCHA recognition, and computational round-off errors we design an algorithm that strengthens security of passwords. The core idea of our method is to split a long and secure password into two components. The first component is memorized by the user. The second component is transformed into a CAPTCHA image and then protected using evolution of a two-dimensional dynamical system close to a phase transition, in such a way that standard brute-force attacks become ineffective. We expect our approach to have wide applications for authentication and encryption technologies.Comment: 5 pages, 6 figer

Prediction of agreement and phonetic overlap shape sublexical identification

First Published May 30, 2016The mapping between the physical speech signal and our internal representations is rarely straightforward. When faced with uncertainty, higher-order information is used to parse the signal and because of this, the lexicon and some aspects of sentential context have been shown to modulate the identification of ambiguous phonetic segments. Here, using a phoneme identification task (i.e., participants judged whether they heard [o] or [a] at the end of an adjective in a noun–adjective sequence), we asked whether grammatical gender cues influence phonetic identification and if this influence is shaped by the phonetic properties of the agreeing elements. In three experiments, we show that phrase-level gender agreement in Spanish affects the identification of ambiguous adjective-final vowels. Moreover, this effect is strongest when the phonetic characteristics of the element triggering agreement and the phonetic form of the agreeing element are identical. Our data are consistent with models wherein listeners generate specific predictions based on the interplay of underlying morphosyntactic knowledge and surface phonetic cues.Andrea E. Martin was supported by Juan de la Cierva Fellowship [JCI-2011-10228] from the Spanish Ministry of Science and Innovation, and by Future Research Leaders grant from the Economic and Social Research Council of the United Kingdom [ES/K009095/1]; Philip J. Monahan was supported by Marie Curie Fellowship from the European Research Council [FP7-People-2010-IIF; Project No. 275751] and by the Social Sciences and Humanities Research Council of Canada. This work was also supported by grants, PSI2010-17781 and PSI2014-53277 from the Spanish Ministerio de Economia y Competividad. Additional support was provided by Ministerio de Ciencia E Innovacion Grant #PSI2014-53277 and by Ayuda Centro de Excelencia Severo Ochoa SEV-2015-0490 to the BCBL