Goat uromodulin promoter directs kidney-specific expression of GFP gene in transgenic mice

BACKGROUND: Uromodulin is the most abundant protein found in the urine of mammals. In an effort to utilize the uromodulin promoter in order to target recombinant proteins in the urine of transgenic animals we have cloned a goat uromodulin gene promoter fragment (GUM promoter) and used it to drive expression of GFP in the kidney of transgenic mice. RESULTS: The GUM-GFP cassette was constructed and transgenic mice were generated in order to study the promoter's tissue specificity, the GFP kidney specific expression and its subcellular distribution. Tissues collected from three GUM-GFP transgenic mouse lines, and analyzed for the presence of GFP by Western blotting and fluorescence confirmed that the GUM promoter drove expression of GFP specifically in the kidney. More specifically, by using immuno-histochemistry analysis of kidney sections, we demonstrated that GFP expression was co-localized, with endogenous uromodulin protein, in the epithelial cells of the thick ascending limbs (TAL) of Henle's loop and the early distal convoluted tubule in the kidney. CONCLUSION: The goat uromodulin promoter is capable of driving recombinant protein expression in the kidney of transgenic mice. The goat promoter fragment cloned may be a useful tool in targeting proteins or oncogenes in the kidney of mammals

From coordination to stochastic models of QoS

Reo is a channel-based coordination model whose operational semantics is given by Constraint Automata (CA). Quantitative Constraint Automat

Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity

Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers

Pathological Narcissism in Adolescents: Relationships with Childhood Maltreatment and Internalizing and Externalizing Difficulties

Background: There are significant gaps in our understanding of vulnerable and grandiose narcissism in adolescents and whether it is associated with psychosocial difficulties as well as risk factors such as child maltreatment. Objective: The aim of this study was to examine vulnerable and grandiose narcissism in adolescents and young adults. Method: 570 participants (ages 14-21) from the community completed an online survey. Vulnerable and grandiose narcissism were assessed with the Pathological Narcissism Inventory, while psycho-social difficulties were assessed with the Child Behaviour Checklist and maltreatment with the Childhood Experiences of Care and Abuse Questionnaire. Results: Gender-specific age trends were identified, with narcissism appearing to decrease with age for females, while increasing for males into early adulthood. For females, vulnerable and grandiose narcissism was associated with maltreatment and partially mediated the relationship between abuse and neglect and internalizing and externalizing difficulties. Conclusion: These findings underscore the importance of considering the relationship between childhood maltreatment experiences and suggest that the relationship between such experiences and adolescent psychosocial difficulties may be partially accounted for by the negative impact that maltreatment has on narcissism

Optimising observing strategies for monitoring animals using drone-mounted thermal infrared cameras

The proliferation of relatively affordable off-the-shelf drones offers great opportunities for wildlife monitoring and conservation. Similarly the recent reduction in cost of thermal infrared cameras also offers new promise in this field, as they have the advantage over conventional RGB cameras of being able to distinguish animals based on their body heat and being able to detect animals at night. However, the use of drone-mounted thermal infrared cameras comes with several technical challenges. In this paper we address some of these issues, namely thermal contrast problems due to heat from the ground, absorption and emission of thermal infrared radiation by the atmosphere, obscuration by vegetation, and optimizing the flying height of drones for a best balance between covering a large area and being able to accurately image and identify animals of interest. We demonstrate the application of these methods with a case study using field data, and make the first ever detection of the critically endangered riverine rabbit (Bunolagus monticularis) in thermal infrared data. We provide a web-tool so that the community can easily apply these techniques to other studies (http://www.astro.ljmu.ac.uk/~aricburk/uav_calc/)

Factors that contribute to social media influence within an Internal Medicine Twitter learning community

Medical societies, faculty, and trainees use Twitter to learn from and educate other social media users. These social media communities bring together individuals with various levels of experience. It is not known if experienced individuals are also the most influential members. We hypothesize that participants with the greatest experience would be the most influential members of a Twitter community. We analyzed the 2013 Association of Program Directors in Internal Medicine Twitter community. We measured the number of tweets authored by each participant and the number of amplified tweets (re-tweets). We developed a multivariate linear regression model to identify any relationship to social media influence, measured by the PageRank. Faculty (from academic institutions) comprised 19% of the 132 participants in the learning community (p < 0.0001). Faculty authored 49% of all 867 tweets (p < 0.0001). Their tweets were the most likely to be amplified (52%, p < 0.01). Faculty had the greatest influence amongst all participants (mean 1.99, p < 0.0001). Being a faculty member had no predictive effect on influence (β = 0.068, p = 0.6). The only factors that predicted influence (higher PageRank) were the number of tweets authored (p < 0.0001) and number of tweets amplified (p < 0.0001) The status of “faculty member� did not confer a greater influence. Any participant who was able to author the greatest number of tweets or have more of his/her tweets amplified could wield a greater influence on the participants, regardless of his/her authority

Translational evidence for two distinct patterns of neuroaxonal injury in sepsis: a longitudinal, prospective translational study

Background Brain homeostasis deteriorates in sepsis, giving rise to a mostly reversible sepsis-associated encephalopathy (SAE). Some survivors experience chronic cognitive dysfunction thought to be caused by permanent brain injury. In this study, we investigated neuroaxonal pathology in sepsis. Methods We conducted a longitudinal, prospective translational study involving (1) experimental sepsis in an animal model; (2) postmortem studies of brain from patients with sepsis; and (3) a prospective, longitudinal human sepsis cohort study at university laboratory and intensive care units (ICUs). Thirteen ICU patients with septic shock, five ICU patients who died as a result of sepsis, fourteen fluid-resuscitated Wistar rats with fecal peritonitis, eleven sham-operated rats, and three human and four rat control subjects were included. Immunohistologic and protein biomarker analysis were performed on rat brain tissue at baseline and 24, 48, and 72 h after sepsis induction and in sham-treated rats. Immunohistochemistry was performed on human brain tissue from sepsis nonsurvivors and in control patients without sepsis. The clinical diagnostics of SAE comprised longitudinal clinical data collection and magnetic resonance imaging (MRI) and electroencephalographic assessments. Statistical analyses were performed using SAS software (version 9.4; SAS Institute, Inc., Cary, NC, USA). Because of non-Gaussian distribution, the nonparametric Wilcoxon test general linear models and the Spearman correlation coefficient were used. Results In postmortem rat and human brain samples, neurofilament phosphoform, β-amyloid precursor protein, β-tubulin, and H&E stains distinguished scattered ischemic lesions from diffuse neuroaxonal injury in septic animals, which were absent in controls. These two patterns of neuroaxonal damage were consistently found in septic but not control human postmortem brains. In experimental sepsis, the time from sepsis onset correlated with tissue neurofilament levels (R = 0.53, p = 0.045) but not glial fibrillary acidic protein. Of 13 patients with sepsis who had clinical features of SAE, MRI detected diffuse axonal injury in 9 and ischemia in 3 patients. Conclusions Ischemic and diffuse neuroaxonal injury to the brain in experimental sepsis, human postmortem brains, and in vivo MRI suggest these two distinct lesion types to be relevant. Future studies should be focused on body fluid biomarkers to detect and monitor brain injury in sepsis. The relationship of neurofilament levels with time from sepsis onset may be of prognostic value

Direct Binding of pRb/E2F-2 to GATA-1 Regulates Maturation and Terminal Cell Division during Erythropoiesis

Cell differentiation is often coupled with cell cycle arrest. Here, we show that direct binding of the erythroid transcription factor GATA-1 to the retinoblastoma protein and the pRb/E2F transcription factor complex is critical for red blood cell formation

Partition function zeros for the Ising model on complete graphs and on annealed scale-free networks

We analyze the partition function of the Ising model on graphs of two different types: complete graphs, wherein all nodes are mutually linked and annealed scale-free networks for which the degree distribution decays as $P(k)\sim k^{-\lambda}$. We are interested in zeros of the partition function in the cases of complex temperature or complex external field (Fisher and Lee-Yang zeros respectively). For the model on an annealed scale-free network, we find an integral representation for the partition function which, in the case $\lambda > 5$, reproduces the zeros for the Ising model on a complete graph. For $3<\lambda < 5$ we derive the $\lambda$-dependent angle at which the Fisher zeros impact onto the real temperature axis. This, in turn, gives access to the $\lambda$-dependent universal values of the critical exponents and critical amplitudes ratios. Our analysis of the Lee-Yang zeros reveals a difference in their behaviour for the Ising model on a complete graph and on an annealed scale-free network when $3<\lambda <5$. Whereas in the former case the zeros are purely imaginary, they have a non zero real part in latter case, so that the celebrated Lee-Yang circle theorem is violated.Comment: 36 pages, 31 figure

Beyond traditional surveillance: applying syndromic surveillance to developing settings – opportunities and challenges

<p>Abstract</p> <p>Background</p> <p>All countries need effective disease surveillance systems for early detection of outbreaks. The revised International Health Regulations [IHR], which entered into force for all 194 World Health Organization member states in 2007, have expanded traditional infectious disease notification to include surveillance for public health events of potential international importance, even if the causative agent is not yet known. However, there are no clearly established guidelines for how countries should conduct this surveillance, which types of emerging disease syndromes should be reported, nor any means for enforcement.</p> <p>Discussion</p> <p>The commonly established concept of syndromic surveillance in developed regions encompasses the use of pre-diagnostic information in a near real time fashion for further investigation for public health action. Syndromic surveillance is widely used in North America and Europe, and is typically thought of as a highly complex, technology driven automated tool for early detection of outbreaks. Nonetheless, low technology applications of syndromic surveillance are being used worldwide to augment traditional surveillance.</p> <p>Summary</p> <p>In this paper, we review examples of these novel applications in the detection of vector-borne diseases, foodborne illness, and sexually transmitted infections. We hope to demonstrate that syndromic surveillance in its basic version is a feasible and effective tool for surveillance in developing countries and may facilitate compliance with the new IHR guidelines.</p