Baryon charge from embedding topology and a continuous meson spectrum in a new holographic gauge theory

We study a new holographic gauge theory based on probe D4-branes in the background dual to D4-branes on a circle with antiperiodic boundary conditions for fermions. Field theory configurations with baryons correspond to smooth embeddings of the probe D4-branes with nontrivial winding around an S^4 in the geometry. As a consequence, physics of baryons and nuclei can be studied reliably in this model using the abelian Born-Infeld action. However, surprisingly, we find that the meson spectrum is not discrete. This is related to a curious result that the action governing small fluctuations of the gauge field on the probe brane is the five-dimensional Maxwell action in Minkowski space despite the non-trivial embedding of the probe brane in the curved background geometry.Comment: 24 pages, LaTeX, 10 figures, v4: previously ignored effects of coupling to RR-fields included, meson spectrum qualitatively changed, v5: journal versio

Black Hole Dynamics From Atmospheric Science

In this note, we derive (to third order in derivatives of the fluid velocity) a 2+1 dimensional theory of fluid dynamics that governs the evolution of generic long-wavelength perturbations of a black brane or large black hole in four-dimensional gravity with negative cosmological constant, applying a systematic procedure developed recently by Bhattacharyya, Hubeny, Minwalla, and Rangamani. In the regime of validity of the fluid-dynamical description, the black-brane evolution will generically correspond to a turbulent flow. Turbulence in 2+1 dimensions has been well studied analytically, numerically, experimentally, and observationally as it provides a first approximation to the large scale dynamics of planetary atmospheres. These studies reveal dramatic differences between fluid flows in 2+1 and 3+1 dimensions, suggesting that the dynamics of perturbed four and five dimensional large AdS black holes may be qualitatively different. However, further investigation is required to understand whether these qualitative differences exist in the regime of fluid dynamics relevant to black hole dynamics.Comment: 16 pages, LaTeX, v2: caveat regarding relativistic vs non-relativistic fluids added v3: typos correcte

RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation

Interleukin 7 (IL-7) promotes pre–B cell survival and proliferation by activating the Pim1 and Akt kinases. These signals must be attenuated to induce G1 cell cycle arrest and expression of the RAG endonuclease, which are both required for IgL chain gene rearrangement. As lost IL-7 signals would limit pre–B cell survival, how cells survive during IgL chain gene rearrangement remains unclear. We show that RAG-induced DNA double-strand breaks (DSBs) generated during IgL chain gene assembly paradoxically promote pre–B cell survival. This occurs through the ATM-dependent induction of Pim2 kinase expression. Similar to Pim1, Pim2 phosphorylates BAD, which antagonizes the pro-apoptotic function of BAX. However, unlike IL-7 induction of Pim1, RAG DSB-mediated induction of Pim2 does not drive proliferation. Rather, Pim2 has antiproliferative functions that prevent the transit of pre–B cells harboring RAG DSBs from G1 into S phase, where these DNA breaks could be aberrantly repaired. Thus, signals from IL-7 and RAG DSBs activate distinct Pim kinase family members that have context-dependent activities in regulating pre–B cell proliferation and survival

Towards A Holographic Model of Color Superconductivity

In this note, we discuss the basic elements that should appear in a gravitational system dual to a confining gauge theory displaying color superconductivity at large baryon density. We consider a simple system with these minimal elements, and show that for a range of parameters, the phase structure of this model as a function of temperature and baryon chemical potential exhibits phases that can be identified with confined, deconfined, and color superconducting phases in the dual field theory. We find that the critical temperature at which the superconducting phase disappears is remarkably small (relative to the chemical potential). This small number arises from the dynamics, and is unrelated to any small parameter in the model that we study. We discuss similar models which exhibit flavor superconductivity.Comment: 34 pages, 14 figure

Potential role of differential medication use in explaining excess risk of cardiovascular events and death associated with chronic kidney disease: A cohort study

<p>Abstract</p> <p>Background</p> <p>Patients with chronic kidney disease (CKD) are less likely to receive cardiovascular medications. It is unclear whether differential cardiovascular drug use explains, in part, the excess risk of cardiovascular events and death in patients with CKD and coronary heart disease (CHD).</p> <p>Methods</p> <p>The ADVANCE Study enrolled patients with new onset CHD (2001-2003) who did (N = 159) or did not have (N = 1088) CKD at entry. The MDRD equation was used to estimate glomerular filtration rate (eGFR) using calibrated serum creatinine measurements. Patient characteristics, medication use, cardiovascular events and death were ascertained from self-report and health plan electronic databases through December 2008.</p> <p>Results</p> <p>Post-CHD event ACE inhibitor use was lower (medication possession ratio 0.50 vs. 0.58, P = 0.03) and calcium channel blocker use higher (0.47 vs. 0.38, P = 0.06) in CKD vs. non-CKD patients, respectively. Incidence of cardiovascular events and death was higher in CKD vs. non-CKD patients (13.9 vs. 11.5 per 100 person-years, P < 0.001, respectively). After adjustment for patient characteristics, the rate of cardiovascular events and death was increased for eGFR 45-59 ml/min/1.73 m²(hazard ratio [HR] 1.47, 95% CI: 1.10 to 2.02) and eGFR < 45 ml/min/1.73 m²(HR 1.58, 95% CI: 1.00 to 2.50). After further adjustment for statins, β-blocker, calcium channel blocker, ACE inhibitor/ARB use, the association was no longer significant for eGFR 45-59 ml/min/1.73 m²(HR 0.82, 95% CI: 0.25 to 2.66) or for eGFR < 45 ml/min/1.73 m²(HR 1.19, 95% CI: 0.25 to 5.58).</p> <p>Conclusions</p> <p>In adults with CHD, differential use of cardiovascular medications may contribute to the higher risk of cardiovascular events and death in patients with CKD.</p

Development of Sensory, Motor and Behavioral Deficits in the Murine Model of Sanfilippo Syndrome Type B

BACKGROUND: Mucopolysaccharidosis (MPS) IIIB (Sanfilippo Syndrome type B) is caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop disturbances of sleep, activity levels, coordination, vision, hearing, and mental functioning culminating in early death. The murine model of MPS IIIB demonstrates lysosomal distention in multiple tissues, a shortened life span, and behavioral changes. PRINCIPAL FINDINGS: To more thoroughly assess MPS IIIB in mice, alterations in circadian rhythm, activity level, motor function, vision, and hearing were tested. The suprachiasmatic nucleus (SCN) developed pathologic changes and locomotor analysis showed that MPS IIIB mice start their daily activity later and have a lower proportion of activity during the night than wild-type controls. Rotarod assessment of motor function revealed a progressive inability to coordinate movement in a rocking paradigm. Purkinje cell counts were significantly reduced in the MPS IIIB animals compared to age matched controls. By electroretinography (ERG), MPS IIIB mice had a progressive decrease in the amplitude of the dark-adapted b-wave response. Corresponding pathology revealed shortening of the outer segments, thinning of the outer nuclear layer, and inclusions in the retinal pigmented epithelium. Auditory-evoked brainstem responses (ABR) demonstrated progressive hearing deficits consistent with the observed loss of hair cells in the inner ear and histologic abnormalities in the middle ear. CONCLUSIONS/SIGNIFICANCE: The mouse model of MPS IIIB has several quantifiable phenotypic alterations and is similar to the human disease. These physiologic and histologic changes provide insights into the progression of this disease and will serve as important parameters when evaluating various therapies

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats

Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine

Inappropriate activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is common in cancer and has many cellular consequences including elevated endoplasmic reticulum (ER) stress. Cells employ autophagy as a critical compensatory survival mechanism during ER stress. This study utilised drug-induced ER stress through nelfinavir in order to examine ER stress tolerance in cell lines with hyper-active mTORC1 signalling. Our initial findings in wild type cells showed nelfinavir inhibited mTORC1 signalling and upregulated autophagy, as determined by decreased rpS6 and S6K1 phosphorylation, and SQTSM1 protein expression, respectively. Contrastingly, cells with hyper-active mTORC1 displayed basally elevated levels of ER stress which was greatly exaggerated following nelfinavir treatment, seen through increased CHOP mRNA and XBP1 splicing. To further enhance the effects of nelfinavir, we introduced chloroquine as an autophagy inhibitor. Combination of nelfinavir and chloroquine significantly increased ER stress and caused selective cell death in multiple cell line models with hyper-active mTORC1, whilst control cells with normalised mTORC1 signalling tolerated treatment. By comparing chloroquine to other autophagy inhibitors, we uncovered that selective toxicity invoked by chloroquine was independent of autophagy inhibition yet entrapment of chloroquine to acidified lysosomal/endosomal compartments was necessary for cytotoxicity. Our research demonstrates that combination of nelfinavir and chloroquine has therapeutic potential for treatment of mTORC1-driven tumours

APC15 drives the turnover of MCC-CDC20 to make the spindle assembly checkpoint responsive to kinetochore attachment

Faithful chromosome segregation during mitosis depends on the Spindle Assembly Checkpoint (SAC) that monitors kinetochore attachment to the mitotic spindle. Unattached kinetochores generate mitotic checkpoint proteins complexes (MCCs) that bind and inhibit the Anaphase Promoting Complex/Cyclosome (APC/C). How the SAC proficiently inhibits the APC/C but still allows its rapid activation when the last kinetochore attaches to the spindle is important to understand how cells maintain genomic stability. We show that the APC/C subunit APC15 is required for the turnover of the APC/C co-activator Cdc20 and release of MCCs during SAC signalling but not for APC/C activity per se. In the absence of APC15, MCCs and ubiquitylated Cdc20 remain ‘locked’ onto the APC/C, which prevents the ubiquitylation and degradation of Cyclin B1 when the SAC is satisfied. We conclude that APC15 mediates the constant turnover of Cdc20 and MCCs on the APC/C to allow the SAC to respond to the attachment state of kinetochores