Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α

Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al

Simulating the exchange of Majorana zero modes with a photonic system

The realization of Majorana zero modes is in the centre of intense theoretical and experimental investigations. Unfortunately, their exchange that can reveal their exotic statistics needs manipulations that are still beyond our experimental capabilities. Here we take an alternative approach. Through the Jordan-Wigner transformation, the Kitaev's chain supporting two Majorana zero modes is mapped to the spin-1/2 chain. We experimentally simulated the spin system and its evolution with a photonic quantum simulator. This allows us to probe the geometric phase, which corresponds to the exchange of two Majorana zero modes positioned at the ends of a three-site chain. Finally, we demonstrate the immunity of quantum information encoded in the Majorana zero modes against local errors through the simulator. Our photonic simulator opens the way for the efficient realization and manipulation of Majorana zero modes in complex architectures

Logistics service provider selection for disaster preparation: a socio-technical systems perspective

Since 1990s, the world has seen a lot of advances in providing humanitarian aid through sophisticated logistics operations. The current consensus seems to be that humanitarian relief organizations (HROs) can improve their relief operations by collaborating with logistics service providers (CLSPs) in the commercial sector. The question remains: how can HROs select the most appropriate CLSP for disaster preparation? Despite its practical significance, no explicit effort has been done to identify the criteria/factors in prioritising and selecting a CLSP for disaster relief. The present study aims to address this gap by consolidating the list of criteria from a socio-technical systems (STS) perspective. Then, to handle the interdependence among the criteria derived from the STS, we develop a hybrid multi-criteria decision making model for CLSP selection in the disaster preparedness stage. The proposed model is then evaluated by a real-life case study, providing insights into the decision-makers in both HROs and CLSPs

Superior antigen-specific CD4+ T-cell response with AS03-adjuvantation of a trivalent influenza vaccine in a randomised trial of adults aged 65 and older

BACKGROUND: The effectiveness of trivalent influenza vaccines may be reduced in older versus younger adults because of age-related immunosenescence. The use of an adjuvant in such a vaccine is one strategy that may combat immunosenescence, potentially by bolstering T-cell mediated responses. METHODS: This observer-blind study, conducted in the United States (US) and Spain during the 2008-2009 influenza season, evaluated the effect of Adjuvant System AS03 on specific T-cell responses to a seasonal trivalent influenza vaccine (TIV) in >/=65 year-old adults.Medically-stable adults aged >/=65 years were randomly allocated to receive a single dose of AS03-adjuvanted TIV (TIV/AS03) or TIV. Healthy adults aged 18-40 years received only TIV. Blood samples were collected on Day 0, Day 21, Day 42 and Day 180. Influenza-specific CD4+ T cells, defined by the induction of the immune markers CD40L, IL-2, IFN-gamma, or TNF-alpha, were measured in ex vivo cultures of antigen-stimulated peripheral blood mononuclear cells. RESULTS: A total of 192 adults were vaccinated: sixty nine and seventy three >/=65 year olds received TIV/AS03 and TIV, respectively; and fifty 18 - 40 year olds received TIV. In the >/=65 year-old group on Day 21, the frequency of CD4+ T cells specific to the three vaccine strains was superior in the TIV/AS03 recipients to the frequency in TIV (p /=65 year-old recipients of TIV/AS03 than in the 18 - 40 year old recipients of TIV on Days 21 (p = 0.006) and 42 (p = 0.011). CONCLUSION: This positive effect of AS03 Adjuvant System on the CD4+ T-cell response to influenza vaccine strains in older adults could confer benefit in protection against clinical influenza disease in this population. TRIAL REGISTRATION: (Clinicaltrials.gov.). NCT00765076

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

A Scalable, Incoherent-Light-Powered, Omnidirectional Self-Oscillator

Peer reviewe

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The Flagellar Transcriptional Regulator FtcR Controls Brucella melitensis 16M Biofilm Formation via a betI-Mediated Pathway in Response to Hyperosmotic Stress

The expression of flagellar proteins in Brucella species likely evolved through genetic transference from other microorganisms, and contributed to virulence, adaptability, and biofilm formation. Despite significant progress in defining the molecular mechanisms behind flagellar gene expression, the genetic program controlling biofilm formation remains unclear. The flagellar transcriptional factor (FtcR) is a master regulator of the flagellar system’s expression, and is critical for B. melitensis 16M’s flagellar biogenesis and virulence. Here, we demonstrate that FtcR mediates biofilm formation under hyperosmotic stress. Chromatin immunoprecipitation with next-generation sequencing for FtcR and RNA sequencing of ftcR-mutant and wild-type strains revealed a core set of FtcR target genes. We identified a novel FtcR-binding site in the promoter region of the osmotic-stress-response regulator gene betI, which is important for the survival of B. melitensis 16M under hyperosmotic stress. Strikingly, this site autoregulates its expression to benefit biofilm bacteria’s survival under hyperosmotic stress. Moreover, biofilm reduction in ftcR mutants is independent of the flagellar target gene fliF. Collectively, our study provides new insights into the extent and functionality of flagellar-related transcriptional networks in biofilm formation, and presents phenotypic and evolutionary adaptations that alter the regulation of B. melitensis 16M to confer increased tolerance to hyperosmotic stress

Molecular Detection of Zoonotic and Veterinary Pathogenic Bacteria in Pet Dogs and Their Parasitizing Ticks in Junggar Basin, North-Western China

Despite the recognized epidemiological importance of ticks as vectors for pathogens that cause numerous zoonotic and veterinary diseases, data regarding the pathogens of pet dogs and their parasitic ticks in the Junggar Basin are scarce. In this study, a total of 178 blood samples and 436 parasitic ticks were collected from pet dogs in Junggar Basin, Xinjiang Uygur Autonomous Region (XUAR), north-western China. All ticks were identified as Rhipicephalus turanicus sensu stricto (s.s.) according to morphological and molecular characteristics. Rh. turanicus s.s. ticks were collected from pet dogs in China for the first time. Seven tick-borne pathogens, such as Ehrlichia chaffeensis, Anaplasma phagocytophilum, Rickettsia massiliae, Candidatus R. barbariae, Brucella spp., Rickettsia sibirica, and Anaplasma ovis, were detected from ticks, whereas the first five bacteria were detected from blood samples of dogs. Brucella spp. was the most predominant pathogen in both blood samples and ticks of pet dogs, with the detection rates of 16.29 and 16.74%, respectively. Moreover, 17 ticks and 1 blood sample were co-infected with two pathogens, and 1 tick was co-infected with three pathogens. This study provided molecular evidence for the occurrence of Anaplasma spp., Ehrlichia spp., Rickettsia spp., and Brucella spp. circulating in pet dogs and their parasitic ticks in Junggar Basin, north-western China. These findings extend our knowledge of the tick-borne pathogens in pet dogs and their parasitic ticks in Central Asia; therefore, further research on these pathogens and their role in human and animal diseases is required

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention