Exotic Differentiable Structures and General Relativity

We review recent developments in differential topology with special concern for their possible significance to physical theories, especially general relativity. In particular we are concerned here with the discovery of the existence of non-standard (``fake'' or ``exotic'') differentiable structures on topologically simple manifolds such as $S^7$, \R and $S^3\times {\bf R^1}.$ Because of the technical difficulties involved in the smooth case, we begin with an easily understood toy example looking at the role which the choice of complex structures plays in the formulation of two-dimensional vacuum electrostatics. We then briefly review the mathematical formalisms involved with differentiable structures on topological manifolds, diffeomorphisms and their significance for physics. We summarize the important work of Milnor, Freedman, Donaldson, and others in developing exotic differentiable structures on well known topological manifolds. Finally, we discuss some of the geometric implications of these results and propose some conjectures on possible physical implications of these new manifolds which have never before been considered as physical models.Comment: 11 pages, LaTe

Modulation of Kv Channel Expression and Function by TCR and Costimulatory Signals during Peripheral CD4+ Lymphocyte Differentiation

Ionic signaling pathways, including voltage-dependent potassium (Kv) channels, are instrumental in antigen-mediated responses of peripheral T cells. However, how Kv channels cooperate with other signaling pathways involved in T cell activation and differentiation is unknown. We report that multiple Kv channels are expressed by naive CD4+ lymphocytes, and that the current amplitude and kinetics are modulated by antigen receptor–mediated stimulation and costimulatory signals. Currents expressed in naive CD4+ lymphocytes are consistent with Kv1.1, Kv1.2, Kv1.3, and Kv1.6. Effector CD4+ cells generated by optimal TCR and costimulation exhibit only Kv1.3 current, but at approximately sixfold higher levels than naive cells. CD4+ lymphocytes anergized through partial stimulation exhibit similar Kv1.1, Kv1.2, and/or Kv1.6 currents, but approximately threefold more Kv1.3 current than naive cells. To determine if Kv channels contribute to the distinct functions of naive, effector, and anergized T cells, we tested their role in immunoregulatory cytokine production. Each Kv channel is required for maximal IL-2 production by naive CD4+ lymphocytes, whereas none appears to play a role in IL-2, IL-4, or IFN-γ production by effector cells. Interestingly, Kv channels in anergized lymphocytes actively suppress IL-4 production, and these functions are consistent with a role in regulating the membrane potential and calcium signaling

Differential Requirement for SLP-76 Domains in T Cell Development and Function

AbstractThe hematopoietic cell-specific adaptor protein, SLP-76, is critical for T cell development and mature T cell receptor (TCR) signaling; however, the structural requirements of SLP-76 for mediating thymopoiesis and mature T cell function remain largely unknown. In this study, transgenic mice were generated to examine the requirements for specific domains of SLP-76 in thymocytes and peripheral T cells in vivo. Examination of mice expressing various mutants of SLP-76 on the null background demonstrates a differential requirement for specific domains of SLP-76 in thymocytes and T cells and provides new insight into the molecular mechanisms underlying SLP-76 function

Small-Molecule Probes Targeting the Viral PPxY-Host Nedd4 Interface Block Egress of a Broad Range of RNA Viruses.

Budding of filoviruses, arenaviruses, and rhabdoviruses is facilitated by subversion of host proteins, such as Nedd4 E3 ubiquitin ligase, by viral PPxY late (L) budding domains expressed within the matrix proteins of these RNA viruses. As L domains are important for budding and are highly conserved in a wide array of RNA viruses, they represent potential broad-spectrum targets for the development of antiviral drugs. To identify potential competitive blockers, we used the known Nedd4 WW domain-PPxY interaction interface as the basis of an in silico screen. Using PPxY-dependent budding of Marburg (MARV) VP40 virus-like particles (VLPs) as our model system, we identified small-molecule hit 1 that inhibited Nedd4-PPxY interaction and PPxY-dependent budding. This lead candidate was subsequently improved with additional structure-activity relationship (SAR) analog testing which enhanced antibudding activity into the nanomolar range. Current lead compounds 4 and 5 exhibit on-target effects by specifically blocking the MARV VP40 PPxY-host Nedd4 interaction and subsequent PPxY-dependent egress of MARV VP40 VLPs. In addition, lead compounds 4 and 5 exhibited antibudding activity against Ebola and Lassa fever VLPs, as well as vesicular stomatitis and rabies viruses (VSV and RABV, respectively). These data provide target validation and suggest that inhibition of the PPxY-Nedd4 interaction can serve as the basis for the development of a novel class of broad-spectrum, host-oriented antivirals targeting viruses that depend on a functional PPxY L domain for efficient egress. IMPORTANCE: There is an urgent and unmet need for the development of safe and effective therapeutics against biodefense and high-priority pathogens, including filoviruses (Ebola and Marburg) and arenaviruses (e.g., Lassa and Junin) which cause severe hemorrhagic fever syndromes with high mortality rates. We along with others have established that efficient budding of filoviruses, arenaviruses, and other viruses is critically dependent on the subversion of host proteins. As disruption of virus budding would prevent virus dissemination, identification of small-molecule compounds that block these critical viral-host interactions should effectively block disease progression and transmission. Our findings provide validation for targeting these virus-host interactions as we have identified lead inhibitors with broad-spectrum antiviral activity. In addition, such inhibitors might prove useful for newly emerging RNA viruses for which no therapeutics would be available

Relations between plasma microRNAs, echocardiographic markers of atrial remodeling, and atrial fibrillation: Data from the Framingham Offspring study

BACKGROUND: Circulating microRNAs may reflect or influence pathological cardiac remodeling and contribute to atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to identify candidate plasma microRNAs that are associated with echocardiographic phenotypes of atrial remodeling, and incident and prevalent AF in a community-based cohort. METHODS: We analyzed left atrial function index (LAFI) of 1788 Framingham Offspring 8 participants. We quantified expression of 339 plasma microRNAs. We examined associations between microRNA levels with LAFI and prevalent and incident AF. We constructed pathway analysis of microRNAs\u27 predicted gene targets to identify molecular processes involved in adverse atrial remodeling in AF. RESULTS: The mean age of the participants was 66 +/- 9 years, and 54% were women. Five percent of participants had prevalent AF at the initial examination and 9% (n = 157) developed AF over a median 8.6 years of follow-up (IQR 8.1-9.2 years). Plasma microRNAs were associated with LAFI (N = 73, p \u3c 0.0001). Six of these plasma microRNAs were significantly associated with incident AF, including 4 also associated with prevalent AF (microRNAs 106b, 26a-5p, 484, 20a-5p). These microRNAs are predicted to regulate genes involved in cardiac hypertrophy, inflammation, and myocardial fibrosis. CONCLUSIONS: Circulating microRNAs 106b, 26a-5p, 484, 20a-5p are associated with atrial remodeling and AF

The Carnegie Supernova Project: First Near-Infrared Hubble Diagram to z~0.7

The Carnegie Supernova Project (CSP) is designed to measure the luminosity distance for Type Ia supernovae (SNe Ia) as a function of redshift, and to set observational constraints on the dark energy contribution to the total energy content of the Universe. The CSP differs from other projects to date in its goal of providing an I-band {rest-frame} Hubble diagram. Here we present the first results from near-infrared (NIR) observations obtained using the Magellan Baade telescope for SNe Ia with 0.1 < z < 0.7. We combine these results with those from the low-redshift CSP at z <0.1 (Folatelli et al. 2009). We present light curves and an I-band Hubble diagram for this first sample of 35 SNe Ia and we compare these data to 21 new SNe Ia at low redshift. These data support the conclusion that the expansion of the Universe is accelerating. When combined with independent results from baryon acoustic oscillations (Eisenstein et al. 2005), these data yield Omega_m = 0.27 +/- 0.0 (statistical), and Omega_DE = 0.76 +/- 0.13 (statistical) +/- 0.09 (systematic), for the matter and dark energy densities, respectively. If we parameterize the data in terms of an equation of state, w, assume a flat geometry, and combine with baryon acoustic oscillations, we find that w = -1.05 +/- 0.13 (statistical) +/- 0.09 (systematic). The largest source of systematic uncertainty on w arises from uncertainties in the photometric calibration, signaling the importance of securing more accurate photometric calibrations for future supernova cosmology programs. Finally, we conclude that either the dust affecting the luminosities of SNe Ia has a different extinction law (R_V = 1.8) than that in the Milky Way (where R_V = 3.1), or that there is an additional intrinsic color term with luminosity for SNe Ia independent of the decline rate.Comment: 44 pages, 23 figures, 9 tables; Accepted for publication in the Astrophysical Journa

Aircraft-Engine Particulate Matter Emissions from Conventional and Sustainable Aviation Fuel Combustion: Comparison of Measurement Techniques for Mass, Number, and Size

Sustainable aviation fuels (SAFs) have different compositions compared to conventional petroleum jet fuels, particularly in terms of fuel sulfur and hydrocarbon content. These differences may change the amount and physicochemical properties of volatile and non-volatile particulate matter (nvPM) emitted by aircraft engines. In this study, we evaluate whether comparable nvPM measurement techniques respond similarly to nvPM produced by three blends of SAFs compared to three conventional fuels. Multiple SAF blends and conventional (Jet A-1) jet fuels were combusted in a V2527-A5 engine, while an additional conventional fuel (JP-8) was combusted in a CFM56-2C1 engine. We evaluated nvPM mass concentration measured by three real-Time measurement techniques: photoacoustic spectroscopy, laser-induced incandescence, and the extinction-minus-scattering technique. Various commercial instruments were tested, including three laser-induced incandescence (LII) 300s, one photoacoustic extinctiometer (PAX), one micro soot sensor (MSS+), and two cavity-Attenuated phase shift PMSSA (CAPS PMSSA) instruments. Mass-based emission indices (EIm) reported by these techniques were similar, falling within 30ĝ€¯% of their geometric mean for EIm above 100ĝ€¯mg per kg fuel (approximately 10ĝ€¯μgĝ€¯PMĝ€¯m-3 at the instrument); this geometric mean was therefore used as a reference value. Additionally, two integrative measurement techniques were evaluated: filter photometry and particle size distribution (PSD) integration. The commercial instruments used were one tricolor absorption photometer (TAP), one particle soot absorption photometer (PSAP), and two scanning mobility particle sizers (SMPSs). The TAP and PSAP were operated at 5ĝ€¯% and 10ĝ€¯% of their nominal flow rates, respectively, to extend the life of their filters. These techniques are used in specific applications, such as on board research aircraft to determine particulate matter (PM) emissions at cruise. EIm reported by the alternative techniques fell within approximately 50ĝ€¯% of the mean aerosol-phase EIm. In addition, we measured PM-number-based emission indices using PSDs and condensation particle counters (CPCs). The commercial instruments used included TSI SMPSs, a Cambustion differential mobility spectrometer (DMS500), and an AVL particle counter (APC), and the data also fell within approximately 50ĝ€¯% of their geometric mean. The number-based emission indices were highly sensitive to the accuracy of the sampling-line penetration functions applied as corrections. In contrast, the EIm data were less sensitive to those corrections since a smaller volume fraction fell within the size range where corrections were substantial. A separate, dedicated experiment also showed that the operating laser fluence used in the LII 300 laser-induced incandescence instrument for aircraft-engine nvPM measurement is adequate for a range of SAF blends investigated in this study. Overall, we conclude that all tested instruments are suitable for the measurement of nvPM emissions from the combustion of SAF blends in aircraft engines

Aircraft Engine Particulate Matter Emissions from Sustainable Aviation Fuels: Results from Ground-Based Measurements during the NASA/DLR Campaign ECLIF2/ND-MAX

The use of alternative jet fuels by commercial aviation has increased substantially in recent years. Beside the reduction of carbon dioxide emission, the use of sustainable aviation fuels (SAF) may have a positive impact on the reduction of particulate emissions. This study summarizes the results from a ground-based measurement activity conducted in January 2018 as part of the ECLIF2/ND-MAX campaign in Ramstein, Germany. Two fossil reference kerosenes and three different blends with the renewable fuel component HEFA-SPK (Hydroprocessed Esters and Fatty Acids Synthetic Paraffinic Kerosene) were burned in an A320 with V2527-A5 engines to investigate the effect of fuel naphthalene/aromatic content and the corresponding fuel hydrogen content on non-volatile particle number and mass emissions. Reductions up to 70% in non-volatile particle mass emission compared to the fossil reference fuel were observed at low power settings. The reduction trends to decrease with increasing power settings. The fuels showed a decrease in particle emission with increasing fuel hydrogen content. Consequently, a second fossil fuel with similar hydrogen content as one of the HEFA blends featured similar reduction factors in particle mass and number. Changes in the fuel naphthalene content had significant impact on the particle number emission. A comparison to in-flight emission data shows similar trends at cruise altitudes. The measurements highlight the importance of individual fuel components in regulating engine emissions, particularly at the low thrust settings typically employed during ground operations (e.g. during idle and taxi). Therefore, when selecting and mixing SAF blends to meet present fuel-certification standards, attention should be paid to minimizing complex aromatic content to achieve the greatest possible air quality and climate benefits

Diabetes prevalence is associated with serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in US middle-aged Caucasian men and women: a cross-sectional analysis within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

Hypovitaminosis D may be associated with diabetes, hypertension and CHD. However, because studies examining the associations of all three chronic conditions with circulating 25-hydroxyvitamin D (25(0H)D) and 1,25-dihydroxyvitamin D (1,25(0H)2D) are limited, we examined these associations in the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (n 2465). Caucasian PLCO participants selected as controls in previous nested case-control studies of 25(0H)D and 1,25(0H)2D were included in this analysis. Diabetes, CHD and hypertension prevalence, risk factors for these conditions and intake of vitamin D and Ca were collected from a baseline questionnaire. Results indicated that serum levels of 25(0H)D were low (\u3c50nmol/1) in 29% and very low ( \u3c 37nmol/1) in 11% of subjects. The prevalence of diabetes, hypertension and CHD was 7, 30 and 10%, respectively. After adjustment for confounding by sex, geographical location, educational level, smoking history, BMI, physical activity, total dietary energy and vitamin D and Ca intake, only diabetes was significantly associated with lower 25(0H)D and 1,25(0H)2D levels. Caucasians who had 25(0H)D 2:80nmol/1 were half as likely to have diabetes (OR 0·5 (95% Cl 0·3, 0·9)) compared with those who had 25(0H)D /l. Those in the highest quartile of 1,25(0H)2D (/1) were less than half as likely to have diabetes (OR 0·3 (95% Cl 0·1, 0·7)) than those in the lowest quartile (\u3c 72pmol/l). In conclusion, the independent associations of 25(0H)D and 1,25(0H)2D with diabetes prevalence in a large population are new findings, and thus warrant confirmation in larger, prospective studies