Differential regulation of innate and adaptive immune responses in viral encephalitis.

Viral encephalitis is a global health concern. The ability of a virus to modulate the immune response can have a pivotal effect on the course of disease and the fate of the infected host. In this study, we sought to understand the immunological basis for the fatal encephalitis following infection with the murine coronavirus, mouse hepatitis virus (MHV)-JHM, in contrast with the more attenuated MHV-A59. Distinct glial cell cytokine and chemokine response patterns were observed within 3 days after infection, became progressively more polarized during the course of infection and with the infiltration of leukocytes. In the brain, MHV-JHM infection induced strong accumulation of IFNbeta mRNA relative to IFNgamma mRNA. This trend was reversed in MHV-A59 infection and was accompanied by increased CD8 T cell infiltration into brain compared to MHV-JHM infection. Increased apoptosis appeared to contribute to the diminished presence of CD8 T cells in MHV-JHM-infected brain with the consequence of a lower potential for IFNgamma production and antiviral activity. MHV-JHM infection also induced sustained mRNA accumulation of the innate immune response products interleukin (IL)-6 and IL-1. Furthermore, high levels of macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta, and MIP-2 mRNA were observed at the onset of MHV-JHM infection and correlated with a marked elevation in the number of macrophages in the brain on day 7 compared to MHV-A59 infection. These observations indicate that differences in the severity of viral encephalitis may reflect the differential ability of viruses to stimulate innate immune responses within the CNS and subsequently the character of infiltrating leukocyte populations

Linear Conjugated Molecular Wires: Organic Materials and Single-Molecule Electronics

In this work, the synthesis and properties of different families of molecule wires are described. These families are made up of collections of linear conjugated oligomers, such as oligoenes and phenylenevinylenes and their derivatives. The bulk properties of each system were examined in order to establish structure-performance relationship between the intrinsic molecular properties of the bridging organic wire and the performance of their single-molecule junctions. The electrical as well as mechanical characteristics of single-molecular junctions were measured using the scanning tunneling-based break junction (STM-BJ) and atomic force microscope-based break junction (AFM-BJ) techniques. In addition, stilbene molecular wires and their derivatives are ideal model compounds for both of these oligomeric families and have helped to isolate and quantify some of the factors that govern charge transport through linear conjugated molecules. After an introduction of molecular electronics, a highly tunable class of oligoenes, the α,ω-diphenyl−μ,ν-dicyano-oligoenes (DPDC) is described in the second chapter. They range from three to eleven linear C=C double bonds in length. Their synthesis is reported while their bulk solution properties show novel electronic structures, as well as broad optical absorptions and high extinction coefficients. Theoretical investigation using DFT calculations as well as strategies for functionalizing DPDCs are described. We have found that functionalization of these intractable materials has opened new doors for their material applications. We envisioned functionalized oligoenes as molecular building blocks (i.e. conducting wires or rigid connectors) in the bottom up construction of new materials and devices. Their prototypical structure and variable length would make DPDCs ideal candidates for molecular wires especially in the field of single-molecule electronics. Molecular junctions of the form metal-oligoene-metal were formed using the STM-BJ method and their charge transport characteristics were quantified in Chapter 2. In addition, we utilize long DPDC oligomers (n > 5) as variable resistance single-molecule potentiometers.In chapter 3, we synthesize and employ our oligoene model compounds, the stilbenes, to differentiate the mechanical from electrical properties in molecular junctions. This enabled the development of new tools for uncovering the transport mechanisms in other molecules. One example is demonstrated in chapter 4, where stilbenes proved useful as mono-functionalized molecular wires. Together with extended oligoenes, stilbene molecular wires helped us to understand how current flows through a conjugated scaffold having only one electrode binding functional group (chapter 5). We observed a π-Au interaction that is weak, however strong enough to couple electronically to the electrode and complete the molecular circuit. In the last chapter, we showcase a variety of new chemical structures that were prepared to probe the IV characteristics of organic single-molecule wires. A series of end-functionalized (p-phenylenevinylene) (PPV) oligomers and DPDC molecular wires were prepared. Exotic end-groups were important modifications for PPV's, since they increase oligomer solubility; the singe-molecule STM-BJ measurements would not be possible on these otherwise insoluble compounds. PPV materials are very stable and can be further functionalized along their main-chains, however due to shorter effective conjugations lengths (smaller than that of the oligoenes), the range of electronic tunability is smaller in these materials. In addition to this family of symmetric molecules other asymmetric oligoene molecules were synthesized as candidates for single-molecule rectification. These molecules allow different electronic coupling to the right and left electrodes, which may modulate their IV characteristics

Novel Secretion Apparatus Maintains Spore Integrity and Developmental Gene Expression in Bacillus subtilis

Sporulation in Bacillus subtilis involves two cells that follow separate but coordinately regulated developmental programs. Late in sporulation, the developing spore (the forespore) resides within a mother cell. The regulation of the forespore transcription factor σG that acts at this stage has remained enigmatic. σG activity requires eight mother-cell proteins encoded in the spoIIIA operon and the forespore protein SpoIIQ. Several of the SpoIIIA proteins share similarity with components of specialized secretion systems. One of them resembles a secretion ATPase and we demonstrate that the ATPase motifs are required for σG activity. We further show that the SpoIIIA proteins and SpoIIQ reside in a multimeric complex that spans the two membranes surrounding the forespore. Finally, we have discovered that these proteins are all required to maintain forespore integrity. In their absence, the forespore develops large invaginations and collapses. Importantly, maintenance of forespore integrity does not require σG. These results support a model in which the SpoIIIA-SpoIIQ proteins form a novel secretion apparatus that allows the mother cell to nurture the forespore, thereby maintaining forespore physiology and σG activity during spore maturation

Mouse hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein expression and immunopathology.

Differences in disease outcome between the highly neurovirulent MHV-JHM and mildly neurovirulent MHV-A59 have been attributed to variations within the spike (S) glycoprotein. Previously, we found that MHV-JHM neurovirulence was marked by diminished expression of interferon-gamma (IFN-gamma) mRNA and a reduced presence of CD8 T cells in the CNS concomitant with heightened macrophage inflammatory protein (MIP)-1 transcript levels and greater macrophage infiltration relative to MHV-A59 infection. Here, the ability of the S and non-spike genes to regulate these immune responses was evaluated using chimeric viruses. Chimeric viruses WTR13 and S4R22 were made on MHV-A59 variant backgrounds and, respectively, contained the S gene of MHV-A59 and MHV-JHM. Unexpectedly, genes other than S appeared to modulate events critical to viral replication and survival. Unlike unresolving MHV-JHM infections, the clearance of WTR13 and S4R22 infections coincided with strong IFN-gamma transcription and an increase in the number of CD8 T cells infiltrating into the CNS. However, despite the absence of detectable viral titers, approximately 40% of S4R22-infected mice succumbed within 3 weeks, indicating that the enhanced mortality following S4R22 infection was not associated with high viral titers. Instead, similar to the MHV-JHM infection, reduced survival following S4R22 infection was observed in the presence of elevated MIP-1alpha and MIP-1beta mRNA accumulation and enhanced macrophage numbers within infected brains. These observations suggest that the S protein of MHV-JHM influences neurovirulence through the induction of MIP-1alpha- and MIP-1beta-driven macrophage immunopathology

DESI Survey Validation Spectra Reveal an Increasing Fraction of Recently Quenched Galaxies at z∼1z\sim1

We utilize $\sim17000$ bright Luminous Red Galaxies (LRGs) from the novel Dark Energy Spectroscopic Instrument Survey Validation spectroscopic sample, leveraging its deep ($\sim2.5$ hour/galaxy exposure time) spectra to characterize the contribution of recently quenched galaxies to the massive galaxy population at $0.4<z<1.3$. We use Prospector to infer non-parametric star formation histories and identify a significant population of post-starburst galaxies that have joined the quiescent population within the past $\sim1$ Gyr. The highest redshift subset (277 at $z>1$) of our sample of recently quenched galaxies represents the largest spectroscopic sample of post-starburst galaxies at that epoch. At $0.4<z<0.8$, we measure the number density of quiescent LRGs, finding that recently quenched galaxies constitute a growing fraction of the massive galaxy population with increasing lookback time. Finally, we quantify the importance of this population amongst massive ($\mathrm{log}(M_\star/M_\odot)>11.2$) LRGs by measuring the fraction of stellar mass each galaxy formed in the Gyr before observation, $f_{\mathrm{1 Gyr}}$. Although galaxies with $f_{\mathrm{1 Gyr}}>0.1$ are rare at $z\sim0.4$ ($\lesssim 0.5\%$ of the population), by $z\sim0.8$ they constitute $\sim3\%$ of massive galaxies. Relaxing this threshold, we find that galaxies with $f_\mathrm{1 Gyr}>5\%$ constitute $\sim10\%$ of the massive galaxy population at $z\sim0.8$. We also identify a small but significant sample of galaxies at $z=1.1-1.3$ that formed with $f_{\mathrm{1 Gyr}}>50\%$, implying that they may be analogues to high-redshift quiescent galaxies that formed on similar timescales. Future analysis of this unprecedented sample promises to illuminate the physical mechanisms that drive the quenching of massive galaxies after cosmic noon.Comment: Submitted to ApJ Letters after DESI Collaboration Review. 14 pages, 5 figures, comments welcome

The Clustering of DESI-like Luminous Red Galaxies Using Photometric Redshifts

We present measurements of the redshift-dependent clustering of a DESI-like luminous red galaxy (LRG) sample selected from the Legacy Survey imaging dataset, and use the halo occupation distribution (HOD) framework to fit the clustering signal. The photometric LRG sample in this study contains 2.7 million objects over the redshift range of $0.4 < z < 0.9$ over 5655 deg$^2$. We have developed new photometric redshift (photo-$z$) estimates using the Legacy Survey DECam and WISE photometry, with $\sigma_{\mathrm{NMAD}} = 0.02$ precision for LRGs. We compute the projected correlation function using new methods that maximize signal-to-noise ratio while incorporating redshift uncertainties. We present a novel algorithm for dividing irregular survey geometries into equal-area patches for jackknife resampling. For a five-parameter HOD model fit using the MultiDark halo catalog, we find that there is little evolution in HOD parameters except at the highest redshifts. The inferred large-scale structure bias is largely consistent with constant clustering amplitude over time. In an appendix, we explore limitations of Markov chain Monte Carlo fitting using stochastic likelihood estimates resulting from applying HOD methods to N-body catalogs, and present a new technique for finding best-fit parameters in this situation. Accompanying this paper we have released the Photometric Redshifts for the Legacy Surveys (PRLS) catalog of photo-$z$'s obtained by applying the methods used in this work to the full Legacy Survey Data Release 8 dataset. This catalog provides accurate photometric redshifts for objects with $z < 21$ over more than 16,000 deg$^2$ of sky.Comment: 24 pages, 25 figures, published in MNRA

The DESI One-Percent Survey: Evidence for Assembly Bias from Low-Redshift Counts-in-Cylinders Measurements

We explore the galaxy-halo connection information that is available in low-redshift samples from the early data release of the Dark Energy Spectroscopic Instrument (DESI). We model the halo occupation distribution (HOD) from z=0.1-0.3 using Survey Validation 3 (SV3; a.k.a., the One-Percent Survey) data of the DESI Bright Galaxy Survey (BGS). In addition to more commonly used metrics, we incorporate counts-in-cylinders (CiC) measurements, which drastically tighten HOD constraints. Our analysis is aided by the Python package, galtab, which enables the rapid, precise prediction of CiC for any HOD model available in halotools. This methodology allows our Markov chains to converge with much fewer trial points, and enables even more drastic speedups due to its GPU portability. Our HOD fits constrain characteristic halo masses tightly and provide statistical evidence for assembly bias, especially at lower luminosity thresholds: the HOD of central galaxies in $z\sim0.15$ samples with limiting absolute magnitude $M_r < -20.0$ and $M_r < -20.5$ samples is positively correlated with halo concentration with a significance of 99.9% and 99.5%, respectively. Our models also favor positive central assembly bias for the brighter $M_r < -21.0$ sample at $z\sim0.25$ (94.8% significance), but there is no significant evidence for assembly bias with the same luminosity threshold at $z\sim0.15$. We provide our constraints for each threshold sample's characteristic halo masses, assembly bias, and other HOD parameters. These constraints are expected to be significantly tightened with future DESI data, which will span an area 100 times larger than that of SV3

The DESI One-percent Survey: Evidence for Assembly Bias from Low-redshift Counts-in-cylinders Measurements

We explore the galaxy-halo connection information that is available in low-redshift samples from the early data release of the Dark Energy Spectroscopic Instrument (DESI). We model the halo occupation distribution (HOD) from z = 0.1 to 0.3 using Survey Validation 3 (SV3; a.k.a., the One-Percent Survey) data of the DESI Bright Galaxy Survey. In addition to more commonly used metrics, we incorporate counts-in-cylinders (CiC) measurements, which drastically tighten HOD constraints. Our analysis is aided by the Python package, galtab, which enables the rapid, precise prediction of CiC for any HOD model available in halotools. This methodology allows our Markov chains to converge with much fewer trial points, and enables even more drastic speedups due to its GPU portability. Our HOD fits constrain characteristic halo masses tightly and provide statistical evidence for assembly bias, especially at lower luminosity thresholds: the HOD of central galaxies in z ∼ 0.15 samples with limiting absolute magnitude M r < −20.0 and M r < −20.5 samples is positively correlated with halo concentration with a significance of 99.9% and 99.5%, respectively. Our models also favor positive central assembly bias for the brighter M r < −21.0 sample at z ∼ 0.25 (94.8% significance), but there is no significant evidence for assembly bias with the same luminosity threshold at z ∼ 0.15. We provide our constraints for each threshold sample’s characteristic halo masses, assembly bias, and other HOD parameters. These constraints are expected to be significantly tightened with future DESI data, which will span an area 100 times larger than that of SV3

The DESI One-Percent survey: constructing galaxy-halo connections for ELGs and LRGs using auto and cross correlations

In the current Dark Energy Spectroscopic Instrument (DESI) survey, emission line galaxies (ELGs) and luminous red galaxies (LRGs) are essential for mapping the dark matter distribution at $z \sim 1$. We measure the auto and cross correlation functions of ELGs and LRGs at $0.8<z\leq 1.0$ from the DESI One-Percent survey. Following Gao et al. (2022), we construct the galaxy-halo connections for ELGs and LRGs simultaneously. With the stellar-halo mass relation (SHMR) for the whole galaxy population (i.e. normal galaxies), LRGs can be selected directly by stellar mass, while ELGs can also be selected randomly based on the observed number density of each stellar mass, once the probability $P_{\mathrm{sat}}$ of a satellite galaxy becoming an ELG is determined. We demonstrate that the observed small scale clustering prefers a halo mass-dependent $P_{\mathrm{sat}}$ model rather than a constant. With this model, we can well reproduce the auto correlations of LRGs and the cross correlations between LRGs and ELGs at $r_{\mathrm{p}}>0.1$ $\mathrm{Mpc}\,h^{-1}$. We can also reproduce the auto correlations of ELGs at $r_{\mathrm{p}}>0.3$ $\mathrm{Mpc}\,h^{-1}$ ($s>1$ $\mathrm{Mpc}\,h^{-1}$) in real (redshift) space. Although our model has only seven parameters, we show that it can be extended to higher redshifts and reproduces the observed auto correlations of ELGs in the whole range of $0.8<z<1.6$, which enables us to generate a lightcone ELG mock for DESI. With the above model, we further derive halo occupation distributions (HODs) for ELGs which can be used to produce ELG mocks in coarse simulations without resolving subhalos.Comment: 27 pages, 16 figures, accepted by Ap