Systematic Bias in Helioseismic Measurements of Meridional Circulation Arising from Nonlocal Averaging Kernels

Meridional circulation in the solar convection zone plays a profound role in regulating the interior dynamics of the Sun and its magnetism. While it is well accepted that meridional flows move from the equator towards the poles at the Sun's surface, helioseismic observations have yet to provide a definitive answer for the depth at which those flows return to the equator, or the number of circulation cells in depth. In this work, we investigate whether the discrepancies regarding the nature of the return flow are intrinsic to how helioseismic observations are made. We examine the seismic signature of possible meridional flow profiles by convolving time-distance averaging kernels with the mean flows obtained from 3-D hydrodynamic simulations of the solar convection zone. At mid and high latitudes, we find that weak flow structures in the deeper regions of the convection zone can be strongly obscured by signal from the much stronger surface flows. This contamination is the result of extended side lobes in the averaging kernels and generates a spurious equatorward signal of 2--3 m s$^{-1}$ at those latitudes, and at $\approx 70~\mathrm{Mm}$ depth. At low latitudes, however, the flows in the simulations tend to be stronger and multiple cells across the shell depth can produce a sufficiently strong seismic signal to survive the convolution process. The signal associated with the deep equatorward return flow in the Sun is expected to be weak and in the same sense as the contamination from the surface. Hence, the return flow needs to exceed $\sim 2$--$3~ \mathrm{m~s^{-1}}$ in magnitude for reported detections to be considered significant.Comment: Submitted to AAS Journal

Quantitative Assessment of Experimental Ocular Inflammatory Disease

Ocular inflammation imposes a high medical burden on patients and substantial costs on the health-care systems that mange these often chronic and debilitating diseases. Many clinical phenotypes are recognized and classifying the severity of inflammation in an eye with uveitis is an ongoing challenge. With the widespread application of optical coherence tomography in the clinic has come the impetus for more robust methods to compare disease between different patients and different treatment centers. Models can recapitulate many of the features seen in the clinic, but until recently the quality of imaging available has lagged that applied in humans. In the model experimental autoimmune uveitis (EAU), we highlight three linked clinical states that produce retinal vulnerability to inflammation, all different from healthy tissue, but distinct from each other. Deploying longitudinal, multimodal imaging approaches can be coupled to analysis in the tissue of changes in architecture, cell content and function. This can enrich our understanding of pathology, increase the sensitivity with which the impacts of therapeutic interventions are assessed and address questions of tissue regeneration and repair. Modern image processing, including the application of artificial intelligence, in the context of such models of disease can lay a foundation for new approaches to monitoring tissue health

Improving the Thermal Stability of Cellobiohydrolase Cel7A from \u3cem\u3eHypocrea jecorina\u3c/em\u3e by Directed Evolution

Secreted mixtures of Hypocrea jecorina cellulases are able to efficiently degrade cellulosic biomass to fermentable sugars at large, commercially relevant scales. H. jecorina Cel7A, cellobiohydrolase I, from glycoside hydrolase family 7, is the workhorse enzyme of the process. However, the thermal stability of Cel7A limits its use to processes where temperatures are no higher than 50 °C. Enhanced thermal stability is desirable to enable the use of higher processing temperatures and to improve the economic feasibility of industrial biomass conversion. Here, we enhanced the thermal stability of Cel7A through directed evolution. Sites with increased thermal stability properties were combined, and a Cel7A variant (FCA398) was obtained, which exhibited a 10.4 °C increase in Tm and a 44-fold greater half-life compared with the wild-type enzyme. This Cel7A variant contains 18 mutated sites and is active under application conditions up to at least 75 °C. The X-ray crystal structure of the catalytic domain was determined at 2.1 Å resolution and showed that the effects of the mutations are local and do not introduce major backbone conformational changes. Molecular dynamics simulations revealed that the catalytic domain of wild-type Cel7A and the FCA398 variant exhibit similar behavior at 300 K, whereas at elevated temperature (475 and 525 K), the FCA398 variant fluctuates less and maintains more native contacts over time. Combining the structural and dynamic investigations, rationales were developed for the stabilizing effect at many of the mutated sites

Molecular Adaptation to Folivory and the Conservation Implications for Madagascar’s Lemurs

The lemurs of Madagascar include numerous species characterized by folivory across several families. Many extant lemuriform folivores exist in sympatry in Madagascar’s remaining forests. These species avoid feeding competition by adopting different dietary strategies within folivory, reflected in behavioral, morphological, and microbiota diversity across species. These conditions make lemurs an ideal study system for understanding adaptation to leaf-eating. Most folivorous lemurs are also highly endangered. The significance of folivory for conservation outlook is complex. Though generalist folivores may be relatively well equipped to survive habitat disturbance, specialist folivores occupying narrow dietary niches may be less resilient. Characterizing the genetic bases of adaptation to folivory across species and lineages can provide insights into their differential physiology and potential to resist habitat change. We recently reported accelerated genetic change in RNASE1, a gene encoding an enzyme (RNase 1) involved in molecular adaptation in mammalian folivores, including various monkeys and sifakas (genus Propithecus; family Indriidae). Here, we sought to assess whether other lemurs, including phylogenetically and ecologically diverse folivores, might show parallel adaptive change in RNASE1 that could underlie a capacity for efficient folivory. We characterized RNASE1in 21 lemur species representing all five families and members of the three extant folivorous lineages: (1) bamboo lemurs (family Lemuridae), (2) sportive lemurs (family Lepilemuridae), and (3) indriids (family Indriidae). We found pervasive sequence change in RNASE1 across all indriids, a dN/dS value \u3e 3 in this clade, and evidence for shared change in isoelectric point, indicating altered enzymatic function. Sportive and bamboo lemurs, in contrast, showed more modest sequence change. The greater change in indriids may reflect a shared strategy emphasizing complex gut morphology and microbiota to facilitate folivory. This case study illustrates how genetic analysis may reveal differences in functional traits that could influence species’ ecology and, in turn, their resilience to habitat change. Moreover, our results support the body of work demonstrating that not all primate folivores are built the same and reiterate the need to avoid generalizations about dietary guild in considering conservation outlook, particularly in lemurs where such diversity in folivory has probably led to extensive specialization via niche partitioning

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project.

Two large-scale phenotyping efforts, the European Mouse Disease Clinic (EUMODIC) and the Wellcome Trust Sanger Institute Mouse Genetics Project (SANGER-MGP), started during the late 2000s with the aim to deliver a comprehensive assessment of phenotypes or to screen for robust indicators of diseases in mouse mutants. They both took advantage of available mouse mutant lines but predominantly of the embryonic stem (ES) cells resources derived from the European Conditional Mouse Mutagenesis programme (EUCOMM) and the Knockout Mouse Project (KOMP) to produce and study 799 mouse models that were systematically analysed with a comprehensive set of physiological and behavioural paradigms. They captured more than 400 variables and an additional panel of metadata describing the conditions of the tests. All the data are now available through EuroPhenome database (www.europhenome.org) and the WTSI mouse portal (http://www.sanger.ac.uk/mouseportal/), and the corresponding mouse lines are available through the European Mouse Mutant Archive (EMMA), the International Knockout Mouse Consortium (IKMC), or the Knockout Mouse Project (KOMP) Repository. Overall conclusions from both studies converged, with at least one phenotype scored in at least 80% of the mutant lines. In addition, 57% of the lines were viable, 13% subviable, 30% embryonic lethal, and 7% displayed fertility impairments. These efforts provide an important underpinning for a future global programme that will undertake the complete functional annotation of the mammalian genome in the mouse model

Design of Group IIA Secreted/Synovial Phospholipase A2 Inhibitors: An Oxadiazolone Derivative Suppresses Chondrocyte Prostaglandin E2 Secretion

Group IIA secreted/synovial phospholipase A2 (GIIAPLA2) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E2 (PGE2), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA2, along with their chemical synthesis and results from PLA2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA2 affinities than did C1, and such predictions were confirmed by in vitro PLA2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction.

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function.The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss

The NANOGrav 15-Year Data Set: Detector Characterization and Noise Budget

Pulsar timing arrays (PTAs) are galactic-scale gravitational wave detectors. Each individual arm, composed of a millisecond pulsar, a radio telescope, and a kiloparsecs-long path, differs in its properties but, in aggregate, can be used to extract low-frequency gravitational wave (GW) signals. We present a noise and sensitivity analysis to accompany the NANOGrav 15-year data release and associated papers, along with an in-depth introduction to PTA noise models. As a first step in our analysis, we characterize each individual pulsar data set with three types of white noise parameters and two red noise parameters. These parameters, along with the timing model and, particularly, a piecewise-constant model for the time-variable dispersion measure, determine the sensitivity curve over the low-frequency GW band we are searching. We tabulate information for all of the pulsars in this data release and present some representative sensitivity curves. We then combine the individual pulsar sensitivities using a signal-to-noise-ratio statistic to calculate the global sensitivity of the PTA to a stochastic background of GWs, obtaining a minimum noise characteristic strain of $7\times 10^{-15}$ at 5 nHz. A power law-integrated analysis shows rough agreement with the amplitudes recovered in NANOGrav's 15-year GW background analysis. While our phenomenological noise model does not model all known physical effects explicitly, it provides an accurate characterization of the noise in the data while preserving sensitivity to multiple classes of GW signals.Comment: 67 pages, 73 figures, 3 tables; published in Astrophysical Journal Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave Background. For questions or comments, please email [email protected]

The mammalian gene function resource: the International Knockout Mouse Consortium.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research