Gradients of glucose metabolism regulate morphogen signalling required for specifying tonotopic organisation in the chicken cochlea

In vertebrates with elongated auditory organs, mechanosensory hair cells (HCs) are organised such that complex sounds are broken down into their component frequencies along a proximal-to-distal long (tonotopic) axis. Acquisition of unique morphologies at the appropriate position along the chick cochlea, the basilar papilla, requires that nascent HCs determine their tonotopic positions during development. The complex signalling within the auditory organ between a developing HC and its local niche along the cochlea is poorly understood. Using a combination of live imaging and NAD(P)H fluorescence lifetime imaging microscopy, we reveal that there is a gradient in the cellular balance between glycolysis and the pentose phosphate pathway in developing HCs along the tonotopic axis. Perturbing this balance by inhibiting different branches of cytosolic glucose catabolism disrupts developmental morphogen signalling and abolishes the normal tonotopic gradient in HC morphology. These findings highlight a causal link between graded morphogen signalling and metabolic reprogramming in specifying the tonotopic identity of developing HCs

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis

Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer (nfkb1−/− mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD+, this leading to increased hepatic NAD+ and elevated activity of the NAD+-dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-κB (p65), and PGC-1α. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease

Identification of the top TESS objects of interest for atmospheric characterization of transiting exoplanets with JWST

Funding: Funding for the TESS mission is provided by NASA's Science Mission Directorate. This work makes use of observations from the LCOGT network. Part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP). MSIP is funded by NSF. This paper is based on observations made with the MuSCAT3 instrument, developed by the Astrobiology Center and under financial support by JSPS KAKENHI (grant No. JP18H05439) and JST PRESTO (grant No. JPMJPR1775), at Faulkes Telescope North on Maui, HI, operated by the Las Cumbres Observatory. This paper makes use of data from the MEarth Project, which is a collaboration between Harvard University and the Smithsonian Astrophysical Observatory. The MEarth Project acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering, the National Science Foundation under grant Nos. AST-0807690, AST-1109468, AST-1616624 and AST-1004488 (Alan T. Waterman Award), the National Aeronautics and Space Administration under grant No. 80NSSC18K0476 issued through the XRP Program, and the John Templeton Foundation. C.M. would like to gratefully acknowledge the entire Dragonfly Telephoto Array team, and Bob Abraham in particular, for allowing their telescope bright time to be put to use observing exoplanets. B.J.H. acknowledges support from the Future Investigators in NASA Earth and Space Science and Technology (FINESST) program (grant No. 80NSSC20K1551) and support by NASA under grant No. 80GSFC21M0002. K.A.C. and C.N.W. acknowledge support from the TESS mission via subaward s3449 from MIT. D.R.C. and C.A.C. acknowledge support from NASA through the XRP grant No. 18-2XRP18_2-0007. C.A.C. acknowledges that this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). S.Z. and A.B. acknowledge support from the Israel Ministry of Science and Technology (grant No. 3-18143). The research leading to these results has received funding from the ARC grant for Concerted Research Actions, financed by the Wallonia-Brussels Federation. TRAPPIST is funded by the Belgian Fund for Scientific Research (Fond National de la Recherche Scientifique, FNRS) under the grant No. PDR T.0120.21. The postdoctoral fellowship of K.B. is funded by F.R.S.-FNRS grant No. T.0109.20 and by the Francqui Foundation. H.P.O.'s contribution has been carried out within the framework of the NCCR PlanetS supported by the Swiss National Science Foundation under grant Nos. 51NF40_182901 and 51NF40_205606. F.J.P. acknowledges financial support from the grant No. CEX2021-001131-S funded by MCIN/AEI/ 10.13039/501100011033. A.J. acknowledges support from ANID—Millennium Science Initiative—ICN12_009 and from FONDECYT project 1210718. Z.L.D. acknowledges the MIT Presidential Fellowship and that this material is based upon work supported by the National Science Foundation Graduate Research Fellowship under grant No. 1745302. P.R. acknowledges support from the National Science Foundation grant No. 1952545. This work is partly supported by JSPS KAKENHI grant Nos. JP17H04574, JP18H05439, JP21K20376; JST CREST grant No. JPMJCR1761; and Astrobiology Center SATELLITE Research project AB022006. This publication benefits from the support of the French Community of Belgium in the context of the FRIA Doctoral Grant awarded to M.T. D.D. acknowledges support from TESS Guest Investigator Program grant Nos. 80NSSC22K1353, 80NSSC22K0185, and 80NSSC23K0769. A.B. acknowledges the support of M.V. Lomonosov Moscow State University Program of Development. T.D. was supported in part by the McDonnell Center for the Space Sciences. V.K. acknowledges support from the youth scientific laboratory project, topic FEUZ-2020-0038.JWST has ushered in an era of unprecedented ability to characterize exoplanetary atmospheres. While there are over 5000 confirmed planets, more than 4000 Transiting Exoplanet Survey Satellite (TESS) planet candidates are still unconfirmed and many of the best planets for atmospheric characterization may remain to be identified. We present a sample of TESS planets and planet candidates that we identify as “best-in-class” for transmission and emission spectroscopy with JWST. These targets are sorted into bins across equilibrium temperature Teq and planetary radius Rp and are ranked by a transmission and an emission spectroscopy metric (TSM and ESM, respectively) within each bin. We perform cuts for expected signal size and stellar brightness to remove suboptimal targets for JWST. Of the 194 targets in the resulting sample, 103 are unconfirmed TESS planet candidates, also known as TESS Objects of Interest (TOIs). We perform vetting and statistical validation analyses on these 103 targets to determine which are likely planets and which are likely false positives, incorporating ground-based follow-up from the TESS Follow-up Observation Program to aid the vetting and validation process. We statistically validate 18 TOIs, marginally validate 31 TOIs to varying levels of confidence, deem 29 TOIs likely false positives, and leave the dispositions for four TOIs as inconclusive. Twenty-one of the 103 TOIs were confirmed independently over the course of our analysis. We intend for this work to serve as a community resource and motivate formal confirmation and mass measurements of each validated planet. We encourage more detailed analysis of individual targets by the community.Peer reviewe

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

Separating NADH and NADPH fluorescence in live cells and tissues using FLIM

NAD is a key determinant of cellular energy metabolism. In contrast, its phosphorylated form, NADP, plays a central role in biosynthetic pathways and antioxidant defence. The reduced forms of both pyridine nucleotides are fluorescent in living cells but they cannot be distinguished, as they are spectrally identical. Here, using genetic and pharmacological approaches to perturb NAD(P)H metabolism, we find that fluorescence lifetime imaging (FLIM) differentiates quantitatively between the two cofactors. Systematic manipulations to change the balance between oxidative and glycolytic metabolism suggest that these states do not directly impact NAD(P)H fluorescence decay rates. The lifetime changes observed in cancers thus likely reflect shifts in the NADPH/NADH balance. Using a mathematical model, we use these experimental data to quantify the relative levels of NADH and NADPH in different cell types of a complex tissue, the mammalian cochlea. This reveals NADPH-enriched populations of cells, raising questions about their distinct metabolic roles

Expression and function of scleraxis in the developing auditory system.

A study of genes expressed in the developing inner ear identified the bHLH transcription factor Scleraxis (Scx) in the developing cochlea. Previous work has demonstrated an essential role for Scx in the differentiation and development of tendons, ligaments and cells of chondrogenic lineage. Expression in the cochlea has been shown previously, however the functional role for Scx in the cochlea is unknown. Using a Scx-GFP reporter mouse line we examined the spatial and temporal patterns of Scx expression in the developing cochlea between embryonic day 13.5 and postnatal day 25. Embryonically, Scx is expressed broadly throughout the cochlear duct and surrounding mesenchyme and at postnatal ages becomes restricted to the inner hair cells and the interdental cells of the spiral limbus. Deletion of Scx results in hearing impairment indicated by elevated auditory brainstem response (ABR) thresholds and diminished distortion product otoacoustic emission (DPOAE) amplitudes, across a range of frequencies. No changes in either gross cochlear morphology or expression of the Scx target genes Col2A, Bmp4 or Sox9 were observed in Scx(-/-) mutants, suggesting that the auditory defects observed in these animals may be a result of unidentified Scx-dependent processes within the cochlea

Expression levels of <i>Sox9, Bmp4 and Col2a</i> are altered in <i>Scx</i>^−/− mice.

<p>Graph shows qRT-PCR analysis of <i>Sox9, Bmp4 and Col2a</i> mRNA expression levels in heterozygous (<i>Scx</i><b>⁻</b>^<i>/+</i>) (black bars) and Scx null (<i>Scx</i><b>⁻</b>^{<i>/</i><b>−</b>}) P3 (white bars) littermates. Expression levels have been normalized to those in wild type (<i>Scx^+/+</i>) animals Data are mean ± SEM, Student’s <i>t</i>-test. P  =  > 0.05 for <i>Col2A1, Sox9</i></p

<i>Scx</i> is expressed in both mesenchymal and epithelial cells within the inner ear.

<p>Images show maximal confocal z-projections through cross-sections of the inner ear from <i>Scx-GFP</i> mice at E13.5 (A) and E15.5 (B). At E13.5 <i>Sc</i>x is expressed in the developing otic capsule, in otic fibrocytes (white arrow heads) and throughout the basal turn of the cochlear duct. Expression of <i>Scx</i> in the middle and apical cochlear turns is noticeably lower. By E15.5 <i>Scx</i> expression is notable in the developing spiral limbus (SL) of the basal turn as well as in all four turns of the cochlear duct. While broad expression persists in the basal turn, expression in the remaining turns is more restricted with the most intense expression localized to the lateral floor and ceiling of the duct. <i>Scx</i> expression is also still evident in otic fibrocytes (arrowheads). Scale bar is 100 µm.</p

<i>Scx</i>-GFP expression the neonatal and adult cochlea.

<p>(<b>A,B</b>) Maximal confocal z-projections through basal and apical cochlear whole-mounts at P2. <i>Scx</i>-GFP expression is shown in green and Myosin 6 in red. By P2, <i>Scx</i>-GFP is restricted primarily to the inner hair cells IHCs. However in the apical turn expression of <i>Scx</i> is also present in the Hensen’s cells adjacent to the third row of outer hair cells. (<b>C</b>) Confocal z-projection through a cochlear whole mount at postnatal day 25 (P25). <i>Scx</i>-GFP expression is restricted to the inner hair cells (IHCs) within the cochlear epithelium and is most prominent in the interdental cells of the spiral limbus (SL). Little expression is observed in the outer hair cells (OHCs). Scx expression is also still observed albeit at lower levels in the Claudius/Hensen’s cell region. Inset (<b>D</b>) highlights the restriction of <i>Scx</i>-GFP to the IHCs. Scale bars are 50 µm.</p

<i>Scx</i> expression in the developing mouse cochlear duct.

<p>(<b>A,B</b>) Images show maximal confocal z-projections through E13.5 cochlear sections showing broad expression of <i>Scx</i>-GFP throughout the cochlear epithelium (green). Note the gradient in expression levels, in particular in the roof of the duct, between base and apex. The prosensory region (PS), flanked by the developing greater and lesser epithelial ridges (GER and LER), is marked based on expression of SOX2 (red). Auditory glia within the spiral ganglion (SG) is also present for Sox2. (<b>C, D</b>) Maximal z-projections taken through the cochlear duct at E15. <i>Scx</i>-GFP expression is present in fibrocytes and the developing otic capsule, most of the cochlear duct, spiral ganglion neurons, and the future spiral limbus. Expression still appears to be more intense in the base, consistent with a base-to-apex gradient of expression (<b>E,F</b>) Maximal z-projections through the cochlear duct at P0. <i>Scx</i>-GFP expression is restricted to the outer sulcus (OS), developing interdental cells (white arrows), medial region of the inner sulcus (IS), spiral limbus (SL), stria vascularis and the inner hair cells (IHCs). Occasional pillar cells also express <i>Scx</i> and weak expression was observed in Reissner’s membrane. The pattern of Scx expression is similar in both the basal and apical regions, indicating that the base-to-apex gradient in <i>Scx</i> expression is no longer present. Scale bar is 100 µm</p