Climate warming has facilitated the expansion of black mangrove
Avicennia germinans
(hereafter ‘
Avicennia
’) into smooth cordgrass
Spartina alterniflora
(hereafter ‘
Spartina
’) salt marshes in ...southeastern Louisiana (USA). As macrophytes contribute to soil organic matter (SOM) and primary production, this transition could alter the basal energy pathways supporting salt marsh food webs. We used bulk-tissue and compound-specific stable isotope analyses (SIA) to determine if changes in dominant macrophytes alter basal energy pathways for 2 salt marsh residents: grass shrimp (
Palaemonetes
spp.) and marsh periwinkle snails
Littoraria irrorata
. Specifically, we used Bayesian stable isotope mixing models to quantify the relative contribution of basal energy sources to SOM and resident food webs across a
Spartina
-
Avicennia
gradient in southeastern Louisiana. We found that sources of SOM changed in
Avicennia
-dominated habitat and that foraging strategy dictated trophic responses of salt marsh residents to
Avicennia
expansion. Marsh periwinkle snail basal energy sources shifted from
Spartina
to algae (phytoplankton and epiphytic macroalgae) reliance, while grass shrimp basal energy sources remained reliant on algal production, regardless of macrophyte dominance. Compound-specific SIA improved basal energy source distinctions and provided more constrained estimates of their contributions to resident food webs than bulk-tissue SIA. The importance of algal energy across the landscape warrants future investigations into the ability of
Avicennia
to support the diversity and abundance of algal energy sources present in Louisiana salt marshes. Understanding coastal wetland food web dynamics could help with planning and evaluating the most effective coastal restoration techniques (e.g. prioritizing salt marsh or mangrove habitat) in southeastern Louisiana.
The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor ...(NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt's lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Persulfides (R−SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that ...releases N‐acetyl cysteine persulfide (NAC‐SSH) in response to the prokaryote‐specific enzyme nitroreductase. The donor, termed NDP‐NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC‐SSH. NDP‐NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2S. NDP‐NAC induced these effects by the upregulation of beneficial small‐ and medium‐chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome‐related diseases by the targeted delivery of reactive sulfur species.
The persulfide donor NDP‐NAC (see structure) was synthesized and found to decompose in response to E. coli nitroreductase with the release of N‐acetyl cysteine persulfide (NAC‐SSH). NDP‐NAC elicited gastroprotective effects in mice by the upregulation of beneficial small‐ and medium‐chain fatty acids, by increasing growth of Turicibacter sanguinis, a beneficial gut bacterium, and by decreasing populations of pathogenic Synergistales bacteria.
SUMMARY
Polygalacturonase‐inhibiting proteins (PGIPs) are plant cell‐wall proteins that specifically inhibit fungal endo‐polygalacturonases (PGs) that contribute to the aggressive decomposition of ...susceptible plant tissues. The inhibition of fungal PGs by PGIPs suggests that PGIPs have a role in plant tolerance to fungal infections and this has been observed in transgenic plants expressing PGIPs. Xylella fastidiosa, the causal agent of Pierce's disease (PD) in grapevines, has genes that encode cell‐wall‐degrading enzymes, including a putative PG. Therefore, we hypothesized that PGIP expression could confer tolerance against this bacterium as well as against the fungal pathogen Botrytis cinerea. To test this hypothesis, Vitis vinifera cvs. ‘Thompson Seedless’ and ‘Chardonnay’ were transformed to express pear fruit PGIP‐encoding gene (pPGIP) under the control of the CaMV 35S promoter. Substantial pear PGIP (pPGIP) activity was found in crude extracts from leaves and in xylem exudate of transgenic lines obtained from independent transformation events, but not in untransformed controls. pPGIP activity was detected in xylem exudate of untransformed scions grafted on to transgenic rootstocks expressing pPGIP. Leaves of transgenic plants infected with B. cinerea had reduced rates of lesion expansion. The development of PD was delayed in some transgenic lines with increased pPGIP activity. PD‐tolerant transgenic lines had reduced leaf scorching, lower Xylella titres and better re‐growth after pruning than the untransformed controls.
Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose ...polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor,
IKX1, and show drug target specific DNA damage and subsequent killing of
and non-
mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic,
IKX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers.
The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development
. The molecular mechanism that underpins these ...reprogramming processes remains largely unexplored, which impedes our understanding and limits rational improvements to reprogramming protocols. Here, to address these issues, we reconstruct molecular reprogramming trajectories of human dermal fibroblasts using single-cell transcriptomics. This revealed that reprogramming into primed and naive pluripotency follows diverging and distinct trajectories. Moreover, genome-wide analyses of accessible chromatin showed key changes in the regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets revealed a role for transcription factors associated with the trophectoderm lineage, and the existence of a subpopulation of cells that enter a trophectoderm-like state during reprogramming. Furthermore, this trophectoderm-like state could be captured, which enabled the derivation of induced trophoblast stem cells. Induced trophoblast stem cells are molecularly and functionally similar to trophoblast stem cells derived from human blastocysts or first-trimester placentas
. Our results provide a high-resolution roadmap for the transcription-factor-mediated reprogramming of human somatic cells, indicate a role for the trophectoderm-lineage-specific regulatory program during this process, and facilitate the direct reprogramming of somatic cells into induced trophoblast stem cells.
The effects of feeding a quebracho–chestnut tannin extract mixture on performance and nitrogen (N) utilization were assessed with 36 multiparous lactating Holstein cows (mean ± standard deviation; ...706 ± 59 kg of body weight; 126 ± 20 d in milk) randomly assigned to 3 dietary treatments in a randomized complete block design. Following a 2-wk covariate adjustment period, cows were fed their assigned treatment diets for 13 wk. Rice hulls were removed from a total mixed ration with a 54:46 forage:concentrate ratio (% of dry matter; DM), and a tannin extract mixture from quebracho and chestnut trees (2:1 ratio) was included at 0, 0.45, and 1.80% of dietary DM. There was no interaction between dietary treatments and experimental week for the reported measurements except milk lactose percentage. Overall, treatments did not affect milk yield (48.6 ± 7.8 kg/d), fat- and protein-corrected milk (46.1 ± 7.6 kg/d), milk fat content (3.88 ± 0.65%) and yield (1.85 ± 0.38 kg/d), and true protein yield (1.45 ± 0.21 kg/d). However, incremental levels of tannin extracts in the diet produced a linear increase in DM intake (29.2 to 30.9 kg/d) and a linear decrease in kilograms of milk per kilogram of DM intake (1.67 to 1.57 kg/kg) and MUN (12.2 to 10.8 mg/dL). Furthermore, there was a quadratic effect of tannin extracts on milk true protein content (2.96, 3.13, and 3.00% for 0, 0.45, and 1.80% tannin extract, respectively) and a tendency for linear and quadratic response for body weight gain (0.31, 0.16, and 0.44 kg/d for 0, 0.45, and 1.80% tannin, respectively). Intake of N increased linearly (782, 795, and 820 g/d) and N utilization efficiency (milk N/intake N) decreased linearly (0.300, 0.301, and 0.275 for 0, 0.45, and 1.80% tannin, respectively). Relative to the 0% diet, 1.80% tannin extract reduced estimated urinary N excretion by 11%. In this study, adding 0.45% tannin extract to the diet reduced feed efficiency but had a positive effect on milk protein content. Feeding a tannin extract mixture from quebracho and chestnut may reduce environmental labile urinary N excretion without affecting milk yield but at the expense of a lower feed utilization efficiency.
ABSTRACT We report here the non-detection of gravitational waves from the merger of binary-neutron star systems and neutron star-black hole systems during the first observing run of the Advanced ...Laser Interferometer Gravitational-wave Observatory (LIGO). In particular, we searched for gravitational-wave signals from binary-neutron star systems with component masses and component dimensionless spins <0.05. We also searched for neutron star-black hole systems with the same neutron star parameters, black hole mass , and no restriction on the black hole spin magnitude. We assess the sensitivity of the two LIGO detectors to these systems and find that they could have detected the merger of binary-neutron star systems with component mass distributions of 1.35 0.13 M at a volume-weighted average distance of ∼70 Mpc, and for neutron star-black hole systems with neutron star masses of 1.4 M and black hole masses of at least 5 M , a volume-weighted average distance of at least ∼110 Mpc. From this we constrain with 90% confidence the merger rate to be less than 12,600 Gpc−3 yr−1 for binary-neutron star systems and less than 3600 Gpc−3 yr−1 for neutron star-black hole systems. We discuss the astrophysical implications of these results, which we find to be in conflict with only the most optimistic predictions. However, we find that if no detection of neutron star-binary mergers is made in the next two Advanced LIGO and Advanced Virgo observing runs we would place significant constraints on the merger rates. Finally, assuming a rate of Gpc−3 yr−1, short gamma-ray bursts beamed toward the Earth, and assuming that all short gamma-ray bursts have binary-neutron star (neutron star-black hole) progenitors, we can use our 90% confidence rate upper limits to constrain the beaming angle of the gamma-ray burst to be greater than ( ).
ABSTRACT
In this work, we report the discovery and analysis of six new compact triply eclipsing triple star systems found with the TESS mission: TICs 37743815, 42565581, 54060695, 178010808, ...242132789, and 456194776. All of these exhibit distinct third-body eclipses where the inner eclipsing binary (EB) occults the third (‘tertiary’) star, or vice versa. We utilized the TESS photometry, archival photometric data, and available archival spectral energy distribution curves (SED) to solve for the properties of all three stars, as well as many of the orbital elements. We describe in detail our SED fits, search of the archival data for the outer orbital period, and the final global photodynamical analyses. From these analyses, we find that all six systems are coplanar to within 0°−5°, and are viewed nearly edge on (i.e. within a couple of degrees). The outer orbital periods and eccentricities of the six systems are {Pout (days), e}: {68.7, 0.36}, {123, 0.16}, {60.7, 0.01}, {69.0, 0.29}, {41.5, 0.01}, {93.9, 0.29}, respectively, in the order the sources are listed above. The masses of all 12 EB stars were in the range of 0.7–1.8 M⊙ and were situated near the main sequence. By contrast, the masses and radii of the tertiary stars ranged from 1.5 to 2.3 M⊙ and 2.9 to 12 R⊙, respectively. We use this information to estimate the occurrence rate of compact flat triple systems..
ABSTRACT A transient gravitational-wave signal, GW150914, was identified in the twin Advanced LIGO detectors on 2015 September 2015 at 09:50:45 UTC. To assess the implications of this discovery, the ...detectors remained in operation with unchanged configurations over a period of 39 days around the time of the signal. At the detection statistic threshold corresponding to that observed for GW150914, our search of the 16 days of simultaneous two-detector observational data is estimated to have a false-alarm rate (FAR) of , yielding a p-value for GW150914 of . Parameter estimation follow-up on this trigger identifies its source as a binary black hole (BBH) merger with component masses at redshift (median and 90% credible range). Here, we report on the constraints these observations place on the rate of BBH coalescences. Considering only GW150914, assuming that all BBHs in the universe have the same masses and spins as this event, imposing a search FAR threshold of 1 per 100 years, and assuming that the BBH merger rate is constant in the comoving frame, we infer a 90% credible range of merger rates between (comoving frame). Incorporating all search triggers that pass a much lower threshold while accounting for the uncertainty in the astrophysical origin of each trigger, we estimate a higher rate, ranging from depending on assumptions about the BBH mass distribution. All together, our various rate estimates fall in the conservative range .
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