Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially ...promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology.
While acetylated, RNA-binding-deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centres of ...HSP70-family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we show that transient oxidative stress, proteasome inhibition or inhibition of the ATP-dependent chaperone activity of HSP70 provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independently of RNA binding or stress granules. Isotope labelling mass spectrometry was used to identify that phase-separated cytoplasmic TDP-43 is bound by the small heat-shock protein HSPB1. Binding is direct, mediated through TDP-43's RNA binding and low-complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced TDP-43 droplets. A decrease in HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion was identified in spinal motor neurons of patients with ALS containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.
Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert ...to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.
Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report ...the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.
Abstract Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic ...pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1−/− mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive symptoms in a time dependent manner and was associated with profound hippocampal alterations such as impaired neurogenesis, reduced expression of neuroplasticity markers and myelin proteins. The onset of depressive-like behavior also coincided with increased hippocampal levels of TNF, and decreased expression of TNF receptor 2 (TNFR2), which were all fully restored after mice spontaneously recovered from pain. Notably, TNFR1−/− mice did not develop depressive-like symptoms after injury, nor were there changes in hippocampal neurogenesis and plasticity. Our data show that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1.
Two water samples from the Great Dismal Swamp National Wildlife Refuge with high dissolved organic matter (DOM) concentrations (51 and 121 mg C L
−1
) were subjected to ultraviolet (UV) light for up ...to 110 days. During the course of the irradiations, 74–88 % of the original dissolved organic carbon was lost along with 95–99 % of the absorption at 300 nm. Based on changes observed during light exposure, three pools of DOM were identified: photo-labile, photo-refractory, and photo-produced compounds. Solid-state
13
C nuclear magnetic resonance (NMR) spectroscopy and Fourier transform infrared (FTIR) spectroscopy were used to determine structural moieties characteristic to each of these pools. These analyses showed aromatic carbons were preferentially removed while carbohydrate-like and amide/peptide-like carbons were preserved during UV exposure. An increase in carbon normalized
13
C NMR signal in the 0–50 ppm region suggests that alkyl moieties were produced, while FTIR signal at 1,745 cm
−1
and two-dimensional
1
H–
13
C NMR results confirmed the photochemical production of acetate. Several properties typically used to trace terrigenous DOM in ocean margin and marine environments were significantly altered. Optical properties, including absorption spectral slopes and fluorescence indices, as well as carbon-normalized lignin yields shifted from terrestrial values towards those more typical of coastal or open ocean samples. The loss of terrestrial signatures during irradiation highlights the difficulty faced when quantifying the contribution of terrigenous DOM to aquatic carbon pools.
Crop yields need to nearly double over the next 35 years to keep pace with projected population growth. Improving photosynthesis, via a range of genetic engineering strategies, has been identified as ...a promising target for crop improvement with regard to increased photosynthetic yield and better water-use efficiency (WUE). One approach is based on integrating components of the highly efficient CO2-concentrating mechanism (CCM) present in cyanobacteria (blue-green algae) into the chloroplasts of key C3 crop plants, particularly wheat and rice. Four progressive phases towards engineering components of the cyanobacterial CCM into C3 species can be envisaged. The first phase (1a), and simplest, is to consider the transplantation of cyanobacterial bicarbonate transporters to C3 chloroplasts, by host genomic expression and chloroplast targeting, to raise CO2 levels in the chloroplast and provide a significant improvement in photosynthetic performance. Mathematical modelling indicates that improvements in photosynthesis as high as 28% could be achieved by introducing both of the single-gene, cyanobacterial bicarbonate transporters, known as BicA and SbtA, into C3 plant chloroplasts. Part of the first phase (1b) includes the more challenging integration of a functional cyanobacterial carboxysome into the chloroplast by chloroplast genome transformation. The later three phases would be progressively more elaborate, taking longer to engineer other functional components of the cyanobacterial CCM into the chloroplast, and targeting photosynthetic and WUE efficiencies typical of C4 photosynthesis. These later stages would include the addition of NDH-1-type CO2 pumps and suppression of carbonic anhydrase and C3 Rubisco in the chloroplast stroma. We include a score card for assessing the success of physiological modifications gained in phase 1a.
Abstract
We used existing data from the New Horizons Long-range Reconnaissance Imager (LORRI) to measure the optical-band (0.4 ≲
λ
≲ 0.9
μ
m) sky brightness within seven high–Galactic latitude ...fields. The average raw level measured while New Horizons was 42–45 au from the Sun is 33.2 ± 0.5 nW m
−2
sr
−1
. This is ∼10× as dark as the darkest sky accessible to the Hubble Space Telescope, highlighting the utility of New Horizons for detecting the cosmic optical background (COB). Isolating the COB contribution to the raw total required subtracting scattered light from bright stars and galaxies, faint stars below the photometric detection limit within the fields, and diffuse Milky Way light scattered by infrared cirrus. We removed newly identified residual zodiacal light from the IRIS 100
μ
m all-sky maps to generate two different estimates for the diffuse Galactic light. Using these yielded a highly significant detection of the COB in the range 15.9 ± 4.2 (1.8 stat., 3.7 sys.) nW m
−2
sr
−1
to 18.7 ± 3.8 (1.8 stat., 3.3 sys.) nW m
−2
sr
−1
at the LORRI pivot wavelength of 0.608
μ
m. Subtraction of the integrated light of galaxies fainter than the photometric detection limit from the total COB level left a diffuse flux component of unknown origin in the range 8.8 ± 4.9 (1.8 stat., 4.5 sys.) nW m
−2
sr
−1
to 11.9 ± 4.6 (1.8 stat., 4.2 sys.) nW m
−2
sr
−1
. Explaining it with undetected galaxies requires the assumption that the galaxy count faint-end slope steepens markedly at
V
> 24 or that existing surveys are missing half the galaxies with
V
< 30.
The Drosophila melanogaster Genetic Reference Panel (DGRP) is a community resource of 205 sequenced inbred lines, derived to improve our understanding of the effects of naturally occurring genetic ...variation on molecular and organismal phenotypes. We used an integrated genotyping strategy to identify 4,853,802 single nucleotide polymorphisms (SNPs) and 1,296,080 non-SNP variants. Our molecular population genomic analyses show higher deletion than insertion mutation rates and stronger purifying selection on deletions. Weaker selection on insertions than deletions is consistent with our observed distribution of genome size determined by flow cytometry, which is skewed toward larger genomes. Insertion/deletion and single nucleotide polymorphisms are positively correlated with each other and with local recombination, suggesting that their nonrandom distributions are due to hitchhiking and background selection. Our cytogenetic analysis identified 16 polymorphic inversions in the DGRP. Common inverted and standard karyotypes are genetically divergent and account for most of the variation in relatedness among the DGRP lines. Intriguingly, variation in genome size and many quantitative traits are significantly associated with inversions. Approximately 50% of the DGRP lines are infected with Wolbachia, and four lines have germline insertions of Wolbachia sequences, but effects of Wolbachia infection on quantitative traits are rarely significant. The DGRP complements ongoing efforts to functionally annotate the Drosophila genome. Indeed, 15% of all D. melanogaster genes segregate for potentially damaged proteins in the DGRP, and genome-wide analyses of quantitative traits identify novel candidate genes. The DGRP lines, sequence data, genotypes, quality scores, phenotypes, and analysis and visualization tools are publicly available.
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