Resilience and cortical thickness: a MRI study Kahl, Michael; Wagner, Gerd; de la Cruz, Feliberto ...
European archives of psychiatry and clinical neuroscience,
08/2020, Letnik:
270, Številka:
5
Journal Article
The plant‐sourced polyketide triacetic acid lactone (TAL) has been recognized as a promising platform chemical for the biorefinery industry. However, its practical application was rather limited due ...to low natural abundance and inefficient cell factories for biosynthesis. Here, we report the metabolic engineering of oleaginous yeast Rhodotorula toruloides for TAL overproduction. We first introduced a 2‐pyrone synthase gene from Gerbera hybrida (GhPS) into R. toruloides and investigated the effects of different carbon sources on TAL production. We then systematically employed a variety of metabolic engineering strategies to increase the flux of acetyl‐CoA by enhancing its biosynthetic pathways and disrupting its competing pathways. We found that overexpression of ATP‐citrate lyase (ACL1) improved TAL production by 45% compared to the GhPS overexpressing strain, and additional overexpression of acetyl‐CoA carboxylase (ACC1) further increased TAL production by 29%. Finally, we characterized the resulting strain I12‐ACL1‐ACC1 using fed‐batch bioreactor fermentation in glucose or oilcane juice medium with acetate supplementation and achieved a titer of 28 or 23 g/L TAL, respectively. This study demonstrates that R. toruloides is a promising host for the production of TAL and other acetyl‐CoA‐derived polyketides from low‐cost carbon sources.
Triacetic acid lactone (TAL) is a promising platform chemical. Cao et al. overexpressed 2‐pyrone synthase in oleaginous yeast Rhodotorula toruloides to produce TAL. They systematically evaluated various metabolic gene targets to increase acetyl‐CoA and malonyl‐CoA levels for TAL production and found that overexpression of both ACL1 and ACC1 led to 28 or 23 g/L of TAL from glucose or oilcane juice with acetate supplementation, respectively, in fed‐batch fermentation.
Establishment of a proper chromatin landscape is central to genome function. Here, we explain H3 variant distribution by specific targeting and dynamics of deposition involving the CAF-1 and HIRA ...histone chaperones. Impairing replicative H3.1 incorporation via CAF-1 enables an alternative H3.3 deposition at replication sites via HIRA. Conversely, the H3.3 incorporation throughout the cell cycle via HIRA cannot be replaced by H3.1. ChIP-seq analyses reveal correlation between HIRA-dependent H3.3 accumulation and RNA pol II at transcription sites and specific regulatory elements, further supported by their biochemical association. The HIRA complex shows unique DNA binding properties, and depletion of HIRA increases DNA sensitivity to nucleases. We propose that protective nucleosome gap filling of naked DNA by HIRA leads to a broad distribution of H3.3, and HIRA association with Pol II ensures local H3.3 enrichment at specific sites. We discuss the importance of this H3.3 deposition as a salvage pathway to maintain chromatin integrity.
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► Failure in H3.1 deposition at replication sites permits replacement by H3.3 via HIRA ► RNA pol II presence correlates with H3.3 enrichment at genes and associates with HIRA ► DNA binding ability of HIRA reveals a gap-filling mechanism for H3.3 deposition ► HIRA-dependent H3.3 deposition as a salvage pathway to maintain chromatin integrity
The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which ...currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 ...drugs. Screening in Vero cells finds few antivirals, while screening in human Huh7.5 cells validates 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we find that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we find nine drugs are antiviral in respiratory cells, seven of which have been used in humans, and three are US Food and Drug Administration (FDA) approved, including cyclosporine. We find that the antiviral activity of cyclosporine is targeting Cyclophilin rather than calcineurin, revealing essential host targets that have the potential for rapid clinical implementation.
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•3,000 compounds screened in two cell types against SARS-CoV-2•Entry pathways are distinct in hepatocyte Huh7.5 and respiratory Calu-3 cells•Only nine compounds that are active in Huh7.5 cells are active in Calu-3 cells•Cyclosporin and cyclophilin inhibitors block SARS-CoV-2 infection in diverse cells
There is an urgent need for antivirals to treat the newly emerged SARS-CoV-2. Dittmar et al. find nine host-directed drugs are antiviral in respiratory cells, seven of which have been given to humans, and three are FDA approved. We show host targets that have the potential for rapid clinical implementation.
Abstract
Observations indicate that turbulent motions are present on most massive star surfaces. Starting from the observed phenomena of spectral lines with widths that are much larger than their ...thermal broadening (e.g., micro- and macroturbulence), and considering the detection of stochastic low-frequency variability (SLFV) in the Transiting Exoplanet Survey Satellite photometry, these stars clearly have large-scale turbulent motions on their surfaces. The cause of this turbulence is debated, with near-surface convection zones, core internal gravity waves, and wind variability being proposed. Our 3D gray radiation hydrodynamic (RHD) models previously characterized the convective dynamics of the surfaces, driven by near-surface convection zones, and provided reasonable matches to the observed SLFV of the most luminous massive stars. We now explore the complex emitting surfaces of these 3D RHD models, which strongly violate the 1D assumption of a plane-parallel atmosphere. By post-processing the gray RHD models with the Monte Carlo radiation transport code
Sedona
, we synthesize stellar spectra and extract information from the broadening of individual photospheric lines. The use of
Sedona
enables the calculation of the viewing angle and temporal dependence of spectral absorption line profiles. By combining uncorrelated temporal snapshots together, we compare the turbulent broadening from the 3D RHD models to the thermal broadening of the extended emitting region, showing that our synthesized spectral lines closely resemble the observed macroturbulent broadening from similarly luminous stars. More generally, the new techniques that we have developed will allow for systematic studies of the origins of turbulent velocity broadening from any future 3D simulations.
The identification of the human homologue of the yeast CST in 2009 posed a new challenge in our understanding of the mechanism of telomere capping in higher eukaryotes. The high-resolution structure ...of the human Stn1-Ten1 (hStn1-Ten1) complex presented here reveals that hStn1 consists of an OB domain and tandem C-terminal wHTH motifs, while hTen1 consists of a single OB fold. Contacts between the OB domains facilitate formation of a complex that is strikingly similar to the replication protein A (RPA) and yeast Stn1-Ten1 (Ten1) complexes. The hStn1-Ten1 complex exhibits non-specific single-stranded DNA activity that is primarily dependent on hStn1. Cells expressing hStn1 mutants defective for dimerization with hTen1 display elongated telomeres and telomere defects associated with telomere uncapping, suggesting that the telomeric function of hCST is hTen1 dependent. Taken together the data presented here show that the structure of the hStn1-Ten1 subcomplex is conserved across species. Cell based assays indicate that hTen1 is critical for the telomeric function of hCST, both in telomere protection and downregulation of telomerase function.
Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in ...pancreatic acinar cells harboring
mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in
-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT-ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA-dependent processes exerts anticancer effects. SIGNIFICANCE: Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways.
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Abstract Major depressive disorder (MDD) is associated with an increased risk for suicide. There is considerable evidence that a predisposition to suicidal behavior may exist which is independent of ...the MDD itself. Recent studies suggest a familial transmission of the diathesis for suicidal behavior, reflected in the observation of suicide aggregation in families and higher rate of suicidal behavior in first-degree relatives of suicide attempters with MDD. One of these transmission factors may be neurobiological alterations. The main goal of the present study was therefore to study abnormalities in cortical thickness in the hypothesized fronto-cingulate network in depressed patients with high risk for suicide. 15 MDD patients with documented own suicidal behavior and/or with suicidal behavior in first-degree relatives (high risk group), 15 depressed patients with non-high risk for suicide and 30 matched healthy controls participated in the study. Using an automated surface based approach (FreeSurfer) structural T1-weighted volumes were analyzed for differences in cortical thickness on a node by node basis covering the entire cortex. Patients with high risk for suicide showed significantly thinner cortex in the left dorsolateral, ventrolateral prefrontal cortex and the anterior cingulate in contrast to non-high risk patients. Together with previous morphometric results of our group, this new finding provides strong evidence for structural brain alterations in depressed patients with high risk for suicide in the fronto-cingulo-striatal network, which is strongly involved in reward processing and behavioral/emotional control. This alteration may constitute the neurobiological basis for an increased predisposition to suicidal behavior.
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