The African naked mole-rat’s (Heterocephalus glaber) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and ...survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.
Centromeres of higher eukaryotes are epigenetically marked by the centromere-specific CENP-A nucleosome. New CENP-A recruitment requires the CENP-A histone chaperone HJURP. In this paper, we show ...that a LacI (Lac repressor) fusion of HJURP drove the stable recruitment of CENP-A to a LacO (Lac operon) array at a noncentromeric locus. Ectopically targeted CENP-A chromatin at the LacO array was sufficient to direct the assembly of a functional centromere as indicated by the recruitment of the constitutive centromere-associated network proteins, the microtubule-binding protein NDC80, and the formation of stable kinetochore-microtubule attachments. An amino-terminal fragment of HJURP was able to assemble CENP-A nucleosomes in vitro, demonstrating that HJURP is a chromatin assembly factor. Furthermore, HJURP recruitment to endogenous centromeres required the Mis18 complex. Together, these data suggest that the role of the Mis18 complex in CENP-A deposition is to recruit HJURP and that the CENP-A nucleosome assembly activity of HJURP is responsible for centromeric chromatin assembly to maintain the epigenetic mark.
Strain engineering beyond substrate limitation of colossal magnetoresistant thin (La
Pr
)
Ca
MnO
(LPCMO) films on LaAlO
-buffered SrTiO
(LAO/STO) substrates has been demonstrated using metalorganic ...aerosol deposition technique. By growing partially relaxed 7-27 nm thick heteroepitaxial LAO buffer layers on STO a perfect lattice matching to the LPCMO has been achieved. As a result, strain-free heteroepitaxial 10-20 nm thick LPCMO/LAO/STO films with bulk-like ferromagnetic metallic ground state were obtained. Without buffer the coherently strained thin LPCMO/STO and LPCMO/LAO films were insulating and weakly magnetic. The reason for the optimized magnetotransport in strain-free LPCMO films was found to be a large octahedral Mn-O-Mn bond angle φ
~ 166-168° as compared to the significantly smaller one of φ
~ 152-156° determined for the tensile (LPCMO/STO) and compressively (LPCMO/LAO) strained films.
The epigenetic mark of the centromere is thought to be a unique centromeric nucleosome that contains the histone H3 variant, centromere protein‐A (CENP‐A). The deposition of new centromeric ...nucleosomes requires the CENP‐A‐specific chromatin assembly factor HJURP (Holliday junction recognition protein). Crystallographic and biochemical data demonstrate that the Scm3‐like domain of HJURP binds a single CENP‐A–histone H4 heterodimer. However, several lines of evidence suggest that HJURP forms an octameric CENP‐A nucleosome. How an octameric CENP‐A nucleosome forms from individual CENP‐A/histone H4 heterodimers is unknown. Here, we show that HJURP forms a homodimer through its C‐terminal domain that includes the second HJURP_C domain. HJURP exists as a dimer in the soluble preassembly complex and at chromatin when new CENP‐A is deposited. Dimerization of HJURP is essential for the deposition of new CENP‐A nucleosomes. The recruitment of HJURP to centromeres occurs independent of dimerization and CENP‐A binding. These data provide a mechanism whereby the CENP‐A pre‐nucleosomal complex achieves assembly of the octameric CENP‐A nucleosome through the dimerization of the CENP‐A chaperone HJURP.
Whether centromeric nucleosomes are hemisomes, or consist of canonical histone octamers with two CENP‐A subunits, is still unresolved. Obligatory dimerization of the CENP‐A assembly chaperone HJURP now provides support for the latter possibility.
Abstract
In Hunt et al., we used the Anderson–Darling (AD) two-sample test to evaluate the probability that the observed linear rank distributions for female and male principal investigators are from ...the same parent sample. We determined the nominal AD
p
-value,
ρ
AD
(
x
,
y
), where
x
and
y
are the female and male linear ranks, and estimated the uncertainty by calculating the mean and 68% confidence intervals from the AD
p
-value bootstrapped distributions,
ρ
AD
boot
. Since the
p
-value is a measure of probability, and the distribution of
p
-values is uniform, this method is not appropriate. Here we calculate
ρ
AD
boot
as the proportion of bootstrapped AD test statistics that are greater than or equal to the nominal AD test statistic. We find that the nominal and bootstrapped AD
p
-values are similar and therefore we do not recommend any changes to the conclusions in Hunt et al.
Gender Systematics in the NRAO Proposal Review System Hunt, Gareth; Schwab, Frederic R.; Henning, P. A. ...
Publications of the Astronomical Society of the Pacific,
11/2021, Letnik:
133, Številka:
1029
Journal Article
Recenzirano
Odprti dostop
Abstract
Several recent investigations indicate the existence of gender-related systematic trends in the peer review of proposals for observations on astronomical facilities. This includes the ...National Radio Astronomy Observatory (NRAO) where there is evidence of a gender imbalance in the rank of proposals with male principal investigators (PIs) favored over female PIs. Since semester 2017A (17A), the NRAO has taken the following steps: (1) inform science review panels (SRPs) and the telescope time allocation committee (TAC) about the gender imbalance; and (2) increase the female representation on SRPs and the TAC to reflect the community demographics. Here we analyze SRP normalized rank-ordered scores, or linear ranks, by PI gender for NRAO observing proposals from semesters 12A–21A. We use bootstrap resampling to generate modeled distributions and the Anderson–Darling (AD) test to evaluate the probability that the linear rank distributions for male and female PIs are drawn from the same parent sample. We find that between semesters 12A–17A that male PIs are favored over female PIs (AD
p
-value 0.0084), whereas between semesters 17B–21A female PIs are favored over male PIs, but at a lower significance (AD
p
-value 0.11). Therefore the gender imbalance is currently being ameliorated, but this imbalance may have been reversed. Regardless, we plan to adopt a dual-anonymous approach to proposal review to reduce the possibility of bias to occur.
The adhesion and degranulation-promoting adaptor protein (ADAP) serves as a multifunctional scaffold and is involved in the formation of immune signaling complexes. To date, only limited data exist ...regarding the role of ADAP in pathogen-specific immunity during
infection, and its contribution in phagocyte-mediated antibacterial immunity remains elusive. Here, we show that mice lacking ADAP (ADAPko) are highly susceptible to the infection with the intracellular pathogen
(
) by showing enhanced immunopathology in infected tissues together with increased morbidity, mortality, and excessive infiltration of neutrophils and monocytes. Despite high phagocyte numbers in the spleen and liver, ADAPko mice only inefficiently controlled pathogen growth, hinting at a functional impairment of infection-primed phagocytes in the ADAP-deficient host. Flow cytometric analysis of hallmark pro-inflammatory mediators and unbiased whole genome transcriptional profiling of neutrophils and inflammatory monocytes uncovered broad molecular alterations in the inflammatory program in both phagocyte subsets following their activation in the ADAP-deficient host. Strikingly,
phagocytosis assay revealed impaired phagocytic capacity of neutrophils derived from
-infected ADAPko mice. Together, our data suggest that an alternative priming of phagocytes in ADAP-deficient mice during
infection induces marked alterations in the inflammatory profile of neutrophils and inflammatory monocytes that contribute to enhanced immunopathology while limiting their capacity to eliminate the pathogen and to prevent the fatal outcome of the infection.
Sensitization of the capsaicin receptor TRPV1 is central to the initiation of pathological forms of pain, and multiple signaling cascades are known to enhance TRPV1 activity under inflammatory ...conditions. How might detrimental escalation of TRPV1 activity be counteracted? Using a genetic-proteomic approach, we identify the GABAB1 receptor subunit as bona fide inhibitor of TRPV1 sensitization in the context of diverse inflammatory settings. We find that the endogenous GABAB agonist, GABA, is released from nociceptive nerve terminals, suggesting an autocrine feedback mechanism limiting TRPV1 sensitization. The effect of GABAB on TRPV1 is independent of canonical G protein signaling and rather relies on close juxtaposition of the GABAB1 receptor subunit and TRPV1. Activating the GABAB1 receptor subunit does not attenuate normal functioning of the capsaicin receptor but exclusively reverts its sensitized state. Thus, harnessing this mechanism for anti-pain therapy may prevent adverse effects associated with currently available TRPV1 blockers.
Display omitted
•GABAB1 forms a complex with TRPV1 to counteract inflammatory pain•GABAB1 modulates TRPV1 via a non-canonical, GABAB2-independent pathway•TRPV1 activation triggers GABA release from peripheral nerve endings•GABA serves as a modulator of nociceptor sensitization in the periphery
The neurotransmitter GABA is released upon stimulation of the pain receptor TRPV1 and engages a non-canonical signaling pathway that inhibits only hyperactive TRPV1, leaving homeostatic pain responses intact.
Cerebral toxoplasmosis is characterized by activation of brain resident cells and recruitment of specific immune cell subsets from the periphery to the central nervous system (CNS). Our studies ...revealed that the rapidly invaded Ly6G
neutrophil granulocytes are an early non-lymphoid source of interferon-gamma (IFN-γ), the cytokine known to be the major mediator of host resistance to
(
). Upon selective depletion of Ly6G
neutrophils, we detected reduced IFN-γ production and increased parasite burden in the CNS. Ablation of Ly6G
cells resulted in diminished recruitment of Ly6C
monocytes into the CNS, indicating a pronounced interplay. Additionally, we identified infiltrated Ly6G
neutrophils to be a heterogeneous population. The Ly6G
CD62-L
CXCR4
subset released cathelicidin-related antimicrobial peptide (CRAMP), which can promote monocyte dynamics. On the other hand, the Ly6G
CD62-L
CXCR4
subset produced IFN-γ to establish early inflammatory response. Collectively, our findings revealed that the recruited Ly6G
CXCR4
neutrophil granulocytes display a heterogeneity in the CNS with a repertoire of effector functions crucial in parasite control and immune regulation upon experimental cerebral toxoplasmosis.
Brain-derived neurotrophic factor (BDNF) exerts its effects on neural plasticity via 2 distinct receptor types, the tyrosine kinase TrkB and the p75 neurotrophin receptor (p75NTR). The latter can ...promote inflammation and cell death while TrkB is critically involved in plasticity and memory, particularly in the hippocampus. Acute and chronic stress have been associated with suppression of hippocampal BDNF expression and impaired hippocampal plasticity. We hypothesized that p75NTR might be involved in the hippocampal stress response, in particular in stress-induced BDNF suppression, which might be accompanied by increased neuroinflammation.
We assessed hippocampal BDNF protein concentrations in wild-type mice compared that in mice lacking the long form of the p75NTR (p75NTR
) with or without prior exposure to a 1-hour restraint stress challenge. Hippocampal BDNF concentrations were measured using an optimized ELISA. Furthermore, whole-brain mRNA expression of pro-inflammatory interleukin-6 (
) was assessed with RT-PCR.
Deletion of full-length p75NTR was associated with higher hippocampal BDNF protein concentration in the stress condition, suggesting persistently high hippocampal BDNF levels in p75NTR-deficient mice, even under stress. Stress elicited increased whole-brain
mRNA expression irrespective of genotype; however, p75NTR
mice showed elevated baseline
expression and thus a lower relative increase.
Our results provide evidence for a role of p75NTR signaling in the regulation of hippocampal BDNF levels, particularly under stress. Furthermore, p75NTR signaling modulates baseline but not stress-related
gene expression in mice. Our findings implicate p75NTR signaling as a potential pathomechanism in BDNF-dependent modulation of risk for neuropsychiatric disorders.
PDF
