We present simulation-based cosmological $w$CDM inference using Dark Energy
Survey Year 3 weak-lensing maps, via neural data compression of weak-lensing
map summary statistics: power spectra, peak ...counts, and direct map-level
compression/inference with convolutional neural networks (CNN). Using
simulation-based inference, also known as likelihood-free or implicit
inference, we use forward-modelled mock data to estimate posterior probability
distributions of unknown parameters. This approach allows all statistical
assumptions and uncertainties to be propagated through the forward-modelled
mock data; these include sky masks, non-Gaussian shape noise, shape measurement
bias, source galaxy clustering, photometric redshift uncertainty, intrinsic
galaxy alignments, non-Gaussian density fields, neutrinos, and non-linear
summary statistics. We include a series of tests to validate our inference
results. This paper also describes the Gower Street simulation suite: 791
full-sky PKDGRAV dark matter simulations, with cosmological model parameters
sampled with a mixed active-learning strategy, from which we construct over
3000 mock DES lensing data sets. For $w$CDM inference, for which we allow
$-1<w<-\frac{1}{3}$, our most constraining result uses power spectra combined
with map-level (CNN) inference. Using gravitational lensing data only, this
map-level combination gives $\Omega_{\rm m} = 0.283^{+0.020}_{-0.027}$, ${S_8 =
0.804^{+0.025}_{-0.017}}$, and $w < -0.80$ (with a 68 per cent credible
interval); compared to the power spectrum inference, this is more than a factor
of two improvement in dark energy parameter ($\Omega_{\rm DE}, w$) precision.
Tuberculous meningitis may rarely be followed by the development of syringomyelia despite appropriate chemotherapy. In the present paper, we report a case of tuberculous meningitis in a 23-year-old ...Vietnamese male complicated by a rapidly progressive myelopathy due to granulomatous arachnoiditis which culminated in the development of a syrinx. The relevant literature is reviewed. The present case supports the hypothesis that vasculitic thrombosis of spinal cord vessels leading to ischemic myelomalacia is the mechanism causing postinflammatory syringomyelia.
Abstract S100B (member of a family of proteins that are 100% soluble in ammonium sulfate at neutral pH) has been widely used as astrocyte marker in animal models and in human brain diseases. Recent ...studies revealed S100B-immunopositivity in oligodendrocytes and O2A oligodendroglial progenitor cells. It is unknown, however, if oligodendrocytes produce S100B themselves, or if the S100B-immunolabeling is caused by binding or absorption of the protein. To address this question, S100B expression and protein release were analyzed in a highly pure oligodendrocytic OLN-93 cell line (from rat), in the astrocytic C6 cell line (from rat) and primary astrocytes. S100B was gene expressed in all cultures, as revealed by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. OLN-93 cells and glial fibrillary acidic protein (GFAP)-negative astrocytes expressed the multiligand receptor for advanced glycation end products (RAGE). S100B protein levels were determined in supernatants and cell homogenates by immunoluminometry under normal conditions and after serum and glucose deprivation (SGD). SGD led to a several-fold increased release of S100B (after 6 and 24 h), which was particularly pronounced in primary astrocytes. Increased S100B in cell homogenates was most notable in OLN-93 cells under SGD, indicating activated S100B synthesis. These cells also showed the highest percentage of dead cells, as determined by propidium iodide-positivity, after SGD. Incubation with 0.5, 2 and 5 μg/l exogenous S100B was not toxic to OLN-93 cells. In conclusion, OLN-93 cells produce more S100B under SGD than astrocytes and are more susceptible to cell death upon SGD, which provokes leakage of S100B. Our data indicate active S100B secretion from astrocytes under SGD since highly elevated levels of S100B were detected in the supernatant despite a low percentage of dead cells. The experimental results provide further evidence for a production/release of S100B in/from oligodendrocytes, e.g. in metabolic stress conditions like cerebral ischemia. Studies on S100B in bodily fluids should be carefully interpreted in order to avoid misleading hypotheses concerning the specific involvement of astrocytes, due to the various cellular sources of S100B.
We infer the mean optical depth of a sample of optically-selected galaxy clusters from the Dark Energy Survey (DES) via the pairwise kinematic Sunyaev-Zel'dovich (kSZ) effect. The pairwise kSZ signal ...between pairs of clusters drawn from the DES Year-3 cluster catalog is detected at \(4.1 \sigma\) in cosmic microwave background (CMB) temperature maps from two years of observations with the SPT-3G camera on the South Pole Telescope. After cuts, there are 24,580 clusters in the \(\sim 1,400\) deg\(^2\) of the southern sky observed by both experiments. We infer the mean optical depth of the cluster sample with two techniques. The optical depth inferred from the pairwise kSZ signal is \(\bar{\tau}_e = (2.97 \pm 0.73) \times 10^{-3}\), while that inferred from the thermal SZ signal is \(\bar{\tau}_e = (2.51 \pm 0.55^{\text{stat}} \pm 0.15^{\rm syst}) \times 10^{-3}\). The two measures agree at \(0.6 \sigma\). We perform a suite of systematic checks to test the robustness of the analysis.
Background
Lanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.
Objective
To assess time to onset of effect and long‐term efficacy of ...lanadelumab, based on exploratory findings from the HELP Study.
Methods
Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0‐69 findings using a Poisson regression model accounting for overdispersion. Least‐squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0‐69 versus steady state (days 70‐182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.
Results
One hundred twenty‐five patients were randomized and treated. During days 0‐69, mean monthly attack rate was significantly lower with lanadelumab (0.41‐0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33‐0.61 vs 1.66) and moderate/severe attacks (0.31‐0.48 vs 1.33, all P ≤ .001). More patients receiving lanadelumab vs placebo were attack free (37.9%‐48.1% vs 7.3%) and responders (85.7%‐100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0‐69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable—HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0‐69 and 70‐182.
Conclusion
Protection with lanadelumab started from the first dose and continued throughout the entire study period.
During days 0‐69, lanadelumab‐treated patients had a significantly lower mean monthly hereditary angioedema (HAE) attack rate vs placebo and were more likely to be responders and attack free. Protection starts early and is sustained; during steady state, lanadelumab efficacy was similar or improved vs days 0‐69. Prophylactic agents with rapid onset, sustained effect, and convenient dosing frequency can improve HAE management plans. Abbreviations: HAE, hereditary angioedema; q2wks, every 2 weeks.
Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within ...families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.
H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that ...knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.
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•A CRISPR screen for HDAC inhibitor sensitizers in DIPG identifies KDM1A (LSD1)•Corin, a dual inhibitor of LSD1 and HDACs, inhibits DIPG growth in vitro and in vivo•Corin alters histone modifications to promote differentiation and block cell cycle•A Corin-induced gene expression signature correlates with prolonged survival in DIPG
Anastas et al. show that inhibition of LSD1 sensitizes diffuse intrinsic pontine glioma (DIPG) cells to HDAC inhibition and that Corin, which inhibits both LSD1 and HDACs, potently suppresses DIPG cell growth. A Corin-induced gene expression profile correlates with improved survival of DIPG patients.
The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. We therefore aimed to assess whether alterations in gut microbial ...composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn’s disease.
We used the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn’s disease. Gut barrier function was assessed using the urinary fractional excretion of lactulose-to-mannitol ratio (LMR). Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. The cohort was divided into a discovery cohort (n = 2472) and a validation cohort (n = 655). A regression model was used to assess microbial associations with the LMR. A random forest classifier algorithm was performed to assess microbial community contribution to barrier function.
Individuals with impaired barrier function (LMR >0.025) had reduced alpha-diversity (Chao1 index, P = 4.0e−4) and altered beta-diversity (Bray-Curtis dissimilarity index, R2 = 0.001, P = 1.0e−3) compared with individuals with an LMR ≤0.025. When taxa were assessed individually, we identified 8 genera and 52 microbial pathways associated with an LMR >0.025 (q < 0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and 8 pathways (including decreased biosynthesis of glutamate, tryptophan, and threonine) were replicated in the validation cohort. The random forest approach revealed that the bacterial community is associated with gut barrier function (area under the curve, 0.63; P = 1.4e−6).
The gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier.
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Alterations in gut microbiome are associated with gut barrier dysfunction in healthy humans.
We use a suite of simulated images based on Year 1 of the Dark Energy Survey to explore the impact of galaxy neighbours on shape measurement and shear cosmology. The hoopoe image simulations include ...realistic blending, galaxy positions, and spatial variations in depth and PSF properties. Using the im3shape maximum-likelihood shape measurement code, we identify four mechanisms by which neighbours can have a non-negligible influence on shear estimation. These effects, if ignored, would contribute a net multiplicative bias of \(m \sim 0.03 - 0.09\) in the DES Y1 im3shape catalogue, though the precise impact will be dependent on both the measurement code and the selection cuts applied. This can be reduced to percentage level or less by removing objects with close neighbours, at a cost to the effective number density of galaxies \(n_\mathrm{eff}\) of 30%. We use the cosmological inference pipeline of DES Y1 to explore the cosmological implications of neighbour bias and show that omitting blending from the calibration simulation for DES Y1 would bias the inferred clustering amplitude \(S_8\equiv \sigma_8 (\Omega _\mathrm{m} /0.3)^{0.5}\) by \(2 \sigma\) towards low values. Finally, we use the hoopoe simulations to test the effect of neighbour-induced spatial correlations in the multiplicative bias. We find the impact on the recovered \(S_8\) of ignoring such correlations to be subdominant to statistical error at the current level of precision.
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