Comparison of normalization and differential expression analyses using RNA-Seq data from 726 individual Drosophila melanogaster

Comparison of normalization methods across conditions. Boxplots show the differences in the coefficient of variation across flies in each genotype/sex/environment condition. (PDF 245 kb

The acidic tumor microenvironment enhances PD-L1 expression via activation of STAT3 in MDA-MB-231 breast cancer cells

Abstract Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2018R1A5A2025964) and the Seoul National University Hospital (SNUH) Research Fund (04–20200230). This study was also carried out with support from the R&D Program for Forest Science Technology (Project No. 2020195A00–2122-BA01) of the Korea Forest Service (Korea Forestry Promotion Institute) and Cooperative Research Program for the Agriculture Science and Technology Development (Project No. PJ01589402 and No. PJ016202022) Rural Development Administration, Republic of Korea

Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population

Background: Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer's disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods: One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results: In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10-8). Prediction performance for Aβ positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74-0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. Conclusion: The novel genetic variants associated with FGL2 decreased risk of Aβ positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations

GW190412: Observation of a Binary-Black-Hole Coalescence with Asymmetric Masses

We report the observation of gravitational waves from a binary-black-hole coalescence during the first two weeks of LIGO’s and Virgo’s third observing run. The signal was recorded on April 12, 2019 at 05∶30∶44 UTC with a network signal-to-noise ratio of 19. The binary is different from observations during the first two observing runs most notably due to its asymmetric masses: a ∼30 M_⊙ black hole merged with a ∼8 M_⊙ black hole companion. The more massive black hole rotated with a dimensionless spin magnitude between 0.22 and 0.60 (90% probability). Asymmetric systems are predicted to emit gravitational waves with stronger contributions from higher multipoles, and indeed we find strong evidence for gravitational radiation beyond the leading quadrupolar order in the observed signal. A suite of tests performed on GW190412 indicates consistency with Einstein’s general theory of relativity. While the mass ratio of this system differs from all previous detections, we show that it is consistent with the population model of stellar binary black holes inferred from the first two observing runs

Properties and Astrophysical Implications of the 150 M_⊙ Binary Black Hole Merger GW190521

The gravitational-wave signal GW190521 is consistent with a binary black hole (BBH) merger source at redshift 0.8 with unusually high component masses, 85⁺²¹₋₁₄ M_⊙ and 66⁺¹⁷₋₁₈ M_⊙, compared to previously reported events, and shows mild evidence for spin-induced orbital precession. The primary falls in the mass gap predicted by (pulsational) pair-instability supernova theory, in the approximate range 65–120 M_⊙. The probability that at least one of the black holes in GW190521 is in that range is 99.0%. The final mass of the merger 142⁺²⁸₋₁₆ M_⊙) classifies it as an intermediate-mass black hole. Under the assumption of a quasi-circular BBH coalescence, we detail the physical properties of GW190521's source binary and its post-merger remnant, including component masses and spin vectors. Three different waveform models, as well as direct comparison to numerical solutions of general relativity, yield consistent estimates of these properties. Tests of strong-field general relativity targeting the merger-ringdown stages of the coalescence indicate consistency of the observed signal with theoretical predictions. We estimate the merger rate of similar systems to be 0.13_(-0.11)^(+0.30) Gpc⁻³ yr⁻¹. We discuss the astrophysical implications of GW190521 for stellar collapse and for the possible formation of black holes in the pair-instability mass gap through various channels: via (multiple) stellar coalescences, or via hierarchical mergers of lower-mass black holes in star clusters or in active galactic nuclei. We find it to be unlikely that GW190521 is a strongly lensed signal of a lower-mass black hole binary merger. We also discuss more exotic possible sources for GW190521, including a highly eccentric black hole binary, or a primordial black hole binary