The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition

Recent Progress and Next Steps for the MATHUSLA LLP Detector

We report on recent progress and next steps in the design of the proposed MATHUSLA Long Lived Particle (LLP) detector for the HL-LHC as part of the Snowmass 2021 process. Our understanding of backgrounds has greatly improved, aided by detailed simulation studies, and significant R&D has been performed on designing the scintillator detectors and understanding their performance. The collaboration is on track to complete a Technical Design Report, and there are many opportunities for interested new members to contribute towards the goal of designing and constructing MATHUSLA in time for HL-LHC collisions, which would increase the sensitivity to a large variety of highly motivated LLP signals by orders of magnitude.Comment: Contribution to Snowmass 2021 (EF09, EF10, IF6, IF9), 18 pages, 12 figures. v2: included additional endorser

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

CD4陽性T細胞に発現するA20(tnfaip3) はTh2型アレルギー性気道炎症を抑制する

研究科: 千葉大学大学院医学薬学府（先端医学薬学専攻）学位記番号: 千大院医薬博甲第医1412号博士（医学）千葉大学 = Chiba Universit

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Adaptive mechanisms regulate preferred utilization of ketones in the heart and brain of a hibernating mammal during arousal from torpor

Hibernating mammals use reduced metabolism, hypothermia, and stored fat to survive up to 5 or 6 mo without feeding. We found serum levels of the fat-derived ketone, d-β-hydroxybutyrate (BHB), are highest during deep torpor and exist in a reciprocal relationship with glucose throughout the hibernation season in the thirteen-lined ground squirrel (Spermophilus tridecemlineatus). Ketone transporter monocarboxylic acid transporter 1 (MCT1) is upregulated at the blood-brain barrier, as animals enter hibernation. Uptake and metabolism of 13C-labeled BHB and glucose were measured by high-resolution NMR in both brain and heart at several different body temperatures ranging from 7 to 38°C. We show that BHB and glucose enter the heart and brain under conditions of depressed body temperature and heart rate but that their utilization as a fuel is highly selective. During arousal from torpor, glucose enters the brain over a wide range of body temperatures, but metabolism is minimal, as only low levels of labeled metabolites are detected. This is in contrast to BHB, which not only enters the brain but is also metabolized via the tricarboxylic acid (TCA) cycle. A similar situation is seen in the heart as both glucose and BHB are transported into the organ, but only 13C from BHB enters the TCA cycle. This finding suggests that fuel selection is controlled at the level of individual metabolic pathways and that seasonally induced adaptive mechanisms give rise to the strategic utilization of BHB during hibernation

Geospatial and Temporal Associations between Increases in Opioid Deaths, Socioeconomics, and Rates of Sexually Transmitted Infections in the Northeast United States 2012–2017

With the introduction of fentanyl to illegal markets in 2013 and an overall rise in rates of synthetic opioid use, opioid-related deaths have increased significantly. A similar trend has been observed for sexually transmitted infections, homicides, and poor mental health outcomes. In this paper, we explore the spatiotemporal relationship between opioid death rates and sexually transmitted infection (STI) rates in counties from the Northeast region of the United States between the years 2012–2017. We hypothesized that rates for gonorrhea, chlamydia, and human immunodeficiency virus (HIV) would all be positively associated with opioid death rates and that there would be a similar association between the STI rates and later time periods relative to earlier time periods. A negative binomial mixed-effects regression model was employed to assess these associations. Contrary to the study hypothesis, opioid death rates were not found to be significantly associated with the STI rates after accounting for other demographic and socioeconomic variables, with the exception of opioid deaths and gonorrhea in urban counties. Additionally, the regression demonstrated a significant association between infection rate and time period beyond the included socioeconomic variables and opioid deaths. Overall, this study indicates that declining sexual health outcomes may parallel rising opioid death, though both trends may be explained by similar underlying factors related to time period

Brain energy metabolism and neurotransmission at near-freezing temperatures: in vivo (1)H MRS study of a hibernating mammal

The brain of a hibernating mammal withstands physiological extremes that would result in cerebral damage and death in a non-hibernating species such as humans. To examine the possibility that this neuroprotection results from alterations in cerebral metabolism, we used in vivo(1)H NMR spectroscopy at high field (9.4 T) to measure the concentration of 18 metabolites (neurochemical profile) in the brain of 13-lined ground squirrels (Spermophilus tridecemlineatus) before, during, and after hibernation. Resolved in vivo(1)H NMR spectra were obtained even at low temperature in torpid hibernators ( approximately 7 degrees C). The phosphocreatine-to-creatine ratio was increased during torpor (+143%) indicating energy storage, and remained increased to a lesser extent during interbout arousal (IBA) (+83%). The total gamma-aminobutyric acid concentration was increased during torpor (+135%) and quickly returned to baseline during IBA. Glutamine (Gln) was decreased (-54%) during torpor but quickly returned to normal levels during IBA and after terminal arousal in the spring. Glutamate (Glu) was also decreased during torpor (-17%), but remained decreased during IBA (-20% compared with fall), and returned to normal level in the spring. Our observation that Glu and Gln levels are depressed in the brain of hibernators suggests that the balance between anaplerosis and loss of Glu and Gln (because of glutamatergic neurotransmission or other mechanisms) is altered in hibernation