Drosophila Kismet Regulates Histone H3 Lysine 27 Methylation and Early Elongation by RNA Polymerase II

Polycomb and trithorax group proteins regulate cellular pluripotency and differentiation by maintaining hereditable states of transcription. Many Polycomb and trithorax group proteins have been implicated in the covalent modification or remodeling of chromatin, but how they interact with each other and the general transcription machinery to regulate transcription is not well understood. The trithorax group protein Kismet-L (KIS-L) is a member of the CHD subfamily of chromatin-remodeling factors that plays a global role in transcription by RNA polymerase II (Pol II). Mutations in CHD7, the human counterpart of kis, are associated with CHARGE syndrome, a developmental disorder affecting multiple tissues and organs. To clarify how KIS-L activates gene expression and counteracts Polycomb group silencing, we characterized defects resulting from the loss of KIS-L function in Drosophila. These studies revealed that KIS-L acts downstream of P-TEFb recruitment to stimulate elongation by Pol II. The presence of two chromodomains in KIS-L suggested that its recruitment or function might be regulated by the methylation of histone H3 lysine 4 by the trithorax group proteins ASH1 and TRX. Although we observed significant overlap between the distributions of KIS-L, ASH1, and TRX on polytene chromosomes, KIS-L did not bind methylated histone tails in vitro, and loss of TRX or ASH1 function did not alter the association of KIS-L with chromatin. By contrast, loss of kis function led to a dramatic reduction in the levels of TRX and ASH1 associated with chromatin and was accompanied by increased histone H3 lysine 27 methylation—a modification required for Polycomb group repression. A similar increase in H3 lysine 27 methylation was observed in ash1 and trx mutant larvae. Our findings suggest that KIS-L promotes early elongation and counteracts Polycomb group repression by recruiting the ASH1 and TRX histone methyltransferases to chromatin

Impaired Left Ventricular Global Longitudinal Strain among Patients with Chronic Kidney Disease and End-Stage Renal Disease and Renal Transplant Recipients

Background: Although heart failure is the most prevalent cardiovascular disease associated with adverse outcome in chronic kidney disease (CKD) and after kidney transplantation, left ventricular (LV) systolic function is often preserved in renal patients. The aim of this study was to evaluate global longitudinal strain (GLS), which is reportedly a more accurate tool for detecting subclinical LV systolic dysfunction, in patients with various degrees of renal function impairment, including kidney transplant recipients (KTRs). Methods: This prospective study evaluated demographic, clinical, and ultrasound data, including the assessment of LV GLS and mitral E peak velocity and averaged ratio of mitral to myocardial early velocities (E/e'), of 70 consecutive renal patients (20 with stage 2-4 CKD, 25 with end-stage renal disease on hemodialysis [HD], and 25 KTRs). All patients had an LV ejection fraction 6550% and no history of heart failure or coronary artery disease. We used multivariable logistic analysis to assess the risk of compromised GLS. One hundred and twenty control subjects with or without hypertension served as controls. Results: A compromised GLS <-18% was shown in 55% of patients with stage 2-4 CKD, 60% of HD patients, and 28% of KTRs, while it was 32% in hypertensive controls and 12% in non-hypertensive controls (p < 0.0001). Patients with HD had higher systolic pressure and a significantly greater prevalence of increased LV mass and diastolic dysfunction. In renal patients, E/e' (p = 0.025), and LV mass index (p = 0.063) were independent predictors of compromised GLS at logistic regression analysis. E/e', systolic artery pressure, and LV mass also exhibited the greatest areas under the curve on receiver operating characteristic analysis to identify a compromised GLS. Conclusions: Renal disease proved to be associated with early and subclinical impairment of LV systolic function, which persists after starting dialysis and even in spite of successful kidney transplantation. An increased E/e' resulted to be the most powerful independent predictor of abnormal GLS

Enhancer-associated H3K4 methylation safeguards in vitro germline competence.

Funder: Studienstiftung des Deutschen VolkesGermline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of an in vitro PGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naïve pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, as in vitro germline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1-deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions

Guided Wave and Damage Detection in Composite Laminates Using Different Fiber Optic Sensors

Guided wave detection using different fiber optic sensors and their applications in damage detection for composite laminates were systematically investigated and compared in this paper. Two types of fiber optic sensors, namely fiber Bragg gratings (FBG) and Doppler effect-based fiber optic (FOD) sensors, were addressed and guided wave detection systems were constructed for both types. Guided waves generated by a piezoelectric transducer were propagated through a quasi-isotropic carbon fiber reinforced plastic (CFRP) laminate and acquired by these fiber optic sensors. Characteristics of these fiber optic sensors in ultrasonic guided wave detection were systematically compared. Results demonstrated that both the FBG and FOD sensors can be applied in guided wave and damage detection for the CFRP laminates. The signal-to-noise ratio (SNR) of guided wave signal captured by an FOD sensor is relatively high in comparison with that of the FBG sensor because of their different physical principles in ultrasonic detection. Further, the FOD sensor is sensitive to the damage-induced fundamental shear horizontal (SH0) guided wave that, however, cannot be detected by using the FBG sensor, because the FOD sensor is omnidirectional in ultrasound detection and, in contrast, the FBG sensor is severely direction dependent

Comprehensive molecular characterization of adamantinoma and OFD-like adamantinoma bone tumors

This is an accepted manuscript of an article published by Wolters Kluwer in American Journal of Surgical Pathology on 01/07/2019, available online: https://doi.org/10.1097/PAS.0000000000001251 The accepted version of the publication may differ from the final published version.Adamantinoma and osteofibrous dysplasia (OFD)-like adamantinoma are rare primary bone tumors that are predominantly confined to the tibia. These 2 entities show similarities in location, histology, and radiologic appearance; however, adamantinoma is malignant and therefore differentiating between these bone tumors is essential for optimal patient care. To elucidate their genomic and transcriptomic alteration profiles and expand their etiological mechanisms, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were conducted on adamantinoma and OFD-like adamantinoma tumors. Copy number variation analysis using WES data revealed distinct chromosomal alteration profiles for adamantinoma tumors compared with OFD-like adamantinomas, allowing molecular differentiation between the 2 tumor subtypes. Combining WES and copy number variation analyses, the chromatin remodelling-related gene KMT2D was recurrently altered in 3/8 adamantinoma tumors (38%), highlighting the potential involvement of deregulated chromatin structure and integrity in adamantinoma tumorigenesis. RNA-Seq analysis revealed a novel somatic gene fusion (EPHB4-MARCH10) in an adamantinoma, the gene fusion was fully characterized. Hierarchical clustering analysis of RNA-Seq data distinctly clustered adamantinoma tumors from OFD-like adamantinomas, allowing to molecularly distinguish between the 2 entities. David Gene Ontology analysis of differentially expressed genes identified distinct altered pathways in adamantinoma and OFD-like adamantinoma tumors, highlighting the different histopathologic characteristics of these bone tumor subtypes. Moreover, RNA-Seq expression profiling analysis identified elevated expression of DLK1 gene in adamantinomas, serving as a potential molecular biomarker. The present study revealed novel genetic and transcriptomic insights for adamantinoma and OFD-like adamantinoma tumors, allowing to differentiate genetically and transcriptomically between the 2 lesions and identifying a potential diagnostic marker for adamantinomas.Published versio

THE ROLE OF KISMET IN MAINTAINING TRANSCRIPTIONAL STATES IN DROSOPHILA

Polycomb and trithorax group proteins play highly conserved roles in cell fate maintenance by affecting gene expression during development. Acting at the level of chromatin regulation, Polycomb group proteins repress transcription while trithorax group proteins promote transcription. My research has focused on the function of the trithorax group protein Kismet (KIS) in Drosophila. KIS is a member of the CHD family of ATP-dependent chromatin-remodeling factors and is related to CHD7, a human protein linked to CHARGE syndrome. KIS maintains HOX gene transcription and facilitates global transcription elongation in Drosophila. In this work, I examined how KIS interacts with other trithorax group proteins to maintain active states of transcription. I found that KIS promotes the localization of the trithorax group histone methyltransferases ASH1 and TRX to chromatin, which antagonizes the methylation of histone H3 on lysine 27 (H3K27) by Polycomb group proteins. KIS recruits ASH1 to chromatin and antagonizes H3K27 methylation independently of its role in facilitating transcription elongation. Finally, I examined the mechanism by which ASH1 counteracts H3K27 methylation and found evidence that ASH1 dimethylates histone H3 on lysine 36 (H3K36) in vivo. My work indicates that KIS plays an important role in coordinating the function of trithorax group histone methyltransferases to antagonize Polycomb group repression by counteracting H3K27 methylation

Interaction of organic solvents with a subbituminous coal below pyrolysis temperature

The interactions of a subbituminous coal with pyridine, quinoline, piperidine, ethylenediamine, and tetrahydrofuran have been studied at temperatures ranging from 100 to 350/sup 0/C under the conditions of constant temperature contracting with pure solvent. The yields of extracted material were as high as 64.3 wt% with ethylenediamine at 250/sup 0/C on a dry, ash-free basis. The hydrogen to carbon molecular ratios in the extracts decreased with the temperature of extraction and as the yield increased and were found to be less than half that of the coal (1.01) in cases of large extracted yields. The extracted materials were generally only slightly soluble in cyclohexane or benzene, that is they consisted largely of preasphaltenes. Proton nuclear magnetic resonance studies indicated the hydrogen content of the extracted material was overwhelmingly (avg. = 88%) aliphatic. The more effective solvents were retained to a high degree in the extracted material. This fact, coupled with a hydrogen deficiency in the extract plus coal residue, suggests the formation of combinations between elements in the coal structure and solvent, accompanied by elimination of water

AIDdCas9Paper

<p>The analysis code for the publication "Accelerated drug resistant variant discovery with an enhanced, scalable mutagenic base editor platform" bioRxiv 2023.10.25.564011; doi: <a href="https://doi.org/10.1101/2023.10.25.564011">https://doi.org/10.1101/2023.10.25.564011</a></p&gt

FutureFlight Central: A Revolutionary Air Traffic Control Tower Simulation Facility

new air traffic control tower research facility dedicated to countering potential air and runway traffic problems at commercial airports is advancing the state- of-the-art in aviation research at the National Aeronautics and Space Administration (NASA) Ames Research Center. FutureFlight Central (FFC), is a unique real-time simulator designed to safely study new technologies, airport design changes or redesigns, and procedural changes in a virtual reality setting. The facility consists of a full-scale control tower, which depicts a 360-degree view of the airport under various weather conditions and times of day. Actual air traffic controllers operate the tower and communicate with pilots, ramp controllers and vehicle operators. "Humans-in-the-loop" provide a key distinction between conventional fast time simulation and what NASA has created in FFC. Human factors such as situational awareness, reaction time, visual perception and oral communication validate new designs and tools at a significantly higher level of accuracy and confidence. Recent integration of the tower with full- mission flight simulation allows assessment of airport changes from both the controller and pilot perspectives. With this new capability, technology developers, airport planners, and airline representatives are able to make more informed decisions. This paper describes the capabilities of FutureFlight Central, provides examples of typical projects, and addresses future applications