SUMMARYEmbryogenesis requires epigenetic information that allows each cell to respond appropriately to developmental cues. Histone modifications are core components of a cell’s epigenome, giving rise to chromatin states that modulate genome function. Here, we systematically profile histone modifications in a diverse panel of mouse tissues at 8 developmental stages from 10.5 days post conception until birth, performing a total of 1,128 ChIP-seq assays across 72 distinct tissue-stages. We combine these histone modification profiles into a unified set of chromatin state annotations, and track their activity across developmental time and space. Through integrative analysis we identify dynamic enhancers, reveal key transcriptional regulators, and characterize the role of chromatin-based repression in developmental gene regulation. We also leverage these data to link enhancers to putative target genes, revealing connections between coding and non-coding sequence variation in disease etiology. Our study provides a compendium of resources for biomedical researchers, and achieves the most comprehensive view of embryonic chromatin states to date.

CAR bacillus infection should be considered as a differential diagnosis for pneumonia in rats in New Zealand.

For evaluating the effect of light absorption in vertically structured thin film light-emitting diodes (VLEDs), we investigate the dependence of the efficiencies on the several specific parameters including thickness and doping concentration (N(D)) of the n-GaN layer, a design of hetero-structures of the n-GaN layer, and a number of pairs of multi-quantum wells (MQWs). Generally, there is a complementary relation between internal quantum efficiency (IQE) and light extraction efficiency (LEE). However, we confirmed that LEE determined by light absorption is more dominant than IQE in VLED structures with a textured surface, from numerical simulation and experimental results. Effect of light absorption is more prominent in the vertical chip with a textured surface than in that with a flat surface, because a travel length of light extracted from the textured surface is longer. Minimizing light absorption in VLEDs is a key technology for improving light output, and light absorption speaks for the index of enhancement by the general technologies for improving LEE.

SUMMARYDNA double strand break (DSB) repair by Homologous recombination (HR) is initiated by the end resection, a process during which 3’ ssDNA overhangs are generated by the nucleolytic degradation. The extent of DNA end resection determines the choice of the DSB repair pathway. The role of several proteins including nucleases for end resection has been studied in detail. However, it is still unclear how the initial, nicked DNA generated by MRE11-RAD50-NBS1 is recognized and how subsequent proteins including EXO1 are recruited to DSB sites to facilitate extensive end resection. We found that the MutSβ (MSH2-MSH3) mismatch repair (MMR) complex is recruited to DSB sites by recognizing the initial nicked DNA at DSB sites through the interaction with the chromatin remodeling protein SMARCAD1. MSH2-MSH3 at DSB sites helps to recruit EXO1 for long-range resection and enhances its enzymatic activity. MSH2-MSH3 furthermore inhibits the access of DNA polymerase θ (POLQ), which promotes polymerase theta-mediated end-joining (TMEJ) of DSB. Collectively, our data show a direct role for MSH2-MSH3 in the initial stages of DSB repair by promoting end resection and influencing DSB repair pathway by favoring HR over TMEJ. Our findings extend the importance of MMR in DSB repair beyond established role in rejecting the invasion of sequences not perfectly homologous to template DNA during late-stage HR.

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.) R are diseases in aggregate affect approximately 30 million persons in the United States alone. 1 Although next-generation sequencing is revolutionizing their diagnosis, the sheer number of distinct conditions (more than 7000 [https://globalgenes . org/ rare -list]) and the limited number of patients affected by each rare disease present major challenges for drug development.This report shows a path to personalized treatment for patients with orphan diseases. It describes the identification of a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (CLN7, a form of Batten's disease), a rare and fatal neurodegenerative disease. 2,3 Identification of the mutation was followed by the development and clinical deployment, within 1 year, of a tailored drug to treat the patient (Fig. 1A). Clinic a l Pr esentationA 6-year-old girl presented with the insidious onset of blindness, ataxia, seizures, and developmental regression. The parents' first concerns dated back to when the girl was 3 years of age, when her right foot began to turn inward. When she was 4 years of age, her family noticed her pulling books close to her face at bedtime. At 5 years of age, she came to medical attention because of modest language and social regression, as well as increased clumsiness and stumbling. In the months before she turned 6 years of age, the progression of symptoms accelerated, and she wasThe authors' full names, academic degrees, and affiliations are listed in the Appendix.