We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

We report on the discovery of FRB 20200120E, a repeating fast radio burst (FRB) with a low dispersion measure (DM) detected by the Canadian Hydrogen Intensity Mapping Experiment FRB project. The source DM of 87.82 pc cm −3 is the lowest recorded from an FRB to date, yet it is significantly higher than the maximum expected from the Milky Way interstellar medium in this direction (∼50 pc cm −3 ). We have detected three bursts and one candidate burst from the source over the period 2020 January-November. The baseband voltage data for the event on 2020 January 20 enabled a sky localization of the source to within ;14 arcmin 2 (90% confidence). The FRB localization is close to M81, a spiral galaxy at a distance of 3.6 Mpc. The FRB appears on the outskirts of M81 (projected offset ∼20 kpc) but well inside its extended H I and thick disks. We empirically estimate the probability of a chance coincidence with M81 to be <10 −2 . However, we cannot reject a Milky Way halo origin for the FRB. Within the FRB localization region, we find several interesting cataloged M81 sources and a radio point source detected in the Very Large Array Sky Survey. We search for prompt X-ray counterparts in Swift Burst Alert Telescope and Fermi/GBM data, and, for two of the FRB 20200120E bursts, we rule out coincident SGR 1806 −20-like X-ray bursts. Due to the proximity of FRB 20200120E, future follow-up for prompt multiwavelength counterparts and subarcsecond localization could be constraining of proposed FRB models. Unified AstronomyThesaurus concepts: Radio transient sources (2008); Radio bursts (1339); Transient sources (1851); Radio pulsars (1353)

Fast radio bursts (FRBs) are bright, millisecond-duration radio transients originating from extragalactic distances 1 . Their origin is unknown. Some FRB sources emit repeat bursts, ruling out cataclysmic origins for those events [2][3][4] . Despite searches for periodicity in repeat burst arrival times on time scales from milliseconds to many days 2, 5-7 , these bursts have hitherto been observed to appear sporadically, and though clustered 8 , without a regular pattern. Here we report the detection of a 16.35 ± 0.18 day periodicity from a repeating FRB 180916.J0158+65 detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project (CHIME/FRB) 4, 9 . In 28 bursts recorded from 16th September 2018 through 30th October 2019, we find that bursts arrive in a 4.0-day phase window, with some cycles showing no bursts, and some showing multiple bursts, within CHIME's limited daily exposure. Our results suggest a mechanism for periodic modulation either of the burst emission itself, or through external amplification or absorption, and disfavour models invoking purely sporadic processes.Last year the CHIME/FRB collaboration reported the discovery of eight new repeating FRB sources 4 , including FRB 180916.J0158+65, which was recently localized to a star-forming region in a nearby massive spiral galaxy at redshift 0.0337±0.0002 10 . From September 2018 to November 2019, CHIME/FRB has detected a total of 28 bursts from FRB 180916.J0158+65, which remains the most active source from this recent CHIME/FRB repeater sample. The barycentric arrival times for the 28 bursts (including those has been published before) from FRB 180916.J0158+65, corrected for delays from pulse dispersion, are listed in Extended Data Table 1.To search for periodicity, the burst arrival times (spanning a 400-day time range) were folded with different periods from 1.57 to 62.8 days (see Methods), with a Pearson's χ 2 test applied to each resulting profile with 8 phase bins 11 . A reduced χ 2 1 with respect to a uniform distribution indicates a periodicity unlikely to arise by chance. Furthermore, to account for the possible non-Poissonian statistics of the bursts 12 , we have applied the search with different weighting schemes that consider clustered bursts of different time range to be correlated events (see Methods).Searches with different weightings return periodograms of similar shape and have the same primary peak with significance varying between 3.5 − 8σ. As an example, the reduced χ 2 versus period using a weighting that counts only active days instead of individual events is shown in Figure 1a. A distinct peak is detected at 16.35 ± 0.18 days, with

A major role of the RNAi pathway in Schizosaccharomyces pombe is to nucleate heterochromatin, but it remains unclear whether this mechanism is conserved. To address this question in Drosophila, we performed genomewide localization of Argonaute2 (AGO2) by chromatin immunoprecipitation (ChIP)-seq in two different embryonic cell lines and found that AGO2 localizes to euchromatin but not heterochromatin. This localization pattern is further supported by immunofluorescence staining of polytene chromosomes and cell lines, and these studies also indicate that a substantial fraction of AGO2 resides in the nucleus. Intriguingly, AGO2 colocalizes extensively with CTCF/CP190 chromatin insulators but not with genomic regions corresponding to endogenous siRNA production. Moreover, AGO2, but not its catalytic activity or Dicer-2, is required for CTCF/CP190-dependent Fab-8 insulator function. AGO2 interacts physically with CTCF and CP190, and depletion of either CTCF or CP190 results in genome-wide loss of AGO2 chromatin association. Finally, mutation of CTCF, CP190, or AGO2 leads to reduction of chromosomal looping interactions, thereby altering gene expression. We propose that RNAi-independent recruitment of AGO2 to chromatin by insulator proteins promotes the definition of transcriptional domains throughout the genome.

Brain glucose metabolism is impaired during hypoglycemia, but, if sined, brain metabolism reverts to normal in animal models-data in man are lacking. We tested the hypothesis that adaptations occur to allow maintenance of normal rates of brain gluc uptake (BGU) following recurrent hypoglycemia in man. Twelve normal humans were studied over 4 days. (6). Based on the preceding series of facts, we presume that in sustained human hypoglycemia, normal increments in epinephrine and glucagon will fail to occur, reflecting a normalization ofglucose availability to the brain secondary to improved glucose uptake.We tested the hypothesis that the systemic glucose concentration required to impair brain glucose uptake (BGU) would occur near the usual basal glucose concentration in nondiabetic subjects but that after 56 hr of interprandial hypoglycemia, BGU would remain normal even at very subbasal glucose levels. Further, we hypothesized that increments in counterregulatory hormones, symptoms of hypoglycemia, and impairment in cognitive functions tests would be delayed until critically low arterial glucose levels were reached after the period of interprandial hypoglycemia. METHODS 9352The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.