Highlights from the IceCube Neutrino Observatory

As IceCube surpasses a decade of operation in the full detector configuration, results that drive forward the fields of neutrino astronomy, cosmic ray physics, multi-messenger astronomy, particle physics, and beyond continue to emerge at an accelerated pace. IceCube data is dominated by background events, and thus teasing out the signal is the common challenge to most analyses. Statistical accumulation of data, along with better understanding of the background fluxes, the detector, and continued development of our analysis tools have produced many profound results that were presented at ICRC2023. Highlights covered here include the first neutrino observation of the Galactic Plane, the first observation of a steady emission neutrino point source NGC1068, new characterizations of the cosmic ray flux and its secondary particles, and a possible new era in measuring the energy spectrum of the diffuse astrophysical flux. IceCube is poised to make more discoveries and drive fields forward in the near future with many novel analyses coming online.Comment: Presented at the 38th International Cosmic Ray Conference (ICRC2023). See arXiv:2307.13047 for all IceCube contribution

Search for Acoustic Signals from Ultra-High Energy Neutrinos in 1500 km^3 of Sea Water

An underwater acoustic sensor array spanning ~1500 km^3 is used to search for cosmic-ray neutrinos of ultra-high energies (UHE, E > 10^18 eV). Approximately 328 million triggers accumulated over an integrated 130 days of data taking are analysed. The sensitivity of the experiment is determined from a Monte Carlo simulation of the array using recorded noise conditions and expected waveforms. Two events are found to have properties compatible with showers in the energy range 10^24 to 5x10^24 eV and 10^22 to 5x10^22 eV. Since the understanding of impulsive backgrounds is limited, a flux upper limit is set providing the most sensitive limit on UHE neutrinos using the acoustic technique.Comment: Submitted to PRD. 8 pages, 12 figure

Oceanic Ambient Noise as a Background to Acoustic Neutrino Detection

Ambient noise measured in the deep ocean is studied in the context of a search for signals from ultra-high energy cosmic ray neutrinos. The spectral shape of the noise at the relevant high frequencies is found to be very stable for an extensive data set collected over several months from 49 hydrophones mounted near the bottom of the ocean at ~1600 m depth. The slopes of the ambient noise spectra above 15 kHz are found to roll-off faster than the -6 dB/octave seen in Knudsen spectra. A model attributing the source to an uniform distribution of surface noise that includes frequency-dependent absorption at large depth is found to fit the data well up to 25 kHz. This depth dependent model should therefore be used in analysis methods of acoustic neutrino pulse detection that require the expected noise spectra.Comment: Minor changes. Submitted to PRD. 5 pages, 7 figure

A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements

Background: Complex genomic rearrangements (CGRs) consisting of interstitial triplications in conjunction with uniparental isodisomy (isoUPD) have rarely been reported in patients with multiple congenital anomalies (MCA)/intellectual disability (ID). One-ended DNA break repair coupled with microhomology-mediated break-induced replication (MMBIR) has been recently proposed as a possible mechanism giving rise to interstitial copy number gains and distal isoUPD, although only a few cases providing supportive evidence in human congenital diseases with MCA have been documented. Case presentation: Here, we report on the chromosomal microarray (CMA)-based identification of the first known case with concurrent interstitial duplication at 1q42.12-q42.2 and triplication at 1q42.2-q43 followed by isoUPD for the remainder of chromosome 1q (at 1q43-qter). In distal 1q duplication/triplication overlapping with 1q42.12-q43, variable clinical features have been reported, and our 25-year-old patient with MCA/ID presented with some of these frequently described features. Further analyses including the precise mapping of breakpoint junctions within the CGR in a sequence level suggested that the CGR found in association with isoUPD in our case is a triplication with flanking duplications, characterized as a triplication with a particularly long duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure. Because microhomology was observed in both junctions between the triplicated region and the flanking duplicated regions, our case provides supportive evidence for recently proposed replication-based mechanisms, such as MMBIR, underlying the formation of CGRs + isoUPD implicated in chromosomal disorders. Conclusions: To the best of our knowledge, this is the first case of CGRs + isoUPD observed in 1q and having DUP-TRP/INV-DUP structure with a long proximal duplication, which supports MMBIR-based model for genomic rearrangements. Molecular cytogenetic analyses using CMA containing single-nucleotide polymorphism probes with further analyses of the breakpoint junctions are recommended in cases suspected of having complex chromosomal abnormalities based on discrepancies between clinical and conventional cytogenetic findings

ISR-DEPENDENT METABOLIC REGULATION

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation‐dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand‐activated skeletal muscle–specific derivative of the eIF2α protein kinase R‐like ER kinase revealed the expected up‐regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small‐molecule ISR activator that promoted Fgf21 expression in cell‐based screens and by implication of the ISR‐inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell‐autonomous proteostasis and amino acid metabolism, but also affects non‐cell‐autonomous metabolic regulation by induced expression of a potent myokine.—Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle‐specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21‐mediated non‐cell‐autonomous energy metabolism

Skeletal muscle–specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21–mediated non–cell-autonomous energy metabolism

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine.Ministry of Education, Culture, Sports, Science and Culture (MEXT) of Japan Inoue Foundation for Science Mitsubishi Foundation Uehara Memorial Foundation Naito Foundation Cell Science Research Foundation Takeda Science Foundation Sankyo Foundation Ono Medical Research Foundation Mochida Memorial Foundation Ube Foundation Kowa Life Science Foundation Suzuken Memorial Foundation Kanae Foundation Japan Diabetes Foundation Japan Society for Promotion of Science (JSPS) EU FP7. Grant Number: 277713 Wellcome Trust. Grant Number: 084812/Z/08/

Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and threematernally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins.We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such asmRNAexport, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in human

The All-sky Medium Energy Gamma-ray Observatory eXplorer (AMEGO-X) Mission Concept

The All-sky Medium Energy Gamma-ray Observatory eXplorer (AMEGO-X) is designed to identify and characterize gamma rays from extreme explosions and accelerators. The main science themes include: supermassive black holes and their connections to neutrinos and cosmic rays; binary neutron star mergers and the relativistic jets they produce; cosmic ray particle acceleration sources including Galactic supernovae; and continuous monitoring of other astrophysical events and sources over the full sky in this important energy range. AMEGO-X will probe the medium energy gamma-ray band using a single instrument with sensitivity up to an order of magnitude greater than previous telescopes in the energy range 100 keV to 1 GeV that can be only realized in space. During its three-year baseline mission, AMEGO-X will observe nearly the entire sky every two orbits, building up a sensitive all-sky map of gamma-ray sources and emission. AMEGO-X was submitted in the recent 2021 NASA MIDEX Announcement of Opportunity.Comment: 23 pages, 16 figures, Published Journal of Astronomical Telescopes, Instruments, and System