Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Unusual Near-Horizon Cosmic-Ray-like Events Observed by ANITA-IV.

ANITA's fourth long-duration balloon flight in 2016 detected 29 cosmic-ray (CR)-like events on a background of 0.37_{-0.17}^{+0.27} anthropogenic events. CRs are mainly seen in reflection off the Antarctic ice sheets, creating a phase-inverted waveform polarity. However, four of the below-horizon CR-like events show anomalous noninverted polarity, a p=5.3×10^{-4} chance if due to background. All anomalous events are from locations near the horizon; ANITA-IV observed no steeply upcoming anomalous events similar to the two such events seen in prior flights.

A fast radio burst associated with a Galactic magnetar.

Since their discovery in 20071, much effort has been devoted to uncovering the sources of the extragalactic, millisecond-duration fast radio bursts (FRBs)2. A class of neutron stars known as magnetars is a leading candidate source of FRBs3,4. Magnetars have surface magnetic fields in excess of 1014 gauss, the decay of which powers a range of high-energy phenomena5. Here we report observations of a millisecond-duration radio burst from the Galactic magnetar SGR 1935+2154, with a fluence of 1.5 ± 0.3 megajansky milliseconds. This event, FRB 200428 (ST 200428A), was detected on 28 April 2020 by the STARE2 radio array6 in the 1,281-1,468 megahertz band. The isotropic-equivalent energy released in FRB 200428 is 4 × 103 times greater than that of any radio pulse from the Crab pulsar-previously the source of the brightest Galactic radio bursts observed on similar timescales7. FRB 200428 is just 30 times less energetic than the weakest extragalactic FRB observed so far8, and is drawn from the same population as the observed FRB sample. The coincidence of FRB 200428 with an X-ray burst9-11 favours emission models that describe synchrotron masers or electromagnetic pulses powered by magnetar bursts and giant flares3,4,12,13. The discovery of FRB 200428 implies that active magnetars such as SGR 1935+2154 can produce FRBs at extragalactic distances.

Impact of reduced-representation sequencing protocols on detecting population structure in a threatened marsupial.

Reduced-representation sequencing methods have wide utility in conservation genetics of non-model species. Several methods are now available that reduce genome complexity to examine a wide range of markers in a large number of individuals. We produced two datasets collected using different laboratory techniques, comprising a common set of samples from the greater bilby (Macrotis lagotis). We examined the impact of differing data filtering thresholds on downstream population inferences. We found that choice of restriction enzyme and data filtering thresholds, especially the rate of allowable missing data, impacted our ability to detect population structure. Estimates of FST were robust to alterations in laboratory and bioinformatic protocols while principal coordinates and STRUCTURE analyses showed variation according to the number of loci and percent missing data. We advise researchers using reduced-representation sequencing in conservation projects to examine a range of data thresholds, and follow these through to downstream population inferences. Multiple measures of population differentiation should be used in order to fully understand how data filtering thresholds influence the final dataset, paying particular attention to the impact of allowable missing data. Our results indicate that failure to follow these checks could impact conclusions drawn, and conservation management decisions made.

A Tasmanian devil breeding program to support wild recovery.

Tasmanian devils are threatened in the wild by devil facial tumour disease: a transmissible cancer with a high fatality rate. In response, the Save the Tasmanian Devil Program (STDP) established an 'insurance population' to enable the preservation of genetic diversity and natural behaviours of devils. This breeding program includes a range of institutions and facilities, from zoo-based intensive enclosures to larger, more natural environments, and a strategic approach has been required to capture and maintain genetic diversity, natural behaviours and to ensure reproductive success. Laboratory-based research, particularly genetics, in tandem with adaptive management has helped the STDP reach its goals, and has directly contributed to the conservation of the species in the wild. Here we review this work and show that the Tasmanian devil breeding program is a powerful example of how genetic research can be used to understand and improve reproductive success in a threatened species.

Observation of an Unusual Upward-Going Cosmic-Ray-like Event in the Third Flight of ANITA.

We report on an upward traveling, radio-detected cosmic-ray-like impulsive event with characteristics closely matching an extensive air shower. This event, observed in the third flight of the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload, is consistent with a similar event reported in a previous flight. These events could be produced by the atmospheric decay of an upward-propagating τ lepton produced by a ν_{τ} interaction, although their relatively steep arrival angles create tension with the standard model neutrino cross section. Each of the two events have a posteriori background estimates of ≲10^{-2} events. If these are generated by τ-lepton decay, then either the charged-current ν_{τ} cross section is suppressed at EeV energies, or the events arise at moments when the peak flux of a transient neutrino source was much larger than the typical expected cosmogenic background neutrinos.

Immune-endocrine interactions in marsupials and monotremes.

Interactions between the immune and endocrine systems are not well studied in marsupials and monotremes. One exception to this is the phenomenon of semelparity, which is well covered in the literature as this is an unusual reproductive strategy amongst mammals and is only observed in some dasyurid and didelphid marsupials. Thymus involution provides a direct link between the endocrine and immune systems and warrants further study in marsupials and monotremes. The thymus is a primary immune tissue which is essential for overall immune function. Whilst the organ is large in juvenile animals, it begins to involute around puberty due to the suppressive effects of sex steroids. Thymus involution has a significant effect on the immune system, as it signals the onset of immune aging and decline in function. The output of naïve T lymphocytes by the thymus decreases, increasing susceptibility of aged individuals to infection and cancers. Understanding the links between the immune and endocrine system in marsupials and monotremes may shed light on diseases such as devil facial tumour disease (DFTD) which threatens the future of the Tasmanian devil. We hypothesise that changes in sex hormones around puberty may drive changes in the immune system, such as thymus involution, which may make devils more susceptible to DFTD as they age. In addition, the Schwann cell origin of DFTD may enable tumours to respond to sex hormones, as occurs in similar cancers in humans.

Cathelicidins in the Tasmanian devil (Sarcophilus harrisii).

Tasmanian devil joeys, like other marsupials, are born at a very early stage of development, prior to the development of their adaptive immune system, yet survive in a pathogen-laden pouch and burrow. Antimicrobial peptides, called cathelicidins, which provide innate immune protection during early life, are expressed in the pouch lining, skin and milk of devil dams. These peptides are active against pathogens identified in the pouch microbiome. Of the six characterised cathelicidins, Saha-CATH5 and 6 have broad-spectrum antibacterial activity and are capable of killing problematic human pathogens including methicillin-resistant S. aureus and vancomycin-resistant E. faecalis, while Saha-CATH3 is active against fungi. Saha-CATH5 and 6 were toxic to human A549 cells at 500 µg/mL, which is over seven times the concentration required to kill pathogens. The remaining devil cathelicidins were not active against tested bacterial or fungal strains, but are widely expressed throughout the body, such as in immune tissues, in digestive, respiratory and reproductive tracts, and in the milk and pouch, which indicates that they are likely also important components of the devil immune system. Our results suggest cathelicidins play a role in protecting naive young during pouch life by passive immune transfer in the milk and may modulate pouch microbe populations to reduce potential pathogens.

Characteristics of Four Upward-Pointing Cosmic-Ray-like Events Observed with ANITA.

We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here, we report on characteristics of these three unusual CR events, which develop nearly horizontally, 20-30 km above the surface of Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible τ-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the standard model τ-neutrino cross section.

Accelerator Measurements of Magnetically Induced Radio Emission from Particle Cascades with Applications to Cosmic-Ray Air Showers.

For 50 years, cosmic-ray air showers have been detected by their radio emission. We present the first laboratory measurements that validate electrodynamics simulations used in air shower modeling. An experiment at SLAC provides a beam test of radio-frequency (rf) radiation from charged particle cascades in the presence of a magnetic field, a model system of a cosmic-ray air shower. This experiment provides a suite of controlled laboratory measurements to compare to particle-level simulations of rf emission, which are relied upon in ultrahigh-energy cosmic-ray air shower detection. We compare simulations to data for intensity, linearity with magnetic field, angular distribution, polarization, and spectral content. In particular, we confirm modern predictions that the magnetically induced emission in a dielectric forms a cone that peaks at the Cherenkov angle and show that the simulations reproduce the data within systematic uncertainties.

Detection of Aspergillus-specific antibodies by agar gel double immunodiffusion and IgG ELISA in feline upper respiratory tract aspergillosis.

Feline upper respiratory tract aspergillosis (URTA) is an emerging infectious disease. The aims of this study were: (1) to assess the diagnostic value of detection of Aspergillus-specific antibodies using an agar gel double immunodiffusion (AGID) assay and an indirect immunoglobulin G (IgG) ELISA; and (2) to determine if an aspergillin derived from mycelia of Aspergillus fumigatus, Aspergillus niger and Aspergillus flavus can be used to detect serum antibodies against cryptic Aspergillus spp. in Aspergillus section Fumigati. Sera from cats with URTA (group 1: n = 21) and two control groups (group 2: cats with other upper respiratory tract diseases, n = 25; group 3: healthy cats and cats with non-respiratory, non-fungal illness, n = 84) were tested. Isolates from cats with URTA comprised A. fumigatus (n = 5), A. flavus (n = 1) and four cryptic species: Aspergillus felis (n = 12), Aspergillus thermomutatus (Neosartorya pseudofischeri, n = 1), Aspergillus lentulus (n = 1) and Aspergillus udagawae (n = 1). Brachycephalic purebred cats were significantly more likely to develop URTA than other breeds (P = 0.013). The sensitivity (Se) of the AGID was 43% and the specificity (Sp) was 100%. At a cut-off value of 6 ELISA units/mL, the Se of the IgG ELISA was 95.2% and the Sp was 92% and 92.9% for groups 2 and 3 cats, respectively. Aspergillus-specific antibodies against all four cryptic species were detected in one or both assays. Assay Se was not associated with species identity. Detection of Aspergillus-specific antibodies by IgG ELISA has high Se and Sp for diagnosis of feline URTA.

[THE DIVERGENCE OF MEDICAL DEMOGRAPHIC SITUATION IN RUSSIA].

The factors impacting demographic situation in largest cities are discussed. The transformation of correlation relationships ofvariation offertility and total mortality ofpopulation with intensity of its aging, labor payment, supply with physicians and capacity of medical institutions is analyzed

Molecular identification of interleukin-2 in the lymphoid tissues of the common brushtail possum, Trichosurus vulpecula.

The common brushtail possum (Trichosurus vulpecula) is an Australian marsupial. Here we describe the identification of possum interleukin-2 in mitogen-stimulated lymph node cells. We used a strategy of Rapid amplification of cDNA ends using probes designed from recently-sequenced marsupial genomes to identify the IL2 gene and then confirmed that IL-2 expression in possum immune tissue occurs in a similar manner to that in their eutherian counterparts. The predictive possum IL-2 peptide showed 28% and 35% amino acid sequence homology with the mouse and human IL-2 molecules, respectively, consistent with the divergence found within this cytokine family. Despite this low sequence identity, possum IL-2 still possessed the characteristic hallmarks of mammalian IL-2, such as a predicted signal peptide and conserved family motifs.

Indications of proton-dominated cosmic-ray composition above 1.6 EeV.

We report studies of ultrahigh-energy cosmic-ray composition via analysis of depth of air shower maximum (X(max)), for air shower events collected by the High-Resolution Fly's Eye (HiRes) observatory. The HiRes data are consistent with a constant elongation rate d/d[log(E)] of 47.9+/-6.0(stat)+/-3.2(syst) g/cm2/decade for energies between 1.6 and 63 EeV, and are consistent with a predominantly protonic composition of cosmic rays when interpreted via the QGSJET01 and QGSJET-II high-energy hadronic interaction models. These measurements constrain models in which the galactic-to-extragalactic transition is the cause of the energy spectrum ankle at 4x10(18) eV.

Observation of ultrahigh-energy cosmic rays with the ANITA balloon-borne radio interferometer.

We report the observation of 16 cosmic ray events with a mean energy of 1.5 × 10¹9 eV via radio pulses originating from the interaction of the cosmic ray air shower with the Antarctic geomagnetic field, a process known as geosynchrotron emission. We present measurements in the 300-900 MHz range, which are the first self-triggered, first ultrawide band, first far-field, and the highest energy sample of cosmic ray events collected with the radio technique. Their properties are inconsistent with current ground-based geosynchrotron models. The emission is 100% polarized in the plane perpendicular to the projected geomagnetic field. Fourteen events are seen to have a phase inversion due to reflection of the radio beam off the ice surface, and two additional events are seen directly from above the horizon. Based on a likelihood analysis, we estimate angular pointing precision of order 2° for the event arrival directions.

Cloning and structural analysis of two highly divergent IgA isotypes, IgA1 and IgA2 from the duck billed platypus, Ornithorhynchus anatinus.

To trace the emergence of modern IgA isotypes during vertebrate evolution we have studied the immunoglobulin repertoire of a model monotreme, the platypus. Two highly divergent IgA-like isotypes (IgA1 and IgA2) were identified and their primary structures were determined from full-length cDNAs. A comparative analysis of the amino acid sequences for IgA from various animal species showed that the two platypus IgA isotypes form a branch clearly separated from their eutherian (placental) counterparts. However, they still conform to the general structure of eutherian IgA, with a hinge region and three constant domains. This indicates that the deletion of the second domain and the formation of a hinge region in IgA did occur very early during mammalian evolution, more than 166 million years ago. The two IgA isotypes in platypus differ in primary structure and appear to have arisen from a very early gene duplication, possibly preceding the metatherian eutherian split. Interestingly, one of these isotypes, IgA1, appears to be expressed in only the platypus, but is present in the echidna based on Southern blot analysis. The platypus may require a more effective mucosal immunity, with two highly divergent IgA forms, than the terrestrial echidna, due to its lifestyle, where it is exposed to pathogens both on land and in the water.

Physical mapping of immune genes in the tammar wallaby (Macropus eugenii).

The tammar wallaby (Macropus eugenii) is a model marsupial that has recently had its genome sequenced to a depth of 2-fold coverage. Although this is a great resource for comparative genomic studies, information on gene location is essential if this resource is to be used to its full potential. In this study, tammar wallaby bacterial artificial chromosomes (BACs) containing key immune genes were isolated from the tammar wallaby BAC library. BACs containing T cell receptor (TCR) and immunoglobulin (Ig) genes were physically mapped using fluorescence in situ hybridisation (FISH) to tammar wallaby chromosomes. Congruence between the locations of these immune genes in the tammar wallaby genome, with those predicted from chromosome painting data, highlights the conservation of genomic context of these important immune genes in marsupials. The isolation and mapping of these key immune genes in the tammar wallaby will aid in the assembly of the recently sequenced light coverage genome and assignment of sequence to chromosomes.

First observation of the Greisen-Zatsepin-Kuzmin suppression.

The High Resolution Fly's Eye (HiRes) experiment has observed the Greisen-Zatsepin-Kuzmin suppression (called the GZK cutoff) with a statistical significance of five standard deviations. HiRes' measurement of the flux of ultrahigh energy cosmic rays shows a sharp suppression at an energy of 6 x 10(19) eV, consistent with the expected cutoff energy. We observe the ankle of the cosmic-ray energy spectrum as well, at an energy of 4 x 10(18) eV. We describe the experiment, data collection, and analysis and estimate the systematic uncertainties. The results are presented and the calculation of the statistical significance of our observation is described.

Class I genes have split from the MHC in the tammar wallaby.

Genes within the Major Histocompatibility Complex (MHC) are critical to the immune response and immunoregulation. Comparative studies have revealed that the MHC has undergone many changes throughout evolution yet in tetrapods the three different classes of MHC genes have maintained linkage, suggesting that there may be some functional advantage obtained by maintaining this clustering of MHC genes. Here we present data showing that class II and III genes, the antigen processing gene TAP2, and MHC framework genes are found together in the tammar wallaby on chromosome 2. Surprisingly class I loci were not found on chromosome 2 but were mapped to ten different locations spread across six chromosomes. This distribution of class I loci in the wallaby on nearly all autosomes is not a characteristic of all marsupials and may be a relatively recent phenomenon. It highlights the need for the inclusion of more than one marsupial species in comparative studies and raises questions regarding the functional significance of the clustering of MHC genes.