Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development.

BACKGROUND: We present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development. RESULTS: The genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements. CONCLUSIONS: Analyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Stable hydrogen isotope variability within and among plumage tracts (δ2HF) of a migratory wood warbler.

Hydrogen isotope analysis of feather keratin (δ2HF) has become an essential tool for tracking movements between breeding and wintering populations of migratory birds. In particular, δ2HF has been used to create δ2HF isoscapes that can be used to assign the geographic origins of molt. The majority of past studies have sampled a portion of a single feather as an isotopic proxy for the entire plumage although surprisingly little is known about variation of stable isotopes within and between feather tracts of individuals in local populations. Here we examine δ2HF variation in 24 pterylographic variables (9 primaries, 6 secondaries, 6 rectrices, and 3 patches of ventral contour feathers) in individual specimens of black-throated blue warbler (Setophaga caerulescens) breeding in the Big Santeetlah Creek watershed (5350 ha), southern Appalachian Mountains. By restricting our study to territorial ASY males (after second year) inhabiting a small watershed, we could focus on δ2HF variation generated during the complete prebasic annual molt in a circumscribed population while factoring out age and sexual differences in foraging behavior, isotopic incorporation, and post-breeding dispersal. Summed within-individual variation (δ2HF) across 24 pterylographic variables ranged from 12 to 60‰ (= 21.8 ± 9.4‰), with 81% of the individuals exhibiting variation ≥ 16‰ (reproducibility of analyses was ≤ 4 ‰). Adjacent feathers in feather tracts tend to have more similar δ2HF values than feathers grown weeks apart, consistent with the stepwise replacement of flight feathers. The pooled population sample exhibited significant δ2HF variation in primaries (-78 to -21‰), secondaries (-80 to -17‰), rectrices (-78 to -23‰), and ventral contour feathers (-92 to -32‰). Strong year effects in δ2HF variation were observed in each of the 24 pterylographic variables. Altitudinal effects were observed only in ventral contour feathers. The current findings demonstrate that within-individual variation (δ2HF) may be much greater than previously thought in migratory species that molt on or near breeding territories. Our study also highlights the need for greater pterylographic precision in research design of isotope-based studies of avian movement. Within-individual and within-population δ2HF variation should be incorporated in geographic assignment models. In a broader context, the staggered Staffelmauser pattern of molt in wood warblers provides an exceptional view of the seasonal variation of hydrogen isotopes circulating in blood plasma during the six-week period of annual molt

Stable hydrogen isotope variability within and among plumage tracts (δ2HF) of a migratory wood warbler

Hydrogen isotope analysis of feather keratin (δ2HF) has become an essential tool for tracking movements between breeding and wintering populations of migratory birds. In particular, δ2HF has been used to create δ2HF isoscapes that can be used to assign the geographic origins of molt. The majority of past studies have sampled a portion of a single feather as an isotopic proxy for the entire plumage although surprisingly little is known about variation of stable isotopes within and between feather tracts of individuals in local populations. Here we examine δ2HF variation in 24 pterylographic variables (9 primaries, 6 secondaries, 6 rectrices, and 3 patches of ventral contour feathers) in individual specimens of black-throated blue warbler (Setophaga caerulescens) breeding in the Big Santeetlah Creek watershed (5350 ha), southern Appalachian Mountains. By restricting our study to territorial ASY males (after second year) inhabiting a small watershed, we could focus on δ2HF variation generated during the complete prebasic annual molt in a circumscribed population while factoring out age and sexual differences in foraging behavior, isotopic incorporation, and post-breeding dispersal. Summed within-individual variation (δ2HF) across 24 pterylographic variables ranged from 12 to 60‰ (= 21.8 ± 9.4‰), with 81% of the individuals exhibiting variation ≥ 16‰ (reproducibility of analyses was ≤ 4 ‰). Adjacent feathers in feather tracts tend to have more similar δ2HF values than feathers grown weeks apart, consistent with the stepwise replacement of flight feathers. The pooled population sample exhibited significant δ2HF variation in primaries (-78 to -21‰), secondaries (-80 to -17‰), rectrices (-78 to -23‰), and ventral contour feathers (-92 to -32‰). Strong year effects in δ2HF variation were observed in each of the 24 pterylographic variables. Altitudinal effects were observed only in ventral contour feathers. The current findings demonstrate that within-individual variation (δ2HF) may be much greater than previously thought in migratory species that molt on or near breeding territories. Our study also highlights the need for greater pterylographic precision in research design of isotope-based studies of avian movement. Within-individual and within-population δ2HF variation should be incorporated in geographic assignment models. In a broader context, the staggered Staffelmauser pattern of molt in wood warblers provides an exceptional view of the seasonal variation of hydrogen isotopes circulating in blood plasma during the six-week period of annual molt