Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit ...SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.
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•Adenovirus transduction of human ACE2 enables SARS-CoV-2 infection of BALB/c mice•High levels of viral RNA and infectious SARS-CoV-2 accumulate in lungs•Mice transduced with human ACE2 develop viral pneumonia after SARS-CoV-2 infection•Neutralizing mAbs protect from SARS-CoV-2-induced lung infection and inflammation
Laboratory mice transduced with adenoviruses encoding human ACE2 are permissive for SARS-CoV-2 and develop pneumonia. Passive transfer of a neutralizing monoclonal antibody reduces lung infection, inflammation, and disease.
Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal ...concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.
Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships. Here, we describe a ...systematic map of ∼14,000 high-quality human binary protein-protein interactions. At equal quality, this map is ∼30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a “broader” human interactome network than currently appreciated. The map also uncovers significant interconnectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high-quality interactome models will help “connect the dots” of the genomic revolution.
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•Network map of 14,000 high-quality binary human protein-protein interactions•Uniform coverage of the interactome space overlooked by other approaches•This map allows detection of functional relationships beyond previous knowledge•Unbiased network-based evidence for an expanded cancer landscape
A second-generation systematic binary map provides proteome-wide coverage of the human interactome network, expanding connections among human disease genes beyond previous knowledge.
Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells affected by radiation to cause the GI ...syndrome are derived from the epithelium or endothelium and whether the target cells die by apoptosis or other mechanisms are controversial issues. Studying mouse models, we found that selective deletion of the proapoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after sub-total-body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not from endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by the death of GI epithelial cells and that these epithelial cells die by a mechanism that is regulated by p53 but independent of apoptosis.
Paleofeces or coprolites are often used to reconstruct diet at archaeological sites, usually using macroscopic analyses or targeted DNA amplification and sequencing. Here we present an integrative ...analysis of dog coprolites, combining macroscopic analyses, stable isotope measurements, and DNA shotgun sequencing to examine diet and health status. Dog coprolites used in this study were recovered from the Janey B. Goode and East Saint Louis archaeological sites, both of which are located in the American Bottom, an extensive Mississippi River floodplain in Southwestern Illinois. Based on the context of recovery, coprolites are assigned to the Late Woodland and Terminal Late Woodland periods (ca. 600-1050 AD). Given the scarcity of human remains from this time period, these dog coprolites can be useful as a proxy for understanding human diet during the Late Woodland period. We find that the Late Woodland dogs consumed a variety of fish as well as bird and plant taxa, possibly including maize, and also harbored intestinal parasites and pathogenic bacteria. By sequencing the fecal microbiome of the coprolites, we find some similarities to modern dog microbiomes, as well as specific taxa that can be used to discriminate between modern and ancient microbiomes, excluding soil contaminants. As dogs are often used as a surrogate to assess human diet, humans living with these dogs likely had a similar diet and were affected by similar parasites. These analyses, when integrated, show a more comprehensive view of ancient dog and human diet and health in the region during the initial expansion of maize agriculture than any individual method could alone.
Organisms that have repeatedly evolved similar morphologies owing to the same selective pressures provide excellent cases in which to examine specific morphological changes and their relevance to the ...ecology and evolution of taxa. Hosts of permanent parasites act as an independent evolutionary experiment, as parasites on these hosts are thought to be undergoing similar selective pressures. Parasitic feather lice have repeatedly diversified into convergent ecomorphs in different microhabitats on their avian hosts. We quantified specific morphological characters to determine (i) which traits are associated with each ecomorph, (ii) the quantitative differences between these ecomorphs, and (iii) if there is evidence of displacement among co-occurring lice as might be expected under louse-louse competition on the host. We used nano-computed tomography scan data of 89 specimens, belonging to four repeatedly evolved ecomorphs, to examine their mandibular muscle volume, limb length and three-dimensional head shape data. Here, we find evidence that lice repeatedly evolve similar morphologies as a mechanism to escape host defences, but also diverge into different ecomorphs related to the way they escape these defences. Lice that co-occur with other genera on a host exhibit greater morphological divergence, indicating a potential role of competition in evolutionary divergence.
CRISPR-Cas9 systems provide powerful tools for genome editing. However, optimal employment of this technology will require control of Cas9 activity so that the timing, tissue specificity, and ...accuracy of editing may be precisely modulated. Anti-CRISPR proteins, which are small, naturally occurring inhibitors of CRISPR-Cas systems, are well suited for this purpose. A number of anti-CRISPR proteins have been shown to potently inhibit subgroups of CRISPR-Cas9 systems, but their maximal inhibitory activity is generally restricted to specific Cas9 homologs. Since Cas9 homologs vary in important properties, differing Cas9s may be optimal for particular genome-editing applications. To facilitate the practical exploitation of multiple Cas9 homologs, here we identify one anti-CRISPR, called AcrIIA5, that potently inhibits nine diverse type II-A and type II-C Cas9 homologs, including those currently used for genome editing. We show that the activity of AcrIIA5 results in partial in vivo cleavage of a single-guide RNA (sgRNA), suggesting that its mechanism involves RNA interaction.
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•Anti-CRISPR AcrIIA5 potently inhibits all Cas9 homologs used in genome editing•AcrIIA5 functions well in a variety of mammalian cell genome-editing applications•The AcrIIA5 functional mechanism leads to sgRNA cleavage
Garcia et al. show that anti-CRISPR protein AcrIIA5 strongly inhibits all of the CRISPR-Cas9 homologs that are commonly used for genome editing. They show that it functions effectively in bacterial and mammalian cells. This anti-CRISPR will be useful for a wide variety of biotechnological applications.
A new class of highly luminescent nine-coordinated europium(III) tris(beta-diketonate) bis(ethylenedioxythiophene)pyrazolylpyridine (L) complexes has been synthesized and the photophysical properties ...studied: 1 = Eu(hfac)(3)(L); 2 = Eu(tta)(3)(L); 3 = Eu(btfac)(3)(L). The solid-state structure of complex 1 has been determined by single-crystal X-ray crystallography and shows the geometry of the local coordination environment around the Eu(III) ion to be a slightly distorted tricapped trigonal prism. Luminescence lifetimes were found to be 581, 473, and 576 micros for complexes 1-3, respectively. Absolute quantum yields for complexes 1-3 were measured as 16.4 +/- 1.4%, 27.5 +/- 1.2%, and 22.2% +/- 0.3%, respectively.
This study is an integrated efficacy analysis of the five clinical trials of tositumomab and iodine-131 tositumomab in patients with relapsed or refractory low-grade, follicular, or transformed ...low-grade non-Hodgkin's lymphoma (NHL) that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration.
This integrated analysis included 250 patients. Patients received a single course of iodine-131 tositumomab. Responses were assessed by an independent panel of radiologists and oncologists.
Response rates in the five trials ranged from 47% to 68%; complete response rates ranged from 20% to 38%. With a median follow-up of 5.3 years, the 5-year progression-free survival was 17%. Eighty-one (32%) of 250 patients had a time to progression of > or = 1 year (termed durable response population). For the durable response population, 44% had not progressed at > or = 2.5 to > or = 9.5 years and had a median duration of response of 45.8 months. The median duration of complete response was not reached. The durable response population had many poor prognostic characteristics, including bone marrow involvement (41%), bulky disease > or = 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies and 36% had not responded to their most recent therapy.
The tositumomab and iodine-131 tositumomab therapeutic regimen produces high response rates in patients with relapsed or refractory low-grade, follicular, and transformed low-grade NHL, with a sizable subgroup of patients achieving long-term durable responses.
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•Various coordination modes were obtained by a PNP ligand with Cu, Ag, Pt, and Pd.•Complexes were characterized by X-ray Crystallography, 1H NMR, 31P{1H} NMR, HRMS, EA.•Absorption and ...luminescence behaviors were reported; NMR and MS data were discussed.
Complexes of copper, silver, platinum, and palladium with N,N-bis2-(diphenylphosphino)ethyl-phenylamine (a PNP ligand) have been synthesized and characterized by 1H NMR, 31P{1H} NMR, HRMS, Elemental Analysis, and X-ray Crystallography. NMR data that were obtained at various temperatures resulted in different patterns in terms of peak multiplicity and coupling constants. Absorption and luminescence behaviors were reported, NMR and MS data were discussed and the coordination modes were investigated. The platinum complex that was synthesized in the present study was found to be a trans complex (by X-ray diffraction and 31P{1H} NMR data) contrary to the 31P{1H} NMR data for the cis isomer published last year in the literature by Kostas I. D. et al.
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