Gravitational anomalies: a recipe for Hawking radiation

We explore the method of Robinson and Wilczek for deriving the Hawking temperature of a black hole. In this method, the Hawking radiation restores general covariance in an effective theory of near-horizon physics which otherwise exhibits a gravitational anomaly at the quantum level. The method has been shown to work for broad classes of black holes in arbitrary spacetime dimensions. These include static black holes, accreting or evaporating black holes, charged black holes, rotating black holes, and even black rings. In the case of charged and rotating black holes, the expected super-radiant current is also reproduced.Comment: 7 pages; This essay received an "Honorable Mention" in the 2007 Essay Competition of the Gravity Research Foundation; (v2) Short comments and references added; (v3) Minor revisions and updated references to agree with published versio

Nomenclature for the human Arf family of GTP-binding proteins: ARF, ARL, and SAR proteins

The Ras superfamily is comprised of at least four large families of regulatory guanosine triphosphate–binding proteins, including the Arfs. The Arf family includes three different groups of proteins: the Arfs, Arf-like (Arls), and SARs. Several Arf family members have been very highly conserved throughout eukaryotic evolution and have orthologues in evolutionally diverse species. The different means by which Arf family members have been identified have resulted in an inconsistent and confusing array of names. This confusion is further compounded by differences in nomenclature between different species. We propose a more consistent nomenclature for the human members of the Arf family that may also serve as a guide for nomenclature in other species

International validation of Enhanced Recovery After Surgery Society guidelines on enhanced recovery for gynecologic surgery

Background: Enhanced Recovery After Surgery Society publishes guidelines on perioperative care, but these guidelines should be validated prospectively. Objective: To evaluate the association between compliance with Enhanced Recovery After Surgery Gynecologic/Oncology guideline elements and postoperative outcomes in an international cohort. Study Design: The study comprised 2101 patients undergoing elective gynecologic/oncology surgery between January 2011 and November 2017 in 10 hospitals across Canada, the United States, and Europe. Patient demographics, surgical/anesthesia details, and Enhanced Recovery After Surgery protocol compliance elements (pre-, intra-, and postoperative phases) were entered into the Enhanced Recovery After Surgery Interactive Audit System. Surgical complexity was stratified according to the Aletti scoring system (low vs medium/high). The following covariates were accounted for in the analysis: age, body mass index, smoking status, presence of diabetes, American Society of Anesthesiologists class, International Federation of Gynecology and Obstetrics stage, preoperative chemotherapy, radiotherapy, operating time, surgical approach (open vs minimally invasive), intraoperative blood loss, hospital, and Enhanced Recovery After Surgery implementation status. The primary end points were primary hospital length of stay and complications. Negative binomial regression was used to model length of stay, and logistic regression to model complications, as a function of compliance score and covariates. Results: Patient demographics included a median age 56 years, 35.5% obese, 15% smokers, and 26.7% American Society of Anesthesiologists Class III-IV. Final diagnosis was malignant in 49% of patients. Laparotomy was used in 75.9% of cases, and the remainder minimally invasive surgery. The majority of cases (86%) were of low complexity (Aletti score ≤3). In patients with ovarian cancer, 69.5% had a medium/high complexity surgery (Aletti score 4–11). Median length of stay was 2 days in the low- and 5 days in the medium/high-complexity group. Every unit increase in Enhanced Recovery After Surgery guideline score was associated with 8% (IRR, 0.92; 95% confidence interval, 0.90–0.95; P\u3c.001) decrease in days in hospital among low-complexity, and 12% (IRR, 0.88; 95% confidence interval, 0.82–0.93; P\u3c.001) decrease among patients with medium/high-complexity scores. For every unit increase in Enhanced Recovery After Surgery guideline score, the odds of total complications were estimated to be 12% lower (P\u3c.05) among low-complexity patients. Conclusion: Audit of surgical practices demonstrates that improved compliance with Enhanced Recovery After Surgery Gynecologic/Oncology guidelines is associated with an improvement in clinical outcomes, including length of stay, highlighting the importance of Enhanced Recovery After Surgery implementation

De novo Assembly of the Burying Beetle Nicrophorus orbicollis (Coleoptera: Silphidae) Transcriptome Across Developmental Stages with Identification of Key Immune Transcripts

Burying beetles (Nicrophorus spp.) are among the relatively few insects that provide parental care while not belonging to the eusocial insects such as ants or bees. This behavior incurs energy costs as evidenced by immune deficits and shorter life-spans in reproducing beetles. In the absence of an assembled transcriptome, relatively little is known concerning the molecular biology of these beetles. This work details the assembly and analysis of the Nicrophorus orbicollis transcriptome at multiple developmental stages. RNA-Seq reads were obtained by next-generation sequencing and the transcriptome was assembled using the Trinity assembler. Validation of the assembly was performed by functional characterization using Gene Ontology (GO), Eukaryotic Orthologous Groups (KOG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Differential expression analysis highlights developmental stage-specific expression patterns, and immunity-related transcripts are discussed. The data presented provides a valuable molecular resource to aid further investigation into immunocompetence throughout this organism’s sexual development

Poor CD4+ T Cell Immunogenicity Limits Humoral Immunity to P. falciparum Transmission-Blocking Candidate Pfs25 in Humans.

Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4+ and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4+ T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4+/Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission

Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite--MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors--ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses

Gene content evolution in the arthropods

Arthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods. Using 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality, and chemoperception. These analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity

An ancient family of lytic polysaccharide monooxygenases with roles in arthropod development and biomass digestion.

Thermobia domestica belongs to an ancient group of insects and has a remarkable ability to digest crystalline cellulose without microbial assistance. By investigating the digestive proteome of Thermobia, we have identified over 20 members of an uncharacterized family of lytic polysaccharide monooxygenases (LPMOs). We show that this LPMO family spans across several clades of the Tree of Life, is of ancient origin, and was recruited by early arthropods with possible roles in remodeling endogenous chitin scaffolds during development and metamorphosis. Based on our in-depth characterization of Thermobia's LPMOs, we propose that diversification of these enzymes toward cellulose digestion might have endowed ancestral insects with an effective biochemical apparatus for biomass degradation, allowing the early colonization of land during the Paleozoic Era. The vital role of LPMOs in modern agricultural pests and disease vectors offers new opportunities to help tackle global challenges in food security and the control of infectious diseases

Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation.

Induction of antigen-specific CD8(+) T cells offers the prospect of immunization against many infectious diseases, but no subunit vaccine has induced CD8(+) T cells that correlate with efficacy in humans. Here we demonstrate that a replication-deficient chimpanzee adenovirus vector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequency T-cell responses (median >2400 SFC/10(6) peripheral blood mononuclear cells) to the liver-stage Plasmodium falciparum malaria antigen ME-TRAP. It induces sterile protective efficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delays time to patency through substantial reduction of liver-stage parasite burden in five more (5/14, 36%), P=0.008 compared with controls. The frequency of monofunctional interferon-γ-producing CD8(+) T cells, but not antibodies, correlates with sterile protection and delay in time to patency (P(corrected)=0.005). Vaccine-induced CD8(+) T cells provide protection against human malaria, suggesting that a major limitation of previous vaccination approaches has been the insufficient magnitude of induced T cells