Deep Photometry of GRB 041006 Afterglow: Hypernova Bump at Redshift z=0.716

We present deep optical photometry of the afterglow of gamma-ray burst (GRB) 041006 and its associated hypernova obtained over 65 days after detection (55 R-band epochs on 10 different nights). Our early data (t<4 days) joined with published GCN data indicates a steepening decay, approaching F_nu ~t^{-0.6} at early times (<<1 day) and F_nu ~t^{-1.3} at late times. The break at t_b=0.16+-0.04 days is the earliest reported jet break among all GRB afterglows. During our first night, we obtained 39 exposures spanning 2.15 hours from 0.62 to 0.71 days after the burst that reveal a smooth afterglow, with an rms deviation of 0.024 mag from the local power-law fit, consistent with photometric errors. After t~4 days, the decay slows considerably, and the light curve remains approximately flat at R~24 mag for a month before decaying by another magnitude to reach R~25 mag two months after the burst. This ``bump'' is well-fitted by a k-corrected light curve of SN1998bw, but only if stretched by a factor of 1.38 in time. In comparison with the other GRB-related SNe bumps, GRB 041006 stakes out new parameter space for GRB/SNe, with a very bright and significantly stretched late-time SN light curve. Within a small sample of fairly well observed GRB/SN bumps, we see a hint of a possible correlation between their peak luminosity and their ``stretch factor'', broadly similar to the well-studied Phillips relation for the type Ia supernovae.Comment: ApJ Letters, accepted. Additional material available at ftp://cfa-ftp.harvard.edu/pub/kstanek/GRB041006

Microbial interactions in the mosquito gut determineSerratiacolonization and blood-feeding propensity

How microbe–microbe interactions dictate microbial complexity in the mosquito gut is unclear. Previously we found that, Serratia, a gut symbiont that alters vector competence and is being considered for vector control, poorly colonized Aedes aegypti yet was abundant in Culex quinquefasciatus reared under identical conditions. To investigate the incompatibility between Serratia and Ae. aegypti, we characterized two distinct strains of Serratia marcescens from Cx. quinquefasciatus and examined their ability to infect Ae. aegypti. Both Serratia strains poorly infected Ae. aegypti, but when microbiome homeostasis was disrupted, the prevalence and titers of Serratia were similar to the infection in its native host. Examination of multiple genetically diverse Ae. aegypti lines found microbial interference to S. marcescens was commonplace, however, one line of Ae. aegypti was susceptible to infection. Microbiome analysis of resistant and susceptible lines indicated an inverse correlation between Enterobacteriaceae bacteria and Serratia, and experimental co-infections in a gnotobiotic system recapitulated the interference phenotype. Furthermore, we observed an effect on host behavior; Serratia exposure to Ae. aegypti disrupted their feeding behavior, and this phenotype was also reliant on interactions with their native microbiota. Our work highlights the complexity of host–microbe interactions and provides evidence that microbial interactions influence mosquito behavior

A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function

Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use.I recieved an honorarium from Roche Diagnostics for my participation in the advisory panel meeting leading to this pape

Does chemical cross-linking with NHS esters reflect the chemical equilibrium of protein-protein noncovalent interactions in solution?

Chemical cross-linking in combination with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has emerged as a powerful tool to study non-covalent protein complexes. Nevertheless, there are still many questions to answer: Does the amount of detected cross-linked complex correlate with the amount of protein complex in solution? In which concentration and affinity range is specific cross-linking possible? In order to answer these questions, we performed systematic cross-linking studies with two complexes using the N8 hydroxysuccinimidyl ester disuccinimidyl suberate (DSS): i) NCoA-1 and mutants of the interacting peptide STAT6Y, covering a KD range of 30 nM to > 25 μM and ii) α-thrombin and basic pancreatic trypsin inhibitor (BPTI), which shows a buffer dependent KD value between 100 and 320 μM. Samples were analyzed by MALDI-MS. For NCoA-1•STAT6Y, a good correlation of the amount of cross-linked species with the calculated fraction of complex present in solution was observed. Thus, chemical cross-linking in combination with MALDI-MS can be used to rank binding affinities. The specificity of complex formation for the mid-affinity range up to about KD ≈ 25 μM could be proven by comparing against a non-binding peptide and by studying the concentration dependence. In order to study in which affinity range specific cross-linking can be applied, the weak α-thrombin•BPTI complex was investigated. Although variations of the sodium concentration can change the dissociation constant up to 3-fold for this interaction, no significant effect on the amount of detected complex was observed at different peptide concentrations. Our interpretation of this result is that the detected complex is not specific, but a nonspecifically cross-linked species. Consequently, chemical cross-linking is not applicable to low-affinity complexes with KD >> 25 μM with the experimental approach used in this study

The reaction of hydrogen peroxide with hemoglobin induces extensive alpha-globin crosslinking and impairs the interaction of hemoglobin with endogenous scavenger pathways

Cell-free hemoglobin (Hb) enhances the oxidation-related toxicity associated with inflammation, ischemia, and hemolytic disorders. Hb is highly vulnerable to oxidative damage, and irreversible structural changes involving iron/heme oxidation, heme-adduct products, and amino acid oxidation have been reported. Specific structural features of Hb, such as unconstrained alpha-chains and molecular size, determine the efficiency of interactions between the endogenous Hb scavengers haptoglobin (Hp) and CD163. Using HPLC, mass spectrometry, and Western blotting, we show that H(2)O(2)-mediated Hb oxidation results in the formation of covalently stabilized globin multimers, with prominent intramolecular crosslinking between alpha-globin chains. These structural alterations are associated with reduced Hp binding, reduced CD163 interaction, and severely impaired endocytosis of oxidized Hb by the Hp-CD163 pathway. As a result, when exposed to oxidized Hb, CD163-positive HEK293 cells and human macrophages do not increase hemeoxygenase-1 (HO-1) expression, the physiological anti-oxidative macrophage response to Hb exposure. Failed Hb clearance, inadequate HO-1 expression, and the subsequent accumulation of oxidatively damaged Hb species might thus contribute to pathologies related to oxidative stress

Microbiome Interaction Networks and Community Structure From Laboratory-Reared and Field-Collected Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus Mosquito Vectors

<p>Microbial interactions are an underappreciated force in shaping insect microbiome communities. Although pairwise patterns of symbiont interactions have been identified, we have a poor understanding regarding the scale and the nature of co-occurrence and co-exclusion interactions within the microbiome. To characterize these patterns in mosquitoes, we sequenced the bacterial microbiome of Aedes aegypti, Ae. albopictus, and Culex quinquefasciatus caught in the field or reared in the laboratory and used these data to generate interaction networks. For collections, we used traps that attracted host-seeking or ovipositing female mosquitoes to determine how physiological state affects the microbiome under field conditions. Interestingly, we saw few differences in species richness or microbiome community structure in mosquitoes caught in either trap. Co-occurrence and co-exclusion analysis identified 116 pairwise interactions substantially increasing the list of bacterial interactions observed in mosquitoes. Networks generated from the microbiome of Ae. aegypti often included highly interconnected hub bacteria. There were several instances where co-occurring bacteria co-excluded a third taxa, suggesting the existence of tripartite relationships. Several associations were observed in multiple species or in field and laboratory-reared mosquitoes indicating these associations are robust and not influenced by environmental or host factors. To demonstrate that microbial interactions can influence colonization of the host, we administered symbionts to Ae. aegypti larvae that either possessed or lacked their resident microbiota. We found that the presence of resident microbiota can inhibit colonization of particular bacterial taxa. Our results highlight that microbial interactions in mosquitoes are complex and influence microbiome composition.</p