The Classical Pink-Eyed Dilution Mutation Affects Angiogenic Responsiveness

Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependent diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that affect angiogenic responsiveness in several mouse models. In this study, we used F2 intercrosses between C57BL/6J and the 129 substrains 129P1/ReJ and 129P3/J, as well as the SJL/J strain, where we have identified new QTLs that affect angiogenic responsiveness. In the case of AngFq5, on chromosome 7, congenic animals were used to confirm the existence of this locus and subcongenic animals, combined with a haplotype-based mapping approach that identified the pink-eyed dilution mutation as a candidate polymorphism to explain AngFq5. The ability of mutations in the pink-eyed dilution gene to affect angiogenic response was demonstrated using the p-J allele at the same locus. Using this allele, we demonstrate that pink-eyed dilution mutations in Oca2 can affect both bFGF and VEGF-induced corneal angiogenesis

Visible, Near-Infrared, and Mid-Infrared Spectral Characterization of Hawaiian Fumarolic Alteration Near Kilauea's December 1974 Flow: Implications for Spectral Discrimination of Alteration Environments on Mars

The December 1974 flow in the SW rift zone at Kilauea Volcano, Hawaii, has been established as a Mars analog due to its physical, chemical, and morphological properties, as well as its interaction with the outgassing plume from the primary Kilauea caldera. We focus on a solfatara site that consists of hydrothermally altered basalt and alteration products deposited in and around a passively degassing volcanic vent situated directly adjacent to the December 1974 flow on its northwest side. Reflectance spectra are acquired in the visible/near-infrared (VNIR) region and emission spectra in the mid-infrared (MIR) range to better understand the spectral properties of hydrothermally altered materials. The VNIR signatures are consistent with silica, Fe-oxides, and sulfates (Ca, Fe). Primarily silica-dominated spectral signatures are observed in the MIR and changes in spectral features between samples appear to be driven by grain size effects in this wavelength range. The nature of the sample coating and the thermal emission signatures exhibit variations that may be correlated with distance from the vent. Chemical analyses indicate that most surfaces are characterized by silica-rich material, Fe-oxides, and sulfates (Ca, Fe). The silica and Fe-oxide-dominated MIR/VNIR spectral signatures exhibited by the hydrothermally altered material in this study are distinct from the sulfate-dominated spectral signatures exhibited by previously studied low-temperature aqueous acid-sulfate weathered basaltic glass. This likely reflects a difference in open vs. closed system weathering, where mobile cations are removed from the altered surfaces in the fumarolic setting. This work provides a unique infrared spectral library that includes martian analog materials that were altered in an active terrestrial solfatara (hydrothermal) setting. Hydrothermal environments are of particular interest as they potentially indicate habitable conditions. Key constraints on the habitability and astrobiological potential of ancient aqueous environments are provided through detection and interpretation of secondary mineral assemblages; thus, spectral detection of fumarolic alteration assemblages observed from this study on Mars would suggest a region that could have hosted a habitable environment

Seed dispersal increases local species richness and reduces spatial turnover of tropical tree seedlings

Dispersal is thought to be a key process underlying the high spatial diversity of tropical forests. Just how important dispersal is in structuring plant communities is nevertheless an open question because it is very difficult to isolate dispersal from other processes, and thereby measure its effect. Using a unique situation, the loss of vertebrate seed dispersers on the island of Guam and their presence on the neighboring islands of Saipan and Rota, we quantify the contribution of vertebrate seed dispersal to spatial patterns of diversity of tree seedlings in treefall gaps. The presence of vertebrate seed dispersers approximately doubled seedling species richness within canopy gaps and halved species turnover among gaps. Our study demonstrates that dispersal plays a key role in maintaining local and regional patterns of diversity, and highlights the potential for ongoing declines in vertebrate seed dispersers to profoundly alter tropical forest composition

An Automated Procedure to Identify Biomedical Articles that Contain Cancer-associated Gene Variants

The proliferation of biomedical literature makes it increasingly difficult for researchers to find and manage relevant information. However, identifying research articles containing mutation data, a requisite first step in integrating large and complex mutation data sets, is currently tedious, time-consuming and imprecise. More effective mechanisms for identifying articles containing mutation information would be beneficial both for the curation of mutation databases and for individual researchers. We developed an automated method that uses information extraction, classifier, and relevance ranking techniques to determine the likelihood of MEDLINE abstracts containing information regarding genomic variation data suitable for inclusion in mutation databases. We targeted the CDKN2A (p16) gene and the procedure for document identification currently used by CDKN2A Database curators as a measure of feasibility. A set of abstracts was manually identified from a MEDLINE search as potentially containing specific CDKN2A mutation events. A subset of these abstracts was used as a training set for a maximum entropy classifier to identify text features distinguishing relevant from not relevant abstracts. Each document was represented as a set of indicative word, word pair, and entity tagger-derived genomic variation features. When applied to a test set of 200 candidate abstracts, the classifier predicted 88 articles as being relevant; of these, 29 of 32 manuscripts in which manual curation found CDKN2A sequence variants were positively predicted. Thus, the set of potentially useful articles that a manual curator would have to review was reduced by 56%, maintaining 91% recall (sensitivity) and more than doubling precision (positive predictive value). Subsequent expansion of the training set to 494 articles yielded similar precision and recall rates, and comparison of the original and expanded trials demonstrated that the average precision improved with the larger data set. Our results show that automated systems can effectively identify article subsets relevant to a given task and may prove to be powerful tools for the broader research community. This procedure can be readily adapted to any or all genes, organisms, or sets of documents

Investigating genetic correlations and causal effects between caffeine consumption and sleep behaviours

Observationally, higher caffeine consumption is associated with poorer sleep and insomnia. We investigated whether these associations are a result of shared genetic risk factors and/or (possibly bidirectional) causal effects. Summary-level data were available from genome-wide association studies on caffeine intake (n = 91 462), plasma caffeine and caffeine metabolic rate (n = 9876), sleep duration and chronotype (being a “morning” versus an “evening” person) (n = 128 266), and insomnia complaints (n = 113 006). First, genetic correlations were calculated, reflecting the extent to which genetic variants influencing caffeine consumption and those influencing sleep overlap. Next, causal effects were estimated with bidirectional, two-sample Mendelian randomization. This approach utilizes the genetic variants most robustly associated with an exposure variable as an “instrument” to test causal effects. Estimates from individual variants were combined using inverse-variance weighted meta-analysis, weighted median regression and MR-Egger regression. We found no clear evidence for a genetic correlation between caffeine intake and sleep duration (rg = 0.000, p =.998), chronotype (rg = 0.086, p =.192) or insomnia complaints (rg = −0.034, p =.700). For plasma caffeine and caffeine metabolic rate, genetic correlations could not be calculated because of the small sample size. Mendelian randomization did not support causal effects of caffeine intake on sleep, or vice versa. There was weak evidence that higher plasma caffeine levels causally decrease the odds of being a morning person. Although caffeine may acutely affect sleep when taken shortly before bedtime, our findings suggest that a sustained pattern of high caffeine consumption is more likely to be associated with poorer sleep through shared environmental factors. Future research should identify such environments, which could aid the development of interventions to improve sleep

The XMAP215 family drives microtubule polymerization using a structurally diverse TOG array

Structures of Drosophila Msps TOG4 and human ch-TOG TOG4 are presented. TOG4 departs from the other TOG structures and predicts novel α-tubulin engagement. Whereas TOG domains across the array have different tubulin-binding properties, cellular studies show that a fully functional TOG array is required for microtubule polymerase activity.XMAP215 family members are potent microtubule (MT) polymerases, with mutants displaying reduced MT growth rates and aberrant spindle morphologies. XMAP215 proteins contain arrayed tumor overexpressed gene (TOG) domains that bind tubulin. Whether these TOG domains are architecturally equivalent is unknown. Here we present crystal structures of TOG4 from Drosophila Msps and human ch-TOG. These TOG4 structures architecturally depart from the structures of TOG domains 1 and 2, revealing a conserved domain bend that predicts a novel engagement with α-tubulin. In vitro assays show differential tubulin-binding affinities across the TOG array, as well as differential effects on MT polymerization. We used Drosophila S2 cells depleted of endogenous Msps to assess the importance of individual TOG domains. Whereas a TOG1-4 array largely rescues MT polymerization rates, mutating tubulin-binding determinants in any single TOG domain dramatically reduces rescue activity. Our work highlights the structurally diverse yet positionally conserved TOG array that drives MT polymerization

Detection of SARS-CoV-2-specific mucosal antibodies in saliva following concomitant COVID-19 and influenza vaccination in the ComFluCOV trial

The ComFluCOV trial randomized 679 participants to receive an age-appropriate influenza vaccine, or placebo, alongside their second COVID-19 vaccine. Concomitant administration was shown to be safe, and to preserve systemic immune responses to both vaccines. Here we report on a secondary outcome of the trial investigating SARS-CoV-2-specific mucosal antibody responses. Anti-spike IgG and IgA levels in saliva were measured with in-house ELISAs. Concomitant administration of an influenza vaccine did not affect salivary anti-spike IgG positivity rates to Pfizer/BioNTech BNT162b2 (99.1 cf. 95.6%), or AstraZeneca ChAdOx1 (67.8% cf. 64.9%), at 3-weeks post-vaccination relative to placebo. Furthermore, saliva IgG positively correlated with serum titres highlighting the potential utility of saliva for assessing differences in immunogenicity in future vaccine studies. Mucosal IgA was not detected in response to either COVID-19 vaccine, reinforcing the need for novel vaccines capable of inducing sterilising immunity or otherwise reducing transmission. The trial is registered as ISRCTN 14391248

\u3cem\u3eStreptococcus agalactiae \u3c/em\u3eStrains with Chromosomal Deletions Evade Detection with Molecular Methods

Surveillance of circulating microbial populations is critical for monitoring the performance of a molecular diagnostic test. In this study, we characterized 31 isolates of Streptococcus agalactiae (group B Streptococcus [GBS]) from several geographic locations in the United States and Ireland that contain deletions in or adjacent to the region of the chromosome that encodes the hemolysin gene cfb, the region targeted by the Xpert GBS and GBS LB assays. PCR-negative, culture-positive isolates were recognized during verification studies of the Xpert GBS assay in 12 laboratories between 2012 and 2018. Whole-genome sequencing of 15 GBS isolates from 11 laboratories revealed four unique deletions of chromosomal DNA ranging from 181 bp to 49 kb. Prospective surveillance studies demonstrated that the prevalence of GBS isolates containing deletions in the convenience sample wa

A morphometric analysis of the infant calvarium and dura

Literature addressing the anatomic development of the dura and calvarium during childhood is limited. Nevertheless, histological features of a subdural neomembrane (NM), including its thickness and vascularity, developing in response to an acute subdural hematoma (SDH) have been compared to the dura of adults to estimate when an injury occurred. Therefore, we measured the morphometric growth of the calvarium and dura and the vascular density within the dura during infancy. The mean thicknesses of the calvarium and dura as a function of occipitofrontal circumference (OFC), as well as the mean number of vessels per 25× field, were determined from the right parasagittal midparietal bone lateral to the sagittal suture of 128 infants without a history of head trauma. Our results showed that as OFC increased, the mean thicknesses of the calvarium and dura increased while the vascular density within the dura decreased. Our morphometric data may assist in the interpretation of subdural NM occurring during infancy. We recommend future investigations to confirm and extend our present data, especially by evaluating cases during later infancy and beyond as well as by sampling other anatomic sites from the calvarium. We also recommend morphometric evaluation of subdural NM associated with SDH in infancy and childhood

Real-time motion monitoring improves functional MRI data quality in infants

Imaging the infant brain with MRI has improved our understanding of early neurodevelopment. However, head motion during MRI acquisition is detrimental to both functional and structural MRI scan quality. Though infants are typically scanned while asleep, they commonly exhibit motion during scanning causing data loss. Our group has shown that providing MRI technicians with real-time motion estimates via Framewise Integrated Real-Time MRI Monitoring (FIRMM) software helps obtain high-quality, low motion fMRI data. By estimating head motion in real time and displaying motion metrics to the MR technician during an fMRI scan, FIRMM can improve scanning efficiency. Here, we compared average framewise displacement (FD), a proxy for head motion, and the amount of usable fMRI data (FD ≤ 0.2 mm) in infants scanned with (n = 407) and without FIRMM (n = 295). Using a mixed-effects model, we found that the addition of FIRMM to current state-of-the-art infant scanning protocols significantly increased the amount of usable fMRI data acquired per infant, demonstrating its value for research and clinical infant neuroimaging