The Red Sea has long been recognized as a region of high biodiversity and endemism. Despite this diversity and early history of scientific work, our understanding of the ecology of coral reefs in the ...Red Sea has lagged behind that of other large coral reef systems. We carried out a quantitative assessment of ISI-listed research published from the Red Sea in eight specific topics (apex predators, connectivity, coral bleaching, coral reproductive biology, herbivory, marine protected areas, non-coral invertebrates and reef-associated bacteria) and compared the amount of research conducted in the Red Sea to that from Australia’s Great Barrier Reef (GBR) and the Caribbean. On average, for these eight topics, the Red Sea had 1/6th the amount of research compared to the GBR and about 1/8th the amount of the Caribbean. Further, more than 50 % of the published research from the Red Sea originated from the Gulf of Aqaba, a small area (<2 % of the area of the Red Sea) in the far northern Red Sea. We summarize the general state of knowledge in these eight topics and highlight the areas of future research priorities for the Red Sea region. Notably, data that could inform science-based management approaches are badly lacking in most Red Sea countries. The Red Sea, as a geologically “young” sea located in one of the warmest regions of the world, has the potential to provide insight into pressing topics such as speciation processes as well as the capacity of reef systems and organisms to adapt to global climate change. As one of the world’s most biodiverse coral reef regions, the Red Sea may yet have a significant role to play in our understanding of coral reef ecology at a global scale.
Modern nautilids (Nautilus and Allonautilus) have often been studied by paleontologists to better understand the anatomy and ecology of fossil relatives. Because direct observations of these animals ...are difficult, the analysis of light stable isotopes (C, O) preserved in their shells has been employed to reveal their habitat and life history. We aim to (1) reconstruct the habitat depth of Nautilus macromphalus and (2) decipher the fraction of metabolic carbon in its shell by analyzing oxygen and carbon isotopes (delta.sup.18 O, delta.sup.13 C) in the septa of two specimens in combination with analyses of water samples from the area. Additionally, we investigate whether morphological changes during ontogeny are reflected in the isotopic values of the shells. Results reveal that the patterns of change of delta.sup.18 O and delta.sup.13 C in the septa of N. macromphalus pre- and post-hatching are consistent with previous studies. Values of delta.sup.18 O.sub.water range from 0.7 to 1.4% (VSMOW), with a maximum value coincident with a salinity maximum at ~150 m. We use the temperature and delta.sup.18 O.sub.water profiles to calculate equilibrium values of delta.sup.18 O.sub.aragonite with depth. Comparing these values with the measured delta.sup.18 O of the septa shows that the habitat depth of N. macromphalus is ~140 m pre-hatching and ~370 m post-hatching. Using delta.sup.13 C of shell carbonate and published data on metabolic carbon, the fraction of metabolic carbon is reconstructed as ~21% and 14% pre- and post-hatching, respectively. The reconstructed depth pre-hatching is slightly shallower than in N. pompilius from the Philippines and Fiji, but the post-hatching depth is similar. However, it is important to emphasize that these estimates represent average over time and space because nautilus is a mobile animal. Lastly, the changes in morphological parameters and the changes in delta.sup.13 C and delta.sup.18 O during ontogeny do not coincide except at hatching and at the onset of maturity.
Normally post-mitotic neurons that aberrantly re-enter the cell cycle without dividing account for a substantial fraction of the neurons that die in Alzheimer's disease (AD). We now report that this ...ectopic cell cycle re-entry (CCR) requires soluble amyloid-β (Aβ) and tau, the respective building blocks of the insoluble plaques and tangles that accumulate in AD brain. Exposure of cultured wild type (WT) neurons to Aβ oligomers caused CCR and activation of the non-receptor tyrosine kinase, fyn, the cAMP-regulated protein kinase A and calcium-calmodulin kinase II, which respectively phosphorylated tau on Y18, S409 and S416. In tau knockout (KO) neurons, Aβ oligomers activated all three kinases, but failed to induce CCR. Expression of WT, but not Y18F, S409A or S416A tau restored CCR in tau KO neurons. Tau-dependent CCR was also observed in vivo in an AD mouse model. CCR, a seminal step in AD pathogenesis, therefore requires signaling from Aβ through tau independently of their incorporation into plaques and tangles.
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). ...Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.
Molecular orientation critically influences the mechanical, chemical, optical and electronic properties of organic materials. So far, molecular-scale ordering in soft matter could be characterized ...with X-ray or electron microscopy techniques only if the sample exhibited sufficient crystallinity. Here, we show that the resonant scattering of polarized soft X-rays (P-SoXS) by molecular orbitals is not limited by crystallinity and that it can be used to probe molecular orientation down to size scales of 10 nm. We first apply the technique on highly crystalline small-molecule thin films and subsequently use its high sensitivity to probe the impact of liquid-crystalline ordering on charge mobility in polymeric transistors. P-SoXS also reveals scattering anisotropy in amorphous domains of all-polymer organic solar cells where interfacial interactions pattern orientational alignment in the matrix phase, which probably plays an important role in the photophysics. The energy and q-dependence of the scattering anisotropy allows the identification of the composition and the degree of orientational order in the domains.
We consider the problem of seeking the source of a scalar signal using an autonomous vehicle modeled as the nonholonomic unicycle. The vehicle does not have the capability of sensing its position or ...the position of the source but is capable of sensing the scalar signal originating from the source. The signal field is assumed to decay away from the position of the source but the vehicle does not have the knowledge of the functional form of the field. We employ extremum seeking to steer the vehicle to the source. Our control strategy keeps the forward velocity constant and tunes the angular velocity, a setting suitable for most autonomous vehicles, including aerial ones. Because of the constant forward velocity constraint, after it has converged near the source, the vehicle exhibits extremely interesting and complex motions. Using averaging theory, we prove local exponential convergence to an ldquoorbit-likerdquo attractor around the source. We also present a thorough analysis of non-local behaviors and attractors that the vehicle can exhibit near the source. The richness and complexity of behaviors makes only some of them amenable to analysis, whereas others are illustrated through a carefully laid out simulation study.
Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ...ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.
Motivation: The ability to detect copy-number variation (CNV) and loss of heterozygosity (LOH) from exome sequencing data extends the utility of this powerful approach that has mainly been used for ...point or small insertion deletion detection.
Results: We present ExomeCNV, a statistical method to detect CNV and LOH using depth-of-coverage and B-allele frequencies, from mapped short sequence reads, and we assess both the method's power and the effects of confounding variables. We apply our method to a cancer exome resequencing dataset. As expected, accuracy and resolution are dependent on depth-of-coverage and capture probe design.
Availability: CRAN package 'ExomeCNV'.
Contact:
fsathira@fas.harvard.edu; snelson@ucla.edu
Supplementary information:
Supplementary data are available at Bioinformatics online.
Women have a higher incidence of Alzheimer’s disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 ...is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research.
•Reduced PIN1 levels are driven by females in aging and Alzheimer’s disease.•PIN1 is negatively correlated with neurofibrillary tangle density in females.•PIN1 levels are negatively correlated with global cognitive function in females.•PIN1 levels are decreased in subjects with mild cognitive impairment.
Determining the equilibrium-binding affinity (Kd) of two interacting proteins is essential not only for the biochemical study of protein signaling and function but also for the engineering of ...improved protein and enzyme variants. One common technique for measuring protein-binding affinities uses flow cytometry to analyze ligand binding to proteins presented on the surface of a cell. However, cell-binding assays require specific considerations to accurately quantify the binding affinity of a protein-protein interaction. Here we will cover the basic assumptions in designing a cell-based binding assay, including the relevant equations and theory behind determining binding affinities. Further, two major considerations in measuring binding affinities-time to equilibrium and ligand depletion-will be discussed. As these conditions have the potential to greatly alter the Kd, methods through which to avoid or minimize them will be provided. We then outline detailed protocols for performing direct- and competitive-binding assays against proteins displayed on the surface of yeast or mammalian cells that can be used to derive accurate Kd values. Finally, a comparison of cell-based binding assays to other types of binding assays will be presented.
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