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"Fitch, A"
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A description of the New York Central Park
A facsimile reproduction of the 1869 edition, along with a new introduction by Maureen Meister.
Book
Developmental constraints in the repeated evolution of male tail characters in rhabditid and diplogastrid nematodes
A longstanding question in evolutionary biology is how change might be restricted or biased due to developmental constraints. To address this question, we investigated three recurrently evolving characters in rhabditid nematode male tails: tail tip morphogenesis, the number of genital papillae (GPs or \"rays\"), and phasmid position relative to the three most posterior GPs. This new analysis incorporates taxa (rhabditids Cruznema tripartitum, Haematozoon subulatum, Poikilolaimus oxycercus, diplogastrid Diplogasteroides nasuensis, and outgroup representative Brevibucca saprophaga) representing more and deeper divergence points in the rhabditid phylogeny than in previous analyses, allowing better resolution of ancestral states and changes. Analysis of GP characters was accomplished via immunofluorescent staining of adherens junctions at different stages of GP development and laser microbeam ablations of GP primordia. Findings include the following: (1) Loss and gain of tail tip morphogenesis occurred multiple times, possibly involving differences in fusion. (2) The pattern of GP anlagen in early L4 males is highly conserved and compatible with the previously proposed \"archetype,\" but is established at different developmental times in different species, consistent with constraint on GP patterning by the cell lineage and anteroposterior and dorsoventral patterning systems. (3) The stem species of Rhabditina likely had 8 GPs, with the second GP (v2) gained after the divergence of Poikilolaimus; within rhabditids, a different GP (v6) appears to be lost twice independently. (4) Laser ablation showed that changes in phasmid position relative to GPs are not due to changes in cell lineage, but instead due to migratory switches in the relative positions of precursors of phasmid socket cells and GPs; these cell migrations occur at different developmental times in different species. In summary, our results indicate a strong constraint imposed on the cell lineage and dorsoventral positioning of GP precursors, with GP pattern diversity allowed by cell-specific migratory behavior.
Journal Article
The best horror of the year. Volume ten
A group of mountain climbers, caught in the dark, fights to survive their descent; An American band finds more than they bargained for in Mexico while scouting remote locations for a photo shoot; A young student's exploration into the origins of a mysterious song leads him on a winding, dangerous path through the US's deep south; A group of kids scaring each other with ghost stories discovers alarming consequences. The Best Horror of the Year showcases the previous year's best offerings in horror short fiction. This edition includes award-winning and critically acclaimed authors Mark Morris, Kaaron Warren, John Langan, Carole Johnstone, Brian Hodge, and others. For more than three decades, award-winning editor and anthologist Ellen Datlow has had her finger on the pulse of the latest and most terrifying in horror writing. Night Shade Books is proud to present the tenth volume in this annual series, a new collection of stories to keep you up at night.
BOOK
Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-Week, Randomized, Double-blind, Placebo-Controlled Trial to Evaluate Efficacy and Safety
Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide treatment in patients with irritable bowel syndrome with constipation (IBS-C) over 26 weeks.
This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg of oral linaclotide once daily for a 26-week treatment period. The primary and the secondary efficacy assessments were evaluated over the first 12 weeks of treatment. Primary end points included the Food and Drug Administration's (FDA's) end point for IBS-C (responder: a patient who reported (i) improvement of ≥ 30 % from baseline in average daily worst abdominal pain score and (ii) increase of ≥ 1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for ≥ 6 / 12 weeks) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.
In all, 804 patients (mean age = 44 years, female = 90 % , white = 78 % ) were evaluated; 33.7 % of linaclotide-treated patients were FDA end point responders, vs. 13.9 % of placebo-treated patients ( P < 0.0001) (number needed to treat = 5.1, 95 % confidence interval (CI): 3.9, 7.1). The pain responder criterion of the FDA end point was met by 48.9 % of linaclotide-treated patients vs. 34.5 % of placebo-treated patients (number needed to treat = 7.0, 95 % CI: 4.7, 13.1), and the CSBM responder criterion was met by 47.6 % of linaclotide-treated patients, vs. 22.6 % of placebo patients (number needed to treat = 4.0, 95 % CI: 3.2, 5.4). Remaining primary end points ( P < 0.0001) and all secondary end points ( P < 0.001), including abdominal pain, abdominal bloating, and bowel symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining), were also statistically significantly improved with linaclotide vs. placebo. Statistically significant differences from placebo were observed for responder and continuous end points over 26 weeks of treatment. AE incidence was similar between treatment groups, except for diarrhea, which caused discontinuation in 4.5 % of linaclotide patients vs. 0.2 % of placebo patients.
Linaclotide 290 μg once daily significantly improved abdominal and bowel symptoms associated with IBS-C over 26 weeks of treatment.
Journal Article
Two Randomized Trials of Linaclotide for Chronic Constipation
In two 12-week trials, linaclotide, a minimally absorbed peptide agonist of the guanylate cyclase-C receptor, increased the frequency of spontaneous bowel movements and improved symptoms in patients with chronic constipation. Longer-term studies are needed.
Chronic constipation affects between 12 and 19% of the U.S. population.
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,
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The symptoms of chronic constipation, including infrequent bowel movements, hard stools, straining during defecation, bloating, abdominal discomfort, and a sense of incomplete evacuation,
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adversely affect quality of life
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,
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and are associated with substantial costs.
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,
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Few currently available therapies for chronic constipation have been shown to be effective and safe in well-controlled, long-term trials,
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and many persons with this disorder are not completely satisfied with their current treatment options.
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Linaclotide is a 14-amino-acid synthetic peptide that is structurally related to the endogenous guanylin peptide family. It binds . . .
Journal Article
The high resolution powder diffraction beam line at ESRF
The optical design and performance of the high-resolution powder diffraction beam line BM16 at ESRF are discussed and illustrated. Some recent studies carried out on BM16 are described, including crystal structure solution and refinement, anomalous scattering, in situ measurements, residual strain in engineering components, investigation of microstructure, and grazing-incidence diffraction from surface layers. The beam line is built on a bending magnet, and operates in the energy range from 5 keV to 40 keV. After the move to an undulator source in 2002, it will benefit from an extented energy range up to 60 keV and increased flux and resolution. It is anticipated that enhancements to the data quality will be achieved, leading to the solution of larger crystal structures, and improvements in the accuracy of refined structures. The systematic exploitation of anisotropic thermal expansion will help reduce the effects of peak overlap in the analysis of powder diffraction data. [PUBLICATION ABSTRACT] Keywords: anomalous scattering; grazing incidence; microstructure, powder crystallography; residual strain; Rietveld refinement; structural solution; synchrotron radiation; x-ray diffraction.
Journal Article
EUAdb: A resource for COVID-19 test development and comparison
Due to the sheer number of COVID-19 (coronavirus disease 2019) cases there is a need for increased world-wide SARS-CoV-2 testing capability that is both efficient and effective. Having open and easy access to detailed information about these tests, their sensitivity, the types of samples they use, etc. would be highly useful to ensure their reproducibility, to help clients compare and decide which tests would be best suited for their applications, and to avoid costs of reinventing similar or identical tests. Additionally, this resource would provide a means of comparing the many innovative diagnostic tools that are currently being developed in order to provide a foundation of technologies and methods for the rapid development and deployment of tests for future emerging diseases. Such a resource might thus help to avert the delays in testing and screening that was observed in the early stages of the pandemic and plausibly led to more COVID-19-related deaths than necessary. We aim to address these needs via a relational database containing standardized ontology and curated data about COVID-19 diagnostic tests that have been granted Emergency Use Authorizations (EUAs) by the FDA (US Food and Drug Administration). Simple queries of this actively growing database demonstrate considerable variation among these tests with respect to sensitivity (limits of detection, LoD), controls and targets used, criteria used for calling results, sample types, reagents and instruments, and quality and amount of information provided.
Journal Article
Resistance to mTOR Kinase Inhibitors in Lymphoma Cells Lacking 4EBP1
Inhibitors of the mechanistic target of rapamycin (mTOR) hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ATP-competitive \"active-site\" mTOR inhibitors produce more complete mTOR inhibition and are more effective than rapamycin in preclinical models of leukemia, lymphoma and multiple myeloma. In parallel to clinical trials of active-site mTOR inhibitors, it will be important to identify resistance mechanisms that might limit drug efficacy in certain patients. From a panel of diffuse large B-cell lymphoma cell lines, we found that the VAL cell line is particularly resistant to apoptosis in the presence of active-site mTOR inhibitors. Mechanistic investigation showed that VAL does not express eukaryotic initiation factor 4E-binding protein-1 (4EBP1), a key negative regulator of translation controlled by mTOR. Although VAL cells express the related protein 4EBP2, mTOR inhibitor treatment fails to displace eukaryotic initiation factor 4G from the mRNA cap-binding complex. Knockdown of eukaryotic initiation factor 4E, or re-expression of 4EBP1, sensitizes cells to apoptosis when treated with active-site mTOR inhibitors. These findings provide a naturally occurring example of 4EBP deficiency driving lymphoma cell resistance to active-site mTOR inhibitors.
Journal Article
From “the Worm” to “the Worms” and Back Again: The Evolutionary Developmental Biology of Nematodes
Biologists have long appreciated natural variation in the nematode phylum. The development of Caenorhabditis elegans as a model organism has provided a rich set of specific genetic and cellular mechanisms that have been subjected to... Since the earliest days of research on nematodes, scientists have noted the developmental and morphological variation that exists within and between species. As various cellular and developmental processes were revealed through intense focus on Caenorhabditis elegans, these comparative studies have expanded. Within the genus Caenorhabditis, they include characterization of intraspecific polymorphisms and comparisons of distinct species, all generally amenable to the same laboratory culture methods and supported by robust genomic and experimental tools. The C. elegans paradigm has also motivated studies with more distantly related nematodes and animals. Combined with improved phylogenies, this work has led to important insights about the evolution of nematode development. First, while many aspects of C. elegans development are representative of Caenorhabditis, and of terrestrial nematodes more generally, others vary in ways both obvious and cryptic. Second, the system has revealed several clear examples of developmental flexibility in achieving a particular trait. This includes developmental system drift, in which the developmental control of homologous traits has diverged in different lineages, and cases of convergent evolution. Overall, the wealth of information and experimental techniques developed in C. elegans is being leveraged to make nematodes a powerful system for evolutionary cellular and developmental biology.
Journal Article
A Bow-Tie Genetic Architecture for Morphogenesis Suggested by a Genome-Wide RNAi Screen in Caenorhabditis elegans
During animal development, cellular morphogenesis plays a fundamental role in determining the shape and function of tissues and organs. Identifying the components that regulate and drive morphogenesis is thus a major goal of developmental biology. The four-celled tip of the Caenorhabditis elegans male tail is a simple but powerful model for studying the mechanism of morphogenesis and its spatiotemporal regulation. Here, through a genome-wide post-embryonic RNAi-feeding screen, we identified 212 components that regulate or participate in male tail tip morphogenesis. We constructed a working hypothesis for a gene regulatory network of tail tip morphogenesis. We found regulatory roles for the posterior Hox genes nob-1 and php-3, the TGF-β pathway, nuclear hormone receptors (e.g. nhr-25), the heterochronic gene blmp-1, and the GATA transcription factors egl-18 and elt-6. The majority of the pathways converge at dmd-3 and mab-3. In addition, nhr-25 and dmd-3/mab-3 regulate each others' expression, thus placing these three genes at the center of a complex regulatory network. We also show that dmd-3 and mab-3 negatively regulate other signaling pathways and affect downstream cellular processes such as vesicular trafficking (e.g. arl-1, rme-8) and rearrangement of the cytoskeleton (e.g. cdc-42, nmy-1, and nmy-2). Based on these data, we suggest that male tail tip morphogenesis is governed by a gene regulatory network with a bow-tie architecture.
Journal Article