WormBase (www.wormbase.org) is a central repository for research data on the biology, genetics and genomics of Caenorhabditis elegans and other nematodes. The project has evolved from its original ...remit to collect and integrate all data for a single species, and now extends to numerous nematodes, ranging from evolutionary comparators of C. elegans to parasitic species that threaten plant, animal and human health. Research activity using C. elegans as a model system is as vibrant as ever, and we have created new tools for community curation in response to the ever-increasing volume and complexity of data. To better allow users to navigate their way through these data, we have made a number of improvements to our main website, including new tools for browsing genomic features and ontology annotations. Finally, we have developed a new portal for parasitic worm genomes. WormBase ParaSite (parasite.wormbase.org) contains all publicly available nematode and platyhelminth annotated genome sequences, and is designed specifically to support helminth genomic research.
The accurate description of ancestry is essential to interpret, access, and integrate human genomics data, and to ensure that these benefit individuals from all ancestral backgrounds. However, there ...are no established guidelines for the representation of ancestry information. Here we describe a framework for the accurate and standardized description of sample ancestry, and validate it by application to the NHGRI-EBI GWAS Catalog. We confirm known biases and gaps in diversity, and find that African and Hispanic or Latin American ancestry populations contribute a disproportionately high number of associations. It is our hope that widespread adoption of this framework will lead to improved analysis, interpretation, and integration of human genomics data.
Conspectus The rise of multidrug resistant bacteria has significantly compromised our supply of antibiotics and poses an alarming medical and economic threat to society. To combat this problem, it is ...imperative that new antibiotics and treatment modalities be developed, especially those toward which bacteria are less capable of developing resistance. Peptide natural products stand as promising candidates to meet this need as bacterial resistance is typically slow in response to their unique modes of action. They also have additional benefits including favorable modulation of host immune responses and often possess broad-spectrum activity against notoriously treatment resistant bacterial biofilms. Moreover, nature has provided a wealth of peptide-based natural products from a range of sources, including bacteria and fungi, which can be hijacked in order to combat more dangerous clinically relevant infections. This Account highlights recent advances in the total synthesis and development of a range of peptide-based natural product antibiotics and details the medicinal chemistry approaches used to optimize their activity. In the context of antibiotics with potential to treat Gram-positive bacterial infections, this Account covers the synthesis and optimization of the natural products daptomycin, glycocin F, and alamethicin. In particular, the reported synthesis of daptomycin highlights the utility of on-resin ozonolysis for accessing a key kynurenine residue from the canonical amino acid tryptophan. Furthermore, the investigation into glycocin F analogues uncovered a potent lead compound against Lactobacillus plantarum that bears a non-native thioacetal linkage to a N-acetyl-d-glucosamine (GlcNAc) sugar, which is otherwise O-linked in its native form. For mycobacterial infections, this Account covers the synthesis and optimization of teixobactin, callyaerin A, lassomycin, and trichoderin A. The synthesis of callyaerin A, in particular, highlighted the importance of a (Z)-2,3-diaminoacrylamide motif for antimicrobial activity against Mycobacterium tuberculosis, while the synthesis of trichoderin A highlighted the importance of (R)-stereoconfiguration in a key 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue. Lastly, this Account covers lipopeptide antibiotics bearing activity toward Gram-negative bacterial infections, namely, battacin and paenipeptin C. In both cases, optimization of the N-terminal lipid tails led to the identification of analogues with potent activity toward Escherichia coli and Pseudomonas aeruginosa.
Background Effective nonsurgical modalities are limited in the treatment of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Objective We sought to evaluate the efficacy and viability of ...superficial x-ray therapy in the treatment of BCC and SCC in an outpatient setting. Methods A retrospective analysis was performed on 1715 histologically confirmed primary cutaneous BCC and SCC treated with superficial x-ray therapy at Dermatology Associates of Tallahassee in Florida between 2000 and 2010. Results Of the 1715 tumors reviewed during this period, 712 were histologically proven BCC (631 nodular and 81 superficial), 994 were SCC (861 SCC in situ and 133 invasive SCC), and 9 displayed distinct features of both BCC and SCC in the same biopsy specimen. Kaplan-Meier estimates (with 95% confidence intervals) of cumulative recurrence rates of all tumors at 2 and 5 years were 1.9% (1%-2.7%) and 5.0% (3.2%-6.7%), respectively; of BCC at 2 and 5 years were 2% (0.8%-3.3%) and 4.2% (1.9%-6.4%), respectively; and of all SCC at 2 and 5 years were 1.8% (0.8%-2.8%) and 5.8% (2.9%-8.7%), respectively. Tumors on male patients and those with a diameter greater than 2 cm were associated with a statistically significant increase in recurrence likelihood. Limitations This study represents only patients treated in 1 dermatology office in North Florida and may not be representative of the general patient population. Conclusions Superficial x-ray therapy remains a viable nonsurgical option for the treatment of primary BCC and SCC in patients where surgical intervention is declined, unadvisable, or potentially associated with significant cosmetic or functional limitations.
Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this ...association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort.
We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D).
Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = -0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (β ± SE = -0.47 ± 0.18; p = 0.008), executive function (β ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models.
Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.
The Origins, Spectral-Interpretation, Resource-Identification, Security and Regolith-Explorer (OSIRIS-REx) spacecraft supports all aspects of the mission science objectives, from extensive remote ...sensing at the asteroid Bennu, to sample collection and return to Earth. In general, the success of planetary missions requires the collection, return, and analysis of data, which in turn depends on the successful operation of instruments and the host spacecraft. In the case of OSIRIS-REx, a sample-return mission, the spacecraft must also support the acquisition, safe stowage, and return of the sample. The target asteroid is Bennu, a B-class near-Earth asteroid roughly 500 m diameter. The Lockheed Martin-designed and developed OSIRIS-REx spacecraft draws significant heritage from previous missions and features the Touch-and-Go-Sample-Acquisition-Mechanism, or TAGSAM, to collect sample from the surface of Bennu. Lockheed Martin developed TAGSAM as a novel, simple way to collect samples on planetary bodies. During short contact with the asteroid surface, TAGSAM releases curation-grade nitrogen gas, mobilizing the surface regolith into a collection chamber. The contact surface of TAGSAM includes “contact pads”, which are present to collect surface grains that have been subject to space weathering. Extensive 1-g laboratory testing, “reduced-gravity” testing (via parabolic flights on an airplane), and analysis demonstrate that TAGSAM will collect asteroid material in nominal conditions, and a variety of off-nominal conditions, such as the presence of large obstacles under the TAGSAM sampling head, or failure in the sampling gas firing. TAGSAM, and the spacecraft support of the instruments, are central to the success of the mission.
While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, ...heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment.
Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models.
We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients’ clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit.
Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.
Measurements of turnover rates of gas-phase bimolecular ethanol dehydration to diethyl ether (404–438 K) on a suite of hydrophobic and hydrophilic Sn-zeolites (Sn-Beta, Sn-BEC, Sn-MFI) of varying Sn ...content, together with quantitative titration of active Sn sites by pyridine during catalysis, identify two types of Sn sites with reactivity differing by more than an order of magnitude (>20×). Apparent activation entropies to form bimolecular dehydration transition states from predominantly ethanol monomer-covered sites are less negative (ΔΔS app ⧧ = 48 ± 22 J mol–1 K–1) at the more reactive subset of Sn sites, which are present in amounts equivalent to 17–26% of the Sn sites quantified by the peak centered at 2308 cm–1 in CD3CN IR spectra (Sn2308) but not correlated with that at 2316 cm–1 (Sn2316). Synthetic and postsynthetic treatments to prepare Sn-zeolites containing Sn sites hosted within diverse local coordination environments suggest that Sn2316 sites are not associated with Sn bound to residual fluoride anions or Sn sited at external crystallite surfaces, amorphous domains, or among the diverse T-site locations contained within CHA, MFI, BEC, and STT frameworks. Treating Sn-Beta in HF or NH4F solutions, which dissolve zeolitic domains preferentially at defect grain boundaries, decreased the number of Sn2316 sites but not Sn2308 sites. These data indicate that Sn2316 sites are preferentially located at stacking faults in zeolite Beta, which provide tetrahedral coordination environments for Sn in defect-open configurations ((HO)–Sn–(OSi)3) with proximal Si–OH groups that do not permit condensation to tetrahedral closed configurations (Sn–(OSi)4). A computational model was developed for stacking fault defect-open Sn sites, which predict apparent activation free energies for bimolecular ethanol dehydration that are 65–74 kJ mol–1 higher (at 404 K) than those at framework-closed Sn sites that are capable of stabilizing transition states via Sn site opening and closing as part of the catalytic cycle, consistent with the lower experimentally measured ethanol dehydration reactivity for Sn2316 sites. In contrast, defect-open sites possess Si–OH groups that preferentially stabilize hydride shift transition states involved in glucose–fructose isomerization catalytic cycles. These findings highlight the ability of a given zeolite framework to confer structural diversity to nominally site-isolated Lewis acid centers, thus generating configurations with distinct reactivity for different chemical transformations.
An unusually deep (V,I) imaging dataset for the Virgo supergiant M 87 with the Hubble Space Telescope ACS successfully resolves its brightest red-giant stars, reaching MI(lim) = −2.5. After assessing ...the photometric completeness and biasses, we use this material to estimate the metallicity distribution for the inner halo of M 87, finding that the distribution is very broad and likely to peak near m/H ≃ −0.4 and perhaps higher. The shape of the MDF strongly resembles that of the inner halo for the nearby giant E galaxy NGC 5128. As a byproduct of our study, we also obtain a preliminary measurement of the distance to M 87 with the TRGB (red-giant branch tip) method; the result is (m − M)0 = 31.12±0.14 (d = 16.7±0.9 Mpc). Averaging this result with three other recent techniques give a weighted mean d(M87) = (16.4 ± 0.5) Mpc.
Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum ...concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n=71) and control (n=59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of ~50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms.
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