The horse is central to many Indigenous cultures across the American Southwest and the Great Plains. However, when and how horses were first integrated into Indigenous lifeways remain contentious, ...with extant models derived largely from colonial records. We conducted an interdisciplinary study of an assemblage of historic archaeological horse remains, integrating genomic, isotopic, radiocarbon, and paleopathological evidence. Archaeological and modern North American horses show strong Iberian genetic affinities, with later influx from British sources, but no Viking proximity. Horses rapidly spread from the south into the northern Rockies and central plains by the first half of the 17th century CE, likely through Indigenous exchange networks. They were deeply integrated into Indigenous societies before the arrival of 18th-century European observers, as reflected in herd management, ceremonial practices, and culture.
The influence of organic compounds on iodine (I
) emissions from the O
+ I
reaction at the sea surface was investigated in laboratory and modeling studies using artificial solutions, natural ...subsurface seawater (SSW), and, for the first time, samples of the surface microlayer (SML). Gas-phase I
was measured directly above the surface of liquid samples using broadband cavity enhanced absorption spectroscopy. I
emissions were consistently lower for artificial seawater (AS) than buffered potassium iodide (KI) solutions. Natural seawater samples showed the strongest reduction of I
emissions compared to artificial solutions with equivalent I
, and the reduction was more pronounced over SML than SSW. Emissions of volatile organic iodine (VOI) were highest from SML samples but remained a negligible fraction (<1%) of the total iodine flux. Therefore, reduced iodine emissions from natural seawater cannot be explained by chemical losses of I
or hypoiodous acid (HOI), leading to VOI. An interfacial model explains this reduction by increased solubility of the I
product in the organic-rich interfacial layer of seawater. Our results highlight the importance of using environmentally representative concentrations in studies of the O
+ I
reaction and demonstrate the influence the SML exerts on emissions of iodine and potentially other volatile species.
For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and ...pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases.
In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses.
Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent.
This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.
Nine ruthenium CNC pincer complexes (1–9) were tested for anticancer activity in cell culture under both dark and light conditions. These complexes included varied CNC pincer ligands including OH, ...OMe, or Me substituents on the pyridyl ring and wingtip N-heterocyclic carbene (NHC) groups which varied as methyl (Me), phenyl (Ph), mesityl (Mes), and 2,6-diisopropylphenyl (Dipp). The supporting ligands included acetonitrile, Cl, and 2,2′-bipyridine (bpy) donors. The synthesis of complexes 8 and 9 is described herein and are fully characterized by spectroscopic (1H NMR, IR, UV–Vis, MS) and analytical techniques. Single crystal X-ray diffraction results are reported herein for 8 and 9. The other complexes (1–7) are reported elsewhere. The four most lipophilic ruthenium complexes (6, 7, 8, and 9) showed the best activity vs. MCF7 cancer cells with complexes 6 and 9 showing cytotoxicity and complex 7 and 8 showing light activated photocytotoxicity. The distribution of these compounds between octanol and water is reported as log(Do/w) values, and increasing log(Do/w) values correlate roughly with improved activity vs. cancer cells. Overall, lipophilic wingtip groups (e.g. Ph, Mes, Dipp) on the NHC ring and a lower cationic charge (1+ vs. 2+) appears to be beneficial for improved anticancer activity.
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•One Ru complex shows light activated toxicity vs. MDA-MB-231 breast cancer cells.•The most active compound has a phototoxicity index of 21 and micromolar potency.•Structure-function relationships show that lipophilicity correlates with toxicity.•Synthetic procedures for making lipophilic CNC pincer complexes are reported.
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This paper describes the synthesis of H2O2–H2O filled poly(methyl methacrylate) (PMMA) microcapsules as potential candidates for controlled O2 delivery. The microcapsules are prepared ...by a water-in-oil solvent emulsion and evaporation method. The results of this study describe the effect of process parameters on the characteristics of the microcapsules and on their in vitro performance. The size of the microcapsules, as determined from scanning electron microscopy, ranges from ∼5 to 30μm and the size distribution is narrow. The microcapsules exhibit an internal morphology with entrapped H2O2–H2O droplets randomly distributed in the PMMA continuous phase. In vitro release studies of 4.5wt% H2O2-loaded microcapsules show that ∼70% of the H2O2 releases in 24h. This corresponds to a total O2 production of ∼12cc/gram of dry microcapsules. Shelf-life studies show that the microcapsules retain ∼84wt% of the initially loaded H2O2 after nine months storage at 2–8°C, which is an attractive feature for clinical applications.
Adaptive changes in lysosomal capacity are driven by the transcription factors TFEB and TFE3 in response to increased autophagic flux and endolysosomal stress, yet the molecular details of their ...activation are unclear. LC3 and GABARAP members of the ATG8 protein family are required for selective autophagy and sensing perturbation within the endolysosomal system. Here, we show that during the conjugation of ATG8 to single membranes (CASM), Parkin-dependent mitophagy, and
-induced xenophagy, the membrane conjugation of GABARAP, but not LC3, is required for activation of TFEB/TFE3 to control lysosomal capacity. GABARAP directly binds to a previously unidentified LC3-interacting motif (LIR) in the FLCN/FNIP tumor suppressor complex and mediates sequestration to GABARAP-conjugated membrane compartments. This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. Thus, the GABARAP-FLCN/FNIP-TFEB axis serves as a molecular sensor that coordinates lysosomal homeostasis with perturbations and cargo flux within the autophagy-lysosomal network.
, the causative agent of glanders, is a gram-negative intracellular bacterium. Depending on different routes of infection, the disease is manifested by pneumonia, septicemia, and chronic infections ...of the skin.
poses a serious biological threat due to its ability to infect via aerosol route, resistance to multiple antibiotics and to date there are no US Food and Drug Administration (FDA) approved vaccines available. Induction of innate immunity, inflammatory cytokines and chemokines following
infection, have been observed in
and small rodent models; however, a global characterization of host responses has never been systematically investigated using a non-human primate (NHP) model. Here, using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach, we identified alterations in expression levels of host proteins in peripheral blood mononuclear cells (PBMCs) originating from naïve rhesus macaques (
), African green monkeys (
), and cynomolgus macaques (
) exposed to aerosolized
. Gene ontology (GO) analysis identified several statistically significant overrepresented biological annotations including complement and coagulation cascade, nucleoside metabolic process, vesicle-mediated transport, intracellular signal transduction and cytoskeletal protein binding. By integrating an LC-MS/MS derived proteomics dataset with a previously published
host-pathogen interaction dataset, a statistically significant predictive protein-protein interaction (PPI) network was constructed. Pharmacological perturbation of one component of the PPI network, specifically ezrin, reduced
mediated interleukin-1β (IL-1β). On the contrary, the expression of IL-1β receptor antagonist (IL-1Ra) was upregulated upon pretreatment with the ezrin inhibitor. Taken together, inflammasome activation as demonstrated by IL-1β production and the homeostasis of inflammatory response is critical during the pathogenesis of glanders. Furthermore, the topology of the network reflects the underlying molecular mechanism of
infections in the NHP model.
The behaviour and distribution of iodine in the environment are of significant interest in a range of scientific disciplines, from health, as iodine is an essential element for humans and animals, to ...climate and air quality, to geochemistry. Aquatic environments are the reservoir for iodine, where it exists in low concentrations as iodide, iodate and dissolved organic iodine and in which it undergoes redox reactions. The current measurement techniques for iodine species are typically time-consuming, subject to relatively poor precision and require specialist instrumentation including those that require mercury as an electrode. We present a new method for measuring iodine species, that is tailored towards lower dissolved organic carbon waters, such as seawater, rainwater and snow, using ion exchange chromatography (IC) with direct ultra-violet spectrophotometric detection of iodide and without the need for sample pre-concentration. Simple chemical amendments to the sample allow for the quantification of both iodate and dissolved organic iodine in addition to iodide. The developed IC method, which takes 16 min, was applied to contrasting samples that encompass a wide range of aqueous environments, from Arctic sea-ice snow (low concentrations) to coastal seawater (complex sample matrix). Linear calibrations are demonstrated for all matrices, using gravimetrically prepared potassium iodide standards. The detection limit for the iodide ion is 0.12 nM based on the standard deviation of the blank, while sample reproducibility is typically <2% at >8 nM and ∼4% at <8 nM. Since there is no environmental certified reference material for iodine species, the measurements made on seawater samples using this IC method were compared to those obtained using established analytical techniques; iodide voltammetry and iodate spectrophotometry. We calculated recoveries of 102 ± 16% (n = 107) for iodide and 116 ± 9% (n = 103) for iodate, the latter difference may be due to an underestimation of iodate by the spectrophotometric method. We further compared a chemical oxidation and reduction of the sample to an ultra-violet digestion to establish the total dissolved iodine content, the average recovery following chemical amendments was 98 ± 4% (n = 92). The new method represents a simple, efficient, green, precise and sensitive method for measuring dissolved speciated iodine in complex matrices.
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•Simple and rapid iodine speciation analysis.•Pico-molar detection limit for direct iodide analysis.•Comprehensive validation of iodine speciation determination.•The technique is globally applicable to environmental aqueous systems.
Herein, we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression ...changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n = 3) were compared with littermate controls (n = 3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average p = 0.0082; cystatin A, human ortholog); slc25a5 (average fold change of 46.2 and an average p = 0.0318); serpinb3b (average fold change of 35.6 and an average p = 0.0345; serpinB1, human ortholog); and kallikrein related peptidase 6 (average fold change of 4.7 and an average p = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, p < 0.0001), KLK6 (9-fold, p = 0.002), stefin A1 (7.3-fold; p < 0.001), and slc25A5 (1.5-fold; p = 0.05) using qRT-PCR on a second cohort of animals (n = 8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; p < 0.05), 29,000-fold (stefinA1; p < 0.01), 322-fold (KLK6; p < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes versus healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3-fold), KLK6 (5.8-fold), and serpinB1 (76-fold; all p < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover, slc25a5, cystatin A, KLK6, and serpinB1 protein were all increased in lesional psoriasis skin compared with normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments.
Objective
Analyse uptake of the core outcome set (COS) within preterm birth (PTB) clinical trials.
Design
On 26 June 2023, we conducted a systematic search of phase III/IV trial registry entries ...regarding PTB interventions via ClinicalTrials.gov and the International Clinical Trial Registry Platform. These trials were analysed for the outcomes measured.
Setting
N/A.
Sample
After searching the two databases, 5257 randomised controlled trials (RCTs) were screened, resulting in 92 RCTs for analysis.
Methods
Inclusion criteria were the following: subjects were patients receiving an intervention for PTB, study enrolment began within 5 years prior to publication of PTB COS to 26 June 2023, and evaluated the efficacy of interventions. Authors screened and extracted data in masked, duplicate fashion, then performed an interrupted time series analysis, analysis of variance and correlation analysis.
Main outcome measures
We extracted outcomes measured by each clinical trial in our sample. Trials were analysed for the percentage of adopted outcomes from PTB COS.
Results
After COS publication, there was no significant change in percentage of COS outcomes measured. The most measured outcome was ‘offspring mortality’ (54.34%, 50/92) and the least measured outcome was ‘late neonatal neurodevelopment morbidity’ (3.26%, 3/92). Additionally, 22.83% (21/92) of trials measured zero outcomes related to the PTB COS.
Conclusion
Our results demonstrated no significant change in outcome measurement before or after PTB COS publication. We recommend focusing on both the measurement of outcomes and the assessments that are used.
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