Ikarugamycin (IKA) is a previously discovered antibiotic, which has been shown to inhibit the uptake of oxidized low‐density lipoproteins in macrophages. Furthermore, several groups have previously ...used IKA to inhibit clathrin‐mediated endocytosis (CME) in plant cell lines. However, detailed characterization of IKA has yet to be performed. Consequently, we performed biochemistry and microscopy experiments to further characterize the effects of IKA on CME. We show that IKA has an IC50 of 2.7 μm in H1299 cells and acutely inhibits CME, but not other endocytic pathways, in a panel of cell lines. Although long‐term incubation with IKA has cytotoxic effects, the short‐term inhibitory effects on CME are reversible. Thus, IKA can be a useful tool for probing routes of endocytic trafficking.
The authors have characterized the natural product, ikarugamycin, to demonstrate its utility as a potent and selective acute inhibitor of clathrin‐mediated endocytosis.
There is a growing understanding of the role that bedrock weathering can play as a source of nitrogen (N) to soils, groundwater and river systems. The significance is particularly apparent in ...mountainous environments where weathering fluxes can be large. However, our understanding of the relative contributions of rock-derived, or geogenic, N to the total N supply of mountainous watersheds remains poorly understood. In this study, we develop the High-Altitude Nitrogen Suite of Models (HAN-SoMo), a watershed-scale ensemble of process-based models to quantify the relative sources, transformations, and sinks of geogenic and atmospheric N through a mountain watershed. Our study is based in the East River Watershed (ERW) in the Upper Colorado River Basin. The East River is a near-pristine headwater watershed underlain primarily by an N-rich Mancos Shale bedrock, enabling the timing and magnitude of geogenic and atmospheric contributions to watershed scale dissolved N-exports to be quantified. Several calibration scenarios were developed to explore equifinality using >1600 N concentration measurements from streams, groundwater, and vadose zone samples collected over the course of four years across the watershed. When accounting for recycling of N through plant litter turnover, rock weathering accounts for approximately 12% of the annual dissolved N sources to the watershed in the most probable calibration scenario (0-31% in other scenarios), and 21% (0-44% in other scenarios) when considering only "new" N sources (i.e. geogenic and atmospheric). On an annual scale, instream dissolved N elimination, plant turnover (including cattle grazing) and atmospheric deposition are the most important controls on N cycling.
Abstract Introduction The Pulmonary Embolism Severity Index (PESI) is a validated prognostic score to estimate the 30-day mortality of emergency department (ED) patients with acute pulmonary embolism ...(PE). A simplified version (sPESI) was derived
but has not been as well studied in the U.S. We sought to validate both indices in a community hospital setting in the U.S. and compare their performance in predicting 30-day all-cause mortality and classification of cases into low-risk and higher-risk categories. Materials and methods This retrospective cohort study included adults with acute objectively
confirmed PE from 1/2013 to 4/2015 across 21 community EDs. We evaluated the misclassification rate of the sPESI compared with PESI. We assessed accuracy of both indices with regard to 30-day mortality. Results Among 3
006 cases of acute PE, the 30-day all-cause mortality rate was 4.4%. The sPESI performed as well as the PESI in identifying low-risk patients: both had similar sensitivities, negative predictive values, and negative likelihood ratios. The sPESI, however, classified a smaller proportion of patients as low
risk than the PESI (27.5% vs. 41.0%), but with similar low-risk mortality rates (< 1%). Compared with the PESI, the sPESI overclassified 443 low-risk patients (14.7%) as higher
risk, yet their 30-day mortality was 0.7%. sPESI underclassified 100 higher-risk patients (3.3%) as low
risk, who also had a low mortality rate (1.0%). Conclusions Both indices identified patients with PE who were at low risk for 30-day mortality. The sPESI, however, misclassified a significant number of low-mortality patients as higher risk, which could lead to unnecessary hospitalizations.
Actin assembly supplies the structural framework for cell morphology and migration. Beyond structure, this actin framework can also be engaged to drive biochemical signaling programs. Here, we ...describe how the hyperactivation of Rac1 via the P29S mutation (Rac1P29S) in melanoma hijacks branched actin network assembly to coordinate proliferative cues that facilitate metastasis and drug resistance. Upon growth challenge, Rac1P29S-harboring melanoma cells massively upregulate lamellipodia formation by dendritic actin polymerization. These extended lamellipodia form a signaling microdomain that sequesters and phospho-inactivates the tumor suppressor NF2/Merlin, driving Rac1P29S cell proliferation in growth suppressive conditions. These biochemically active lamellipodia require cell-substrate attachment but not focal adhesion assembly and drive proliferation independently of the ERK/MAPK pathway. These data suggest a critical link between cell morphology and cell signaling and reconcile the dichotomy of Rac1’s regulation of both proliferation and actin assembly by revealing a mutual signaling axis wherein actin assembly drives proliferation in melanoma.
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•Rac1P29S confers proliferative advantage during melanoma metastasis and drug treatment•Rac1P29S sustains proliferation in drug-challenged cells by elongation of lamellipodia•Rac1P29S-driven proliferation needs matrix attachment but not focal adhesion signaling•Elongated lamellipodia in Rac1P29S cells sequester and phospho-inactivate NF2/Merlin
The RhoGTPase Rac1 is a regulator of cell morphology and proliferation. Mohan et al. report that these functions converge in Rac1P29S-mutant melanoma cells. Under growth challenge, Rac1P29S cells form extended lamellipodia that sequester and phospho-inactivate NF2/Merlin, resulting in sustained cell proliferation that is advantageous for metastasis and drug tolerance.
A New Paradigm for Pandemic Preparedness Fefferman, Nina H.; McAlister, John S.; Akpa, Belinda S. ...
Current epidemiology reports,
2023/12, Letnik:
10, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Purpose of Review
Preparing for pandemics requires a degree of interdisciplinary work that is challenging under the current paradigm. This review summarizes the challenges faced by the field of ...pandemic science and proposes how to address them.
Recent Findings
The structure of current siloed systems of research organizations hinders effective interdisciplinary pandemic research. Moreover, effective pandemic preparedness requires stakeholders in public policy and health to interact and integrate new findings rapidly, relying on a robust, responsive, and productive research domain. Neither of these requirements are well supported under the current system.
Summary
We propose a new paradigm for pandemic preparedness wherein interdisciplinary research and close collaboration with public policy and health practitioners can improve our ability to prevent, detect, and treat pandemics through tighter integration among domains, rapid and accurate integration, and translation of science to public policy, outreach and education, and improved venues and incentives for sustainable and robust interdisciplinary work.
Actin assembly supplies the structural framework for cell morphology and migration. Beyond structure, this actin framework can also be engaged to drive biochemical signaling programs. Here, we ...describe how the hyperactivation of Rac1 via the P29S mutation (Rac1
) in melanoma hijacks branched actin network assembly to coordinate proliferative cues that facilitate metastasis and drug resistance. Upon growth challenge, Rac1
-harboring melanoma cells massively upregulate lamellipodia formation by dendritic actin polymerization. These extended lamellipodia form a signaling microdomain that sequesters and phospho-inactivates the tumor suppressor NF2/Merlin, driving Rac1
cell proliferation in growth suppressive conditions. These biochemically active lamellipodia require cell-substrate attachment but not focal adhesion assembly and drive proliferation independently of the ERK/MAPK pathway. These data suggest a critical link between cell morphology and cell signaling and reconcile the dichotomy of Rac1's regulation of both proliferation and actin assembly by revealing a mutual signaling axis wherein actin assembly drives proliferation in melanoma.
The drug olsalazine (H4olz) was employed as a ligand to synthesize a new series of mesoporous metal–organic frameworks that are expanded analogues of the well-known M2(dobdc) materials (dobdc4– = ...2,5-dioxido-1,4-benzenedicarboxylate; M-MOF-74). The M2(olz) frameworks (M = Mg, Fe, Co, Ni, and Zn) exhibit high surface areas with large hexagonal pore apertures that are approximately 27 Å in diameter. Variable temperature H2 adsorption isotherms revealed strong adsorption at the open metal sites, and in situ infrared spectroscopy experiments on Mg2(olz) and Ni2(olz) were used to determine site-specific H2 binding enthalpies. In addition to its capabilities for gas sorption, the highly biocompatible Mg2(olz) framework was also evaluated as a platform for the delivery of olsalazine and other encapsulated therapeutics. The Mg2(olz) material (86 wt % olsalazine) was shown to release the therapeutic linker through dissolution of the framework under simulated physiological conditions. Furthermore, Mg2(olz) was used to encapsulate phenethylamine (PEA), a model drug for a broad class of bioactive compounds. Under simulated physiological conditions, Mg2(olz)(PEA)2 disassembled to release PEA from the pores and olsalazine from the framework itself, demonstrating that multiple therapeutic components can be delivered together at different rates. The low toxicity, high surface areas, and coordinatively unsaturated metal sites make these M2(olz) materials promising for a range of potential applications, including drug delivery in the treatment of gastrointestinal diseases.
Many low-risk patients with acute pulmonary embolism (PE) in the emergency department (ED) are eligible for outpatient care but are hospitalized nonetheless. One impediment to home discharge is the ...difficulty of identifying which patients can safely forgo hospitalization.
To evaluate the effect of an integrated electronic clinical decision support system (CDSS) to facilitate risk stratification and decision making at the site of care for patients with acute PE.
Controlled pragmatic trial. (ClinicalTrials.gov: NCT03601676).
All 21 community EDs of an integrated health care delivery system (Kaiser Permanente Northern California).
Adult ED patients with acute PE.
Ten intervention sites selected by convenience received a multidimensional technology and education intervention at month 9 of a 16-month study period (January 2014 to April 2015); the remaining 11 sites served as concurrent controls.
The primary outcome was discharge to home from either the ED or a short-term (<24-hour) outpatient observation unit based in the ED. Adverse outcomes included return visits for PE-related symptoms within 5 days and recurrent venous thromboembolism, major hemorrhage, and all-cause mortality within 30 days. A difference-in-differences approach was used to compare pre-post changes at intervention versus control sites, with adjustment for demographic and clinical characteristics.
Among 881 eligible patients diagnosed with PE at intervention sites and 822 at control sites, adjusted home discharge increased at intervention sites (17.4% pre- to 28.0% postintervention) without a concurrent increase at control sites (15.1% pre- and 14.5% postintervention). The difference-in-differences comparison was 11.3 percentage points (95% CI, 3.0 to 19.5 percentage points; P = 0.007). No increases were seen in 5-day return visits related to PE or in 30-day major adverse outcomes associated with CDSS implementation.
Lack of random allocation.
Implementation and structured promotion of a CDSS to aid physicians in site-of-care decision making for ED patients with acute PE safely increased outpatient management.
Garfield Memorial National Research Fund and The Permanente Medical Group Delivery Science and Physician Researcher Programs.
Background Coronary risk stratification is recommended for emergency department patients with chest pain. Many protocols are designed as "rule-out" binary classification strategies, while others use ...graded-risk stratification. The comparative performance of competing approaches at varying levels of risk tolerance has not been widely reported. Methods and Results This is a prospective cohort study of adult patients with chest pain presenting between January 2018 and December 2019 to 13 medical center emergency departments within an integrated healthcare delivery system. Using an electronic clinical decision support interface, we externally validated and assessed the net benefit (at varying risk thresholds) of several coronary risk scores (History, ECG, Age, Risk Factors, and Troponin HEART score, HEART pathway, Emergency Department Assessment of Chest Pain Score Accelerated Diagnostic Protocol), troponin-only strategies (fourth-generation assay), unstructured physician gestalt, and a novel risk algorithm (RISTRA-ACS). The primary outcome was 60-day major adverse cardiac event defined as myocardial infarction, cardiac arrest, cardiogenic shock, coronary revascularization, or all-cause mortality. There were 13 192 patient encounters included with a 60-day major adverse cardiac event incidence of 3.7%. RISTRA-ACS and HEART pathway had the lowest negative likelihood ratios (0.06, 95% CI, 0.03-0.10 and 0.07, 95% CI, 0.04-0.11, respectively) and the greatest net benefit across a range of low-risk thresholds. RISTRA-ACS demonstrated the highest discrimination for 60-day major adverse cardiac event (area under the receiver operating characteristic curve 0.92, 95% CI, 0.91-0.94,
<0.0001). Conclusions RISTRA-ACS and HEART pathway were the optimal rule-out approaches, while RISTRA-ACS was the best-performing graded-risk approach. RISTRA-ACS offers promise as a versatile single approach to emergency department coronary risk stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03286179.
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