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Background: In this priority-setting exercise, we sought to identify leading research priorities needed for strengthening future pandemic preparedness and response across countries. Methods: The International Society of Global Health (ISoGH) used the Child Health and Nutrition Research Initiative (CHNRI) method to identify research priorities for future pandemic preparedness. Eighty experts in global health, translational and clinical research identified 163 research ideas, of which 42 experts then scored based on five pre-defined criteria. We calculated intermediate criterion-specific scores and overall research priority scores from the mean of individual scores for each research idea. We used a bootstrap (n = 1000) to compute the 95% confidence intervals. Results: Key priorities included strengthening health systems, rapid vaccine and treatment production, improving international cooperation, and enhancing surveillance efficiency. Other priorities included learning from the coronavirus disease 2019 (COVID-19) pandemic, managing supply chains, identifying planning gaps, and promoting equitable interventions. We compared this CHNRI-based outcome with the 14 research priorities generated and ranked by ChatGPT, encountering both striking similarities and clear differences. Conclusions: Priority setting processes based on human crowdsourcing - such as the CHNRI method - and the output provided by ChatGPT are both valuable, as they complement and strengthen each other. The priorities identified by ChatGPT were more grounded in theory, while those identified by CHNRI were guided by recent practical experiences. Addressing these priorities, along with improvements in health planning, equitable community-based interventions, and the capacity of primary health care, is vital for better pandemic preparedness and response in many settings.
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COVID-19 , Preparación para una Pandemia , Niño , Humanos , Consenso , Proyectos de Investigación , COVID-19/epidemiología , COVID-19/prevención & control , Salud InfantilRESUMEN
Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.
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Glucosa/inmunología , Neutrófilos/inmunología , Adulto , Anciano , Animales , Células Cultivadas , Femenino , Gluconeogénesis , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Adulto JovenRESUMEN
In the northern Great Plains (NGP), wheat is the primary grain commodity. There is a need for the NGP to have a detailed analysis of environmental impacts for wheat-based agricultural production systems to better understand regional agroecosystems. This article provides a cradle-to-field gate life cycle assessment (LCA) for NGP dryland wheat (Triticum aestivum L.) production. The environmental impacts for winter wheat production using crop rotation and agricultural intensification are quantified. Fourteen no-till crop rotations ranging in duration from 2 to 6 yr were evaluated and compared using data from a historical 13-yr replicated rotation study (>300 observations). Midpoint LCA categories chosen for this comparison are energy, agricultural land use, climate change potential, freshwater eutrophication, and freshwater ecotoxicity due to their direct links with agricultural management practices. The NGP farmers commonly use a fallow period every other year due to moisture limitations. This specific agricultural practice and allocations within rotations are critical considerations within agricultural LCAs. Two aspects of fallow considerations and a sensitivity analysis were also performed. The allocated midpoint impacts between crops in rotational studies averaged 0.31, 0.79, 0.62, and 0.63 kg CO2 eq. per unit of winter wheat when energy, economic, mass, and cereal unit allocations were used, respectively. Economic analysis of the studied experimental crop was performed; results demonstrated that crop insurance policies improved diversification economics by 20%. Agricultural diversification benefits and burdens were better represented by endpoint damage assessments than by midpoint impact analysis.
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Agricultura , Triticum , Animales , Producción de Cultivos , Productos Agrícolas , Estadios del Ciclo de VidaRESUMEN
BACKGROUND: Hypoxia resulting from ascent to high-altitude or pathological states at sea level is known to increase platelet reactivity. Previous work from our group has suggested that this may be adenosine diphosphate (ADP)-specific. Given the clinical importance of drugs targeting ADP pathways, research into the impact of hypoxia on platelet ADP pathways is highly important. METHODS: Optimul aggregometry was performed on plasma from 29 lowland residents ascending to 4,700 m, allowing systematic assessment of platelet reactivity in response to several platelet agonists. Aggregometry was also performed in response to ADP in the presence of inhibitors of the two main ADP receptors, P2Y1 and P2Y12 (MRS2500 and cangrelor, respectively). Phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a key determinant of platelet aggregation, was analysed using the VASPFix assay. RESULTS: Hypobaric hypoxia significantly reduced the ability of a fixed concentration of cangrelor to inhibit ADP-induced aggregation and increased basal VASP phosphorylation. However, in the absence of P2Y receptor inhibitors, we did not find evidence of increased platelet sensitivity to any of the agonists tested and found reduced sensitivity to thrombin receptor-activating peptide-6 amide. CONCLUSION: Our results provide evidence of increased P2Y1 receptor activity at high altitude and suggest down-regulation of the P2Y12 pathway through increased VASP phosphorylation. These changes in ADP pathway activity are of potential therapeutic significance to high-altitude sojourners and hypoxic sea level patients prescribed platelet inhibitors and warrant further investigation.
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Plaquetas/metabolismo , Hipoxia , Agregación Plaquetaria , Receptores Purinérgicos/metabolismo , Transducción de Señal , Adenosina Difosfato/sangre , Adenosina Difosfato/química , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adolescente , Adulto , Altitud , Moléculas de Adhesión Celular/metabolismo , Estudios de Cohortes , Femenino , Humanos , Masculino , Proteínas de Microfilamentos/metabolismo , Oxígeno/metabolismo , Fosfoproteínas/metabolismo , Fosforilación , Activación Plaquetaria , Inhibidores de Agregación Plaquetaria/farmacología , Pruebas de Función Plaquetaria , Plasma Rico en Plaquetas/metabolismo , Receptores de Trombina/metabolismo , Adulto JovenAsunto(s)
Manuscritos como Asunto , Medicina , Publicaciones Periódicas como Asunto , Humanos , Edición , EscociaRESUMEN
We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a K d of 40 µM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.
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78 kDa glucose-regulated protein (Grp78) is a heat shock protein (HSP) involved in protein folding that plays a role in cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent compounds were 13 (VER-155008) with K(D) = 80 nM and 14 with K(D) = 60 nM. X-ray crystal structures of Grp78 bound to ATP, ADPnP, and adenosine derivative 10 revealed differences in the binding site between Grp78 and homologous proteins.
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Adenosina Trifosfatasas/antagonistas & inhibidores , Furanos/síntesis química , Proteínas de Choque Térmico/antagonistas & inhibidores , Purinas/síntesis química , Adenosina Trifosfatasas/química , Adenosina Trifosfato/química , Adenilil Imidodifosfato/química , Sitios de Unión , Calorimetría , Cristalografía por Rayos X , Chaperón BiP del Retículo Endoplásmico , Furanos/química , Proteínas del Choque Térmico HSC70/química , Proteínas HSP70 de Choque Térmico/química , Proteínas de Choque Térmico/química , Ligandos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/química , Purinas/química , Estereoisomerismo , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie , TermodinámicaRESUMEN
PURPOSE: The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. METHODS: We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. RESULTS: VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI(50)s in the range 5.3-14.4 microM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. CONCLUSION: These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined.