Lung cancer is a product of inflammation and a dysfunctional immune system, and depression has similar dysregulation. Depression disproportionately affects lung cancer patients, having the highest ...rates of all cancers. Systemic inflammation and depression are both predictive of non-small cell lung cancer (NSCLC) survival, but the existence and extent of any co-occurrence is unknown. Studied is the association between systemic inflammation ratio (SIR) biomarker levels and patients' depressive symptoms, with the hypothesis that depression severity would be significantly associated with prognostically poor inflammation. Newly diagnosed stage-IV non-small cell lung cancer (NSCLC; N = 186) patients were enrolled (ClinicalTrials.gov Identifier: NCT03199651) and blood draws and depression self-reports (Patient Health Questionnaire-9) were obtained. For SIRs, cell counts of neutrophils (N), lymphocytes (L), and platelets (P) were abstracted for ratio (R) calculations for NLR, PLR, and the Advanced Lung cancer Inflammation Index (ALI). Patients were followed and biomarkers were tested as predictors of 2-year overall survival (OS) to confirm their relevance. Next, multivariate linear regressions tested associations of depression with NLR, PLR, and ALI. Overall 2-year mortality was 61% (113/186). Cox model analyses confirmed higher NLR hazard ratio (HR) = 1.91; p = 0.001 and PLR (HR = 2.08; p<0.001), along with lower ALI (HR = 0.53; p = 0.005), to be predictive of worse OS. Adjusting for covariates, depression was reliably associated with biomarker levels (p ≤ 0.02). Patients with moderate/severe depressive symptoms were 2 to 3 times more likely to have prognostically poor biomarker levels. Novel data show patients' depressive symptoms were reliably associated with lung-relevant systemic inflammation biomarkers, all assessed at diagnosis/pretreatment. The same SIRs were found prognostic for patients' 2-year OS. Intensive study of depression, combined with measures of cell biology and inflammation is needed to extend these findings to discover mechanisms of depression toxicity for NSCLC patients' treatment responses and survival.
Trade-offs in nature’s contributions to people (NCP), particularly in material NCP versus regulating and non-material NCP, continue to rise. Socio-ecological production landscapes and seascapes ...(SEPLS) represent harmonious human–nature interactions resulting in positive outcomes for both biodiversity and human well-being, thus implying synergies among multiple NCP are possible. In case studies of ten projects selected from biodiversity hotspots under the GEF-Satoyama Project, we investigated whether and how synergies in NCP exist within SEPLS and explored management interventions that enhanced these synergies. Using the responses to an online survey completed by project managers from each project and drawing on project reports, we identified a wide array of NCP deriving from various ecosystems within the project SEPLS. Habitat and food provisions, both attributed to multiple ecosystem types, were key components of the NCP bundles present in the project SEPLS. Among the management options that enhanced NCP in SEPLS were food-centred approaches entailing organic agriculture, eco-labelling, branding and improved agricultural practices. Habitat-centred approaches included participatory biodiversity monitoring, ecosystem restoration, co-management and conservation agreements with landowners. Synergies in NCP were generated by integrating these interventions with enabling governance structures and through community empowerment. If combined with mapping and modelling techniques, identifying NCP bundles in SEPLS from local people’s perspectives as we outlined in this study, would help to better contextualise the analysis of NCP bundles. Such contextualised NCP bundle analyses will help field practitioners understand how to enhance synergies between multiple NCP and the broader conservation community could access untapped NCP knowledge.
Abstract
Over 150 years of investigations into global terrestrial precipitation are revisited to reveal how researchers estimated annual means from in situ observations before the age of ...digitization. After introducing early regional efforts to measure precipitation, the pioneering estimates of terrestrial mean precipitation from the late nineteenth and early twentieth centuries are compared to successive estimates, including those using the latest gridded precipitation datasets available. The investigation reveals that the range of the early estimates is comparable to the interannual variation in terrestrial mean precipitation derived from the latest Climatic Research Unit (CRU) dataset. In-depth revisions of the estimates were infrequent up to the 1970s, due in part to difficulty obtaining and maintaining up-to-date datasets with global coverage. This point is illustrated in a “family tree” that identifies the key publications that subsequent authors referenced, sometimes decades after the original publication. Significant efforts to collate global observations facilitated new investigations and improved data exchange, for example, in the International Hydrological Decade (1965–74) and following the establishment of the Global Telecommunication System under the World Weather Watch Programme of the World Meteorological Organization. Also in the 1970s were the first attempts to adjust in situ observations on a global scale to account for gauge undercatch, and this had a noticeable impact on mean annual estimates. There remains no single satisfactory approach to gauge bias adjustment. Echoing the repeated message of past researchers, today’s authors cite poor spatial coverage, temporal inhomogeneity, and inadequate sharing of in situ observations as the key obstacles to obtaining more accurate estimates of terrestrial mean precipitation.
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•Adsorbed OH– ions on the Au surface behave as active sites for HMF oxidation.•Aldehyde oxidation on Au catalysts is favorable at high OH– ions surface coverage.•Alcohol oxidation is ...kinetically slow on Au catalysts.•Au catalysts become inactive for aldehyde and alcohol oxidation when oxidized.
Au nanoparticle catalysts are promising electrocatalysts for biomass upgrading. Starting from a pristine Au electrode, herein we demonstrate a simple route for the electrochemical preparation of Au NPs supported on thin layers of humin (Au/H). Utilizing an oxidized Au surface as a precursor, these electrocatalytic structures are formed upon reduction of 5-hydroxymethylfurfural (HMF) in alkaline media while performing a potential sweep. We subsequently utilize this Au/H structure for the electrochemical oxidation of ethanol and HMF in a rotating disk electrode (RDE) configuration and perform additional analysis via electrochemical surface-enhanced Raman Scattering (SERS). The RDE test reveals Au/H has different reaction kinetics towards alcohol and aldehyde functional groups, enabling a mechanistic understanding of the reaction pathway for HMF oxidation. The SERS experiment identifies the favorable reduction pathway from Au2O3 to gold, suggesting the possible active site on this catalyst for HMF oxidation.
Immune cells are characterized by diversity, specificity, plasticity, and adaptability-properties that enable them to contribute to homeostasis and respond specifically and dynamically to the many ...threats encountered by the body. Single-cell technologies, including the assessment of transcriptomics, genomics, and proteomics at the level of individual cells, are ideally suited to studying these properties of immune cells. In this review we discuss the benefits of adopting single-cell approaches in studying underappreciated qualities of immune cells and highlight examples where these technologies have been critical to advancing our understanding of the immune system in health and disease.
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the ...latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.
The dysregulated physical interaction between two intracellular membrane proteins, the sarco/endoplasmic reticulum Ca
ATPase and its reversible inhibitor phospholamban, induces heart failure by ...inhibiting calcium cycling. While phospholamban is a bona-fide therapeutic target, approaches to selectively inhibit this protein remain elusive. Here, we report the in vivo application of intracellular acting antibodies (intrabodies), derived from the variable domain of camelid heavy-chain antibodies, to modulate the function of phospholamban. Using a synthetic VHH phage-display library, we identify intrabodies with high affinity and specificity for different conformational states of phospholamban. Rapid phenotypic screening, via modified mRNA transfection of primary cells and tissue, efficiently identifies the intrabody with most desirable features. Adeno-associated virus mediated delivery of this intrabody results in improvement of cardiac performance in a murine heart failure model. Our strategy for generating intrabodies to investigate cardiac disease combined with modified mRNA and adeno-associated virus screening could reveal unique future therapeutic opportunities.
This study investigated the relationship between structural language skills, and communication skills, adaptive behavior, and emotional and behavior problems in pre-school children with autism. ...Participants were aged 3–5 years with autism (
n
= 27), and two comparison groups of children with developmental delay without autism (
n
= 12) and typically developing children (
n
= 20). The participants were administered standardised tests of structural language skills, and parents completed the Vineland Adaptive Behavior Scales and the Developmental Behaviour Checklist. Results indicated that for children with autism, communication skills, and in particular receptive communication skills, were associated with social and daily living skills, and behavior problems. Receptive structural language skills were associated with expressive communication skills. There were no associations found between structural language skills and social or daily living skills, nor behavior problems. The results of this study suggest that communication skills are more closely linked to functional and behavioral outcomes in autism than structural language skills.
Coronary arteriogenesis is a central step in cardiogenesis, requiring coordinated generation and integration of endothelial cell and vascular smooth muscle cells. At present, it is unclear whether ...the cell fate programme of cardiac progenitors to generate complex muscular or vascular structures is entirely cell autonomous. Here we demonstrate the intrinsic ability of vascular progenitors to develop and self-organize into cardiac tissues by clonally isolating and expanding second heart field cardiovascular progenitors using WNT3A and endothelin-1 (EDN1) human recombinant proteins. Progenitor clones undergo long-term expansion and differentiate primarily into endothelial and smooth muscle cell lineages in vitro, and contribute extensively to coronary-like vessels in vivo, forming a functional human-mouse chimeric circulatory system. Our study identifies EDN1 as a key factor towards the generation and clonal derivation of ISL1(+) vascular intermediates, and demonstrates the intrinsic cell-autonomous nature of these progenitors to differentiate and self-organize into functional vasculatures in vivo.
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