Beyond Collective Efficacy: New Brief Measures to Assess the Outer Layers of the Social Ecology

Abstract Introduction: Community support can be a valuable interpersonal resource anywhere, yet past research has largely been focused on adults in urban neighborhoods. Because communities are no longer solely defined by a shared physicality, we offer psychometric data on three new measures to assess other communal resources: informal community support, support for community youth, and workplace integration. Methods: Participants (N=1706) from a largely rural, low-income Southern region completed a computer-assisted questionnaire as part of a larger study on character development and personal strength. Ages range from 11 to 70 years old (M=29.3 years; SD=12.3 years); 63% of participants are female. Results: Internal consistency was good for our 3 new measures, .70 to .86 and each scale comprised a single factor in exploratory factor analyses. Correlations with collective efficacy (convergent validity) were all positive and significant and range from .18 to .57. Correlations with measures of subjective well-being range from .21 to .29, and correlations with mental and physical health outcomes ranged from .14 to .23. Implications: Studying communities in addition to individuals and families can potentially shed light on the variety of ways in which community ties can foster well-being and resilience. The three new measures presented here assess important but understudied aspects of communities

Ponderosa Pine Regeneration,Wildland Fuels Management, and Habitat Conservation: Identifying Trade-Offs Following Wildfire

Increasing wildfires in western North American conifer forests have led to debates surrounding the application of post-fire management practices. There is a lack of consensus on whether (and to what extent) post-fire management assists or hinders managers in achieving goals, particularly in under-studied regions like eastern ponderosa pine forests. This makes it difficult for forest managers to balance among competing interests. We contrast structural and community characteristics across unburned ponderosa pine forest, severely burned ponderosa pine forest, and severely burned ponderosa pine forest treated with post-fire management with respect to three management objectives: ponderosa pine regeneration, wildland fuels control, and habitat conservation. Ponderosa pine saplings were more abundant in treated burned sites than untreated burned sites, suggesting increases in tree regeneration following tree planting; however, natural regeneration was evident in both unburned and untreated burned sites. Wildland fuels management greatly reduced snags and coarse woody debris in treated burned sites. Understory cover measurements revealed bare ground and fine woody debris were more strongly associated with untreated burned sites, and greater levels of forbs and grass were more strongly associated with treated burned sites. Wildlife habitat was greatly reduced following post-fire treatments. There were no tree cavities in treated burned sites, whereas untreated burned sites had an average of 27 ± 7.68 cavities per hectare. Correspondingly, we found almost double the avian species richness in untreated burned sites compared to treated burned sites (22 species versus 12 species). Unburned forests and untreated burned areas had the same species richness, but hosted unique avian communities. Our results indicate conflicting outcomes with respect to management objectives, most evident in the clear costs to habitat conservation following post-fire management application

The multiple potential biomarkers for predicting immunotherapy response : finding the needle in the haystack

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in a variety of advanced malignancies. Despite promising outcomes in certain patients, the majority will not derive benefit and are at risk of potentially serious immune-related adverse events (irAEs). The development of predictive biomarkers is therefore critical to personalise treatments and improve outcomes. A number of biomarkers have shown promising results, including from tumour (programmed cell death ligand 1 (PD-L1), tumour mutational burden (TMB), stimulator of interferon genes (STING) and apoptosis-associated speck-like protein containing a CARD (ASC)), from blood (peripheral blood mononuclear cells (PBMCs), circulating tumour DNA (ctDNA), exosomes, cytokines and metal chelators) and finally the microbiome

Evolution of South Atlantic density and chemical stratification across the last deglaciation.

Explanations of the glacial-interglacial variations in atmospheric pCO2 invoke a significant role for the deep ocean in the storage of CO2. Deep-ocean density stratification has been proposed as a mechanism to promote the storage of CO2 in the deep ocean during glacial times. A wealth of proxy data supports the presence of a "chemical divide" between intermediate and deep water in the glacial Atlantic Ocean, which indirectly points to an increase in deep-ocean density stratification. However, direct observational evidence of changes in the primary controls of ocean density stratification, i.e., temperature and salinity, remain scarce. Here, we use Mg/Ca-derived seawater temperature and salinity estimates determined from temperature-corrected δ(18)O measurements on the benthic foraminifer Uvigerina spp. from deep and intermediate water-depth marine sediment cores to reconstruct the changes in density of sub-Antarctic South Atlantic water masses over the last deglaciation (i.e., 22-2 ka before present). We find that a major breakdown in the physical density stratification significantly lags the breakdown of the deep-intermediate chemical divide, as indicated by the chemical tracers of benthic foraminifer δ(13)C and foraminifer/coral (14)C. Our results indicate that chemical destratification likely resulted in the first rise in atmospheric pCO2, whereas the density destratification of the deep South Atlantic lags the second rise in atmospheric pCO2 during the late deglacial period. Our findings emphasize that the physical and chemical destratification of the ocean are not as tightly coupled as generally assumed.We are grateful to I. Mather, J. Rolfe, F. Dewilde and G. Isguder for preparing and performing isotopic analyses, as well as C. Daunt, S. Souanef-Ureta and M. Greaves for technical assistance in performing trace element analysis. J.R. was funded jointly by the British Geological Survey/British Antarctic Survey (Natural Environment Research Council) and the University of Cambridge. J.G. was funded by the Gates Cambridge Trust. L.C.S. acknowledges support from the Royal Society and NERC grant NE/J010545/1. C.W. acknowledges support from the European Research Council grant ACCLIMATE/no 339108. This is LSCE contribution 5514. This work was funded (in part) by the European Research Council (ERC grant 2010-NEWLOG ADG-267931 HE). N.V.R. acknowledges support from EU RTN NICE (no. 36127). We thank the captain and crew of the RRS James Clark Ross for facilitating the collection of the marine sediment core GC528.This is the author accepted manuscript. The final version is available from PNAS via http://dx.doi.org/10.1073/pnas.151125211

STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle.

Human papillomaviruses (HPV) activate a number of host factors to control their differentiation-dependent life cycles. The transcription factor signal transducer and activator of transcription (STAT)-3 is important for cell cycle progression and cell survival in response to cytokines and growth factors. STAT3 requires phosphorylation on Ser727, in addition to phosphorylation on Tyr705 to be transcriptionally active. In this study, we show that STAT3 is essential for the HPV life cycle in undifferentiated and differentiated keratinocytes. Primary human keratinocytes containing high-risk HPV18 genomes display enhanced STAT3 phosphorylation compared to normal keratinocytes. Expression of the E6 oncoprotein is sufficient to induce the dual phosphorylation of STAT3 at Ser727 and Tyr705 by a mechanism requiring Janus kinases and members of the MAPK family. E6-mediated activation of STAT3 induces the transcription of STAT3 responsive genes including cyclin D1 and Bcl-xL. Silencing of STAT3 protein expression by siRNA or inhibition of STAT3 activation by small molecule inhibitors, or by expression of dominant negative STAT3 phosphorylation site mutants, results in blockade of cell cycle progression. Loss of active STAT3 impairs HPV gene expression and prevents episome maintenance in undifferentiated keratinocytes and upon differentiation, lack of active STAT3 abolishes virus genome amplification and late gene expression. Organotypic raft cultures of HPV18 containing keratinocytes expressing a phosphorylation site STAT3 mutant display a profound reduction in suprabasal hyperplasia, which correlates with a loss of cyclin B1 expression and increased differentiation. Finally, increased STAT3 expression and phosphorylation is observed in HPV positive cervical disease biopsies compared to control samples, highlighting a role for STAT3 activation in cervical carcinogenesis. In summary, our data provides evidence of a critical role for STAT3 in the HPV18 life cycle

Droplet digital PCR based detection of EGFR mutations in advanced lung cancer patient liquid biopsies : a comparison of circulating tumour DNA extraction kits

Background: Mutations in the epidermal growth factor receptor gene, EGFR, predict response or resistance to first generation tyrosine kinase inhibitors in non-small cell lung cancer. These biomarkers can now be conveniently detected from liquid biopsies, however technical details of these assays are still being refined. Objective: To compare detection of four different non-small cell lung cancer (NSCLC) associated EGFR mutations from patient ctDNA isolated with five different ctDNA isolation kit. Methods: Droplet digital PCR (ddPCR) assays detecting four EGFR mutations were developed. ctDNA was isolated with five kits from plasma samples, one pleural and one ascites fluid from nine NSCLC patients with known EGFR mutations. ctDNA fragment sizes and concentrations were also assessed. Results: Each kit isolated DNA from all samples which contained an expected dominant DNA fragment of ~ 170 base pairs. Normalised for plasma input, one kit produced ctDNA extracts which consistently enabled the highest cop n umber detection for all EGFR variants, and importantly was able to validate mutations in all patient samples. Other kits stood out in regards to cost economy as well as ease and speed of processing but were less efficient and one kit was found to be incompatible with ddPCR. Conclusion: This study demonstrated successful ctDNA isolation from plasma, pleural fluid and ascites by four of five ctDNA isolation kits. The QIAmp circulating nucleic acid kit produced consistently the most sensitive detection of EGFR variants. While other kits allow for lower volume plasma input down to 0.1 ml, are faster, more economical and simpler to use, they are challenged by very low ctDNA concentrations in plasma

Next-generation technologies unlock new possibilities to track rangeland productivity and quantify multi-scale conservation outcomes

Historically, relying on plot-level inventories impeded our ability to quantify large-scale change in plant biomass, a key indicator of conservation practice outcomes in rangeland systems. Recent technological advances enable assessment at scales appropriate to inform management by providing spatially comprehensive estimates of productivity that are partitioned by plant functional group across all contiguous US rangelands. We partnered with the Sage Grouse and Lesser Prairie-Chicken Initiatives and the Nebraska Natural Legacy Project to demonstrate the ability of these new datasets to quantify multi-scale changes and heterogeneity in plant biomass following mechanical tree removal, prescribed fire, and prescribed grazing. In Oregon’s sagebrush steppe, for example, juniper tree removal resulted in a 21% increase in one pasture’s productivity and an 18% decline in another. In Nebraska’s Loess Canyons, perennial grass productivity initially declined 80% at sites invaded by trees that were prescriptively burned, but then fully recovered post-fire, representing a 492% increase from nadir. In Kansas’ Shortgrass Prairie, plant biomass increased 4-fold (966,809 kg/ha) in pastures that were prescriptively grazed, with gains highly dependent upon precipitation as evidenced by sensitivity of remotely sensed estimates (SD ± 951,308 kg/ha). Our results emphasize that next-generation remote sensing datasets empower land managers to move beyond simplistic control versus treatment study designs to explore nuances in plant biomass in unprecedented ways. The products of new remote sensing technologies also accelerate adaptive management and help communicate wildlife and livestock forage benefits from management to diverse stakeholders

Plasma next generation sequencing and droplet digital PCR-based detection of epidermal growth factor receptor (EGFR) mutations in patients with advanced lung cancer treated with subsequent-line osimertinib

Background: Gene mutation analysis from plasma circulating tumor DNA (ctDNA) can provide timely information regarding the mechanism of resistance that could translate to personalised treatment. We compared concordance rate of next generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR) in the detection of the EGFR activating and T790M mutation from plasma ctDNA with diagnostic tissue biopsy‐based assays. The second objective was to test whether putative osimertinib resistance associated mutations were detectable from plasma using NGS. Methods: From January 2016 to December 2017, we prospectively collected plasma samples from patients prior to commencement of second‐ or third‐line osimertinib therapy and upon disease progression, in a single tertiary hospital in South Western Sydney, Australia. Amplicon‐based NGS and ddPCR assays were used to detect activating epidermal growth factor receptor (EGFR) and T790M mutations in 18 plasma samples from nine patients; all patients were required to have tissue biopsies with known EGFR status. Results: High concordance of allelic fractions were seen in matched plasma NGS and ddPCR for activating EGFR mutations and T790M mutations (R2 = 0.92, P < 0.0001). Using tissue biopsies as reference standard, sensitivity was 100% for NGS and 94% for ddPCR. Several possible osimertinib resistance associated mutations, including PIK3CA, BRAF and TP53 mutations, were detected by NGS in samples upon progression on osimertinib therapy. Conclusion: ddPCR assays for EGFR mutations appear to be as sensitive and highly concordant as amplicon‐based NGS. NGS has the ability to detect novel resistance mutations

Early Results from GLASS-JWST. VIII. An Extremely Magnified Blue Supergiant Star at Redshift 2.65 in the A2744 Cluster Field

We report the discovery of an extremely magnified star at redshift z = 2.65 in the James Webb Space Telescope (JWST) NIRISS pre-imaging of the A2744 galaxy-cluster field. The star's background host galaxy lies on a fold caustic of the foreground lens, and the cluster creates a pair of images of the region close to the lensed star. We identified the bright transient in one of the merging images at a distance of similar to 0.'' 15 from the critical curve by subtracting the JWST F115W and F150W imaging from coadditions of archival Hubble Space Telescope (HST) F105W and F125W images and F140W and F160W images, respectively. Since the time delay between the two images should be only hours, the transient must be the microlensing event of an individual star, as opposed to a luminous stellar explosion that would persist for days to months. Analysis of individual exposures suggests that the star's magnification is not changing rapidly during the observations. From photometry of the point source through the F115W, F150W, and F200W filters, we identify a strong Balmer break, and modeling allows us to constrain the star's temperature to be approximately 7000-12,000 K.This work is based on observations made with the NASA/ESA/CSA James Webb Space Telescope. The data were obtained from the Mikulski Archive for Space Telescopes at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-03127 for JWST. These observations are associated with program JWST-ERS-1324. The specific observations analyzed can be accessed via 10.17909/y6dh-6g16. We acknowledge financial support from NASA through grant JWST-ERS-1324. Archival images from the Hubble Space Telescope were also used. We would like to thank Dr. Pietro Bergamini, Prof. Piero Rosati, Prof. Claudio Grillo, Dr. Ana Acebron, and Dr. Eros Vanzella for their helpful comments on our paper and for sharing the predictions of their lens model.W.C. acknowledges support from NASA HST grant AR-15791. P.L.K. is supported by NSF grant AST-1908823 and NASA/Keck JPL RSA 1644110. R.A.W. acknowledges support from NASA JWST Interdisciplinary Scientist grants NAG5-12460, NNX14AN10G, and 80NSSC18K0200 from GSFC. J.M.D. acknowledges the support of project PGC2018-101814-B-100 (MCIU/AEI/MINECO/FEDER, UE) Ministerio de Ciencia, Investigacion y Universidades. This project was funded by the Agencia Estatal de Investigacion, Unidad de Excelencia Maria de Maeztu, ref. MDM-2017-0765. A.K. is supported by scientist grants NAG5-12460, NNX14AN10G, and 80NSSC18K0200 from GSFC. A.Z. and A.K.M. acknowledge support by Grant No. 2020750 from the United States-Israel Binational Science Foundation (BSF) and grant No. 2109066 from the United States National Science Foundation (NSF), and by the Ministry of Science & Technology, Israel. M.B. acknowledges support from the Slovenian national research agency ARRS through grant N1-0238