A 12,000 Year Record of Explosive Volcanism in the Siple Dome Ice Core, West Antarctica

Air mass trajectories in the Southern Hemisphere provide a mechanism for transport to and deposition of volcanic products on the Antarctic ice sheet from local volcanoes and from tropical and subtropical volcanic centers. This study extends the detailed record of Antarctic, South American, and equatorial volcanism over the last 12,000 years using continuous glaciochemical series developed from the Siple Dome A (SDMA) ice core, West Antarctica. The largest volcanic sulfate spike ( 280 mu g/L) occurs at 5881 B. C. E. Other large signals with unknown sources are observed around 325 B. C. E. ( 270 mu g/L) and 2818 B. C. E. ( 191 mu g/L). Ages of several large equatorial or Southern Hemisphere volcanic eruptions are synchronous with many sulfate peaks detected in the SDMA volcanic ice chemistry record. The microprobe fingerprinting\u27\u27 of glass shards in the SDMA core points to the following Antarctic volcanic centers as sources of tephra found in the SDMA core: Balenny Island, Pleiades, Mount Berlin, Mount Takahe, and Mount Melbourne as well as Mount Hudson and possibly Mount Burney volcanoes of South America. Identified volcanic sources provide an insight into the poorly resolved transport history of volcanic products from source volcanoes to the West Antarctic ice sheet

Mechanisms of spinal cord stimulation for the treatment of pain: Still in the dark after 50 years

Background and Objective: Despite the value of spinal cord stimulation (SCS) in treating some patients with focal neuropathic pain, technological advances in stimulator design and treatment protocols have not correlated with significant improvements in clinical outcomes. This may be because incomplete understanding of the mechanisms underlying SCS precludes improvement in clinical efficacy. In this brief review, we (a) review phenomenological effects of SCS, (b) review the literature on proposed spinal sites of action of SCS and (c) propose a novel hypothesis of mechanism of action. Results: Dorsal columns, dorsal roots and dorsal horns have each been proposed as spinal sites of action of SCS. We suggest that evidence in favour of the dorsal columns or dorsal roots as the primary mediators of SCS is weak and propose that the dorsal horn is the crucial site of action. Furthermore, we hypothesize that, based on their location, and neurochemical and morphological properties, dorsal horn islet cells may mediate the effects of SCS. Conclusions: The precise spinal mechanisms of action of SCS are still unknown. Dorsal horn islet cells have properties that position them to play a key role in analgesic effects of electrical stimulation. Understanding the mechanisms responsible for positive SCS effects are needed for successful translation into clinical dividends. Significance: We review possible spinal mechanisms of action of spinal cord stimulation for neuropathic pain, proposing that direct modulation of dorsal horn neurons is crucial. We suggest that mechanistic insights are needed for translation into more favourable clinical outcomes

AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer

The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer

Discovery and saturation analysis of cancer genes across 21 tumor types

Summary While a few cancer genes are mutated in a high proportion of tumors of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalog of cancer genes, we analyzed somatic point mutations in exome sequence from 4,742 tumor-normal pairs across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumor types. Our analysis also identified 33 genes not previously known to be significantly mutated, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes, mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5000 samples per tumor type, depending on background mutation rate. The results help guide the next stage of cancer genomics

Opportunities and Challenges: Hepatitis C Testing and Treatment Access Experiences Among People in Methadone and Buprenorphine Treatment During COVID-19, Arizona, 2021

Introduction: The purpose of this study was to characterize hepatitis C virus screening and treatment access experiences among people in treatment for opioid use disorder in Arizona during COVID-19. Methods: Arizonans receiving treatment for opioid use disorder from methadone clinics and buprenorphine providers during COVID-19 were interviewed about hepatitis C virus testing, curative treatment, and knowledge about screening recommendations. Interviews were conducted with 121 people from August 4, 2021 to October 10, 2021. Qualitative data were coded using the categories of hepatitis C virus testing, knowledge of screening recommendations, diagnosis, and experiences seeking curative treatment. Data were also quantitated for bivariate testing with outcome variables of last hepatitis C virus test, diagnosis, and curative treatment process. Findings were arrayed along an adapted hepatitis C virus cascade framework to inform program and policy improvements. Results: Just over half of the sample reported ever having tested for hepatitis C virus (51.2%, n=62) and of this group, 58.1% were tested in the past 12 months. Among those who were ever tested, 54.8% reported a hepatitis C virus diagnosis and 16.1% reported either being in treatment or having been declared cured of the hepatitis C virus. Among those who were diagnosed with hepatitis C, 14.7% indicated that they unsuccessfully tried to access curative treatment and would not attempt to again. Reasons cited for not accessing or receiving curative treatment included beliefs about treatment safety, barriers created by access requirements, natural resolution of the infection, and issues with healthcare coverage and authorization. Conclusions: Structural barriers continue to prevent curative hepatitis C virus treatment access. Given that methadone and buprenorphine treatment providers serve patients who are largely undiagnosed or treated for hepatitis C virus, opportunities exist for them to screen their patients regularly and provide support for and/or navigation to hepatitis C virus curative treatment

Solar Forcing of the Polar Atmosphere

We present highly resolved, annually dated, calibrated proxies for atmospheric circulation from several Antarctic ice cores (ITASE (International Trans-Antarctic Scientific Expedition), Siple Dome, Law Dome) that reveal decadal-scale associations with a South Pole ice-core Be-10 proxy for solar variability over the last 600 years and annual-scale associations with solar variability since AD 1720. We show that increased (decreased) solar irradiance is associated with increased (decreased) zonal wind strength near the edge of the Antarctic polar vortex. The association is particularly strong in the Indian and Pacific Oceans and as such may contribute to understanding climate forcing that controls drought in Australia and other Southern Hemisphere climate events. We also include evidence suggestive of solar forcing of atmospheric circulation near the edge of the Arctic polar vortex based on ice-core records from Mount Logan, Yukon Territory, Canada, and both central and south Greenland as enticement for future investigations. Our identification of solar forcing of the polar atmosphere and its impact on lower latitudes offers a mechanism for better understanding modern climate variability and potentially the initiation of abrupt climate-change events that operate on decadal and faster scales

Liminal Roles as a Source of Creative Agency in Management: The Case of Knowledge-Sharing Communities

Studies suggest that the experience of liminality – of being in an ambiguous, ‘betwixt and between’ position – has creative potential for organizations. We contribute to theory on the link between liminality and creative agency through a study of the coordinators of ‘knowledge-sharing communities’; one of the latest examples of a ‘neo-bureaucratic’ practice that seeks to elicit innovative responses from employees while intensifying control by the organization. Through a role-centred perspective, our study found that both the structural and interpretive aspects of coordinators’ role enactments promoted a degree of creative agency. ‘Front-stage’ and ‘back-stage’ activities were developed to meet the divergent expectations posed by senior management and community members, and the ambiguity of their roles prompted an array of different role interpretations. Our findings contribute to theory by showing how the link between liminality and creative agency is not confined to roles and spaces (consultancy work, professional expertise) that are positioned across organizational boundaries, or free from norms and expectations, but may also apply to roles that are ambiguously situated within organizational contexts and which are subject to divergent expectations. This shows how neo-bureaucratic forms may be both reproduced and renewed through the creative responses of individual managers

Dating the Siple Dome (Antarctica) Ice Core By Manual and Computer Interpretation of Annual Layering

The Holocene portion of the Siple Dome (Antarctica) ice core was dated by interpreting the electrical, visual and chemical properties of the core. The data were interpreted manually and with a computer algorithm. The algorithm interpretation was adjusted to be consistent with atmospheric methane stratigraphic ties to the GISP2 (Greenland Ice Sheet Project 2) ice core, (BE)-B-10 stratigraphic ties to the dendrochronology C-14 record and the dated volcanic stratigraphy. The algorithm interpretation is more consistent and better quantified than the tedious and subjective manual interpretation

Discovery and saturation analysis of cancer genes across 21 tumour types

Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes