The University of Arizona
  • Tucson, Arizona, United States
Recent publications
The voltage-gated sodium channel isoform NaV1.7 is a critical player in the transmission of nociceptive information. This channel has been heavily implicated in human genetic pain disorders and is a validated pain target. However, targeting this channel directly has failed, and an indirect approach – disruption of interactions with accessory protein partners – has emerged as a viable alternative strategy. We recently reported that a small-molecule inhibitor of CRMP2 SUMOylation, compound 194, selectively reduces NaV1.7 currents in DRG neurons across species from mouse to human. This compound also reversed mechanical allodynia in a spared nerve injury and chemotherapy-induced model of neuropathic pain. Here, we show that oral administration of 194 reverses mechanical allodynia in a chronic constriction injury (CCI) model of neuropathic pain. Furthermore, we show that orally administered 194 reverses the increased latency to cross an aversive barrier in a mechanical conflict-avoidance task following CCI. These two findings, in the context of our previous report, support the conclusion that 194 is a robust inhibitor of NaV1.7 function with the ultimate effect of profoundly ameliorating mechanical allodynia associated with nerve injury. The fact that this was observed using both traditional, evoked measures of pain behavior as well as the more recently developed operator-independent mechanical conflict-avoidance assay increases confidence in the efficacy of 194-induced anti-nociception.
Predicting phenotype from genotype is a central challenge in biology. By understanding genomic information to predict and improve traits, scientists can address the challenges and opportunities of achieving sustainable genetic improvement of complex, economically important traits in agriculturally relevant species. Converting the enormous, recent technical advances in all areas of genomics and phenomics into sustained and ecologically responsible improvements in food and fuel production is complex. It will require engaging agricultural genome to phenome (G2P) experts, drawing from a broad community, including crop and livestock scientists and essential integrative disciplines (e.g., engineers, economists, data and social scientists). To achieve this vision, the USDA NIFA-funded project inaugurating the Agricultural Genome to Phenome Initiative (AG2PI) is working to: Develop a cohesive vision for agricultural G2P research by identifying research gaps and opportunities; advancing community solutions to these challenges and gaps; and rapidly disseminating findings to the broader community. Towards these ends, this AG2PI project is organizing virtual field days, conferences, training workshops, and awarding seed grants to conceive new insights (details at www.ag2pi.org). Since October 2020, more than 10,000 unique participants from every inhabited continent have engaged in these activities. To illustrate AG2PI’s scope, we present survey results on agricultural G2P research needs and opportunities, highlighting opinions and suggestions for the future. We invite stakeholders interested in this complex but critical effort to help create an optimal, sustainable food supply for society and challenge the community to add to our vision for future accomplishments by a fully actualized AG2PI enterprise.
“Race” and “ethnicity” are socially constructed terms, not based on biology - in contrast to biologic ancestry and genetic admixture - and are flexible, contested, and unstable concepts, often driven by power. Although individuals may self-identify with a given race and ethnic group, as multidimensional beings exposed to differential life influencing factors that contribute to disease risk, additional social determinants of health (SDOH) should be explored to understand the relationship of race or ethnicity to health. Potential health effects of structural racism, defined as “the structures, policies, practices, and norms resulting in differential access to goods, services, and opportunities of society by “race,” have been largely ignored in medical research. The Women’s Health Initiative (WHI) was expected to enroll a racially and ethnically diverse cohort of older women at 40 U.S. clinical centers between 1993 and 1998; yet, key information on the racial and ethnic make-up of the WHI cohort of 161,808 women was limited until a 2020–2021 Task Force was charged by the WHI Steering Committee to better characterize the WHI cohort and develop recommendations for WHI investigators who want to include “race” and/or “ethnicity” in papers and presentations. As the lessons learned are of relevance to most cohorts, the essence of the WHI Race and Ethnicity Language and Data Interpretation Guide is presented in this paper. Recommendations from the WHI Race and Ethnicity Language and Data Interpretation Guide include: Studies should be designed to include all populations and researchers should actively, purposefully and with cultural-relevance, commit to recruiting a diverse sample; Researchers should collect robust data on race, ethnicity and SDOH variables that may intersect with participant identities, such as immigration status, country of origin, acculturation, current residence and neighborhood, religion; Authors should use appropriate terminology, based on a participant’s self-identified “race” and “ethnicity”, and provide clear rationale, including a conceptual framework, for including race and ethnicity in the analytic plan; Researchers should employ appropriate analytical methods, including mixed-methods, to study the relationship of these sociocultural variables to health; Authors should address how representative study participants are of the population to which results might apply, such as by age, race and ethnicity.
Emerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.
Sonic Hedgehog (Shh), secreted from gastric parietal cells, contributes to the regeneration of the epithelium. The recruitment of macrophages plays a central role in the regenerative process. The mechanism that regulates macrophage recruitment in response to gastric injury is largely unknown. Here we tested the hypothesis that Shh stimulates macrophage chemotaxis to the injured epithelium and contributes to gastric regeneration. A mouse model expressing a myeloid cell-specific deletion of Smoothened (LysMcre/+;Smof/f) was generated using transgenic mice bearing loxP sites flanking the Smo gene (Smo loxP) and mice expressing a Cre recombinase transgene from the Lysozyme M locus (LysMCre). Acetic acid injury was induced in the stomachs of both control and LysMcre/+;Smof/f (SmoKO) mice and gastric epithelial regeneration and macrophage recruitment analyzed over a period of 7 days post-injury. Bone marrow-derived macrophages (BM-Mø) were collected from control and SmoKO mice. Human-derived gastric organoid/macrophage co-cultures were established, and macrophage chemotaxis measured. Compared to control mice, SmoKO animals exhibited inhibition of ulcer repair and normal epithelial regeneration, which correlated with decreased macrophage infiltration at the site of injury. Bone marrow chimera experiments using SmoKO donor cells showed that control chimera mice transplanted with SmoKO bone marrow donor cells exhibited a loss of ulcer repair, and transplantation of control bone marrow donor cells to SmoKO mice rescued epithelial cell regeneration. Histamine-stimulated Shh secretion in human organoid/macrophage co-cultures resulted in macrophage migration toward the gastric epithelium, a response that was blocked with Smo inhibitor Vismodegib. Shh-induced macrophage migration was mediated by AKT signaling. In conclusion, Shh signaling acts as a macrophage chemoattractant via a Smo-dependent mechanism during gastric epithelial regeneration in response to injury.
Background Most North American temperate forests are plantation or regrowth forests, which are actively managed. These forests are in different stages of their growth cycles and their ability to sequester atmospheric carbon is affected by extreme weather events. In this study, the impact of heat and drought events on carbon sequestration in an age-sequence (80, 45, and 17 years as of 2019) of eastern white pine ( Pinus strobus L.) forests in southern Ontario, Canada was examined using eddy covariance flux measurements from 2003 to 2019. Results Over the 17-year study period, the mean annual values of net ecosystem productivity (NEP) were 180 ± 96, 538 ± 177 and 64 ± 165 g C m –2 yr –1 in the 80-, 45- and 17-year-old stands, respectively, with the highest annual carbon sequestration rate observed in the 45-year-old stand. We found that air temperature (Ta) was the dominant control on NEP in all three different-aged stands and drought, which was a limiting factor for both gross ecosystem productivity (GEP) and ecosystems respiration (RE), had a smaller impact on NEP. However, the simultaneous occurrence of heat and drought events during the early growing seasons or over the consecutive years had a significant negative impact on annual NEP in all three forests. We observed a similar trend of NEP decline in all three stands over three consecutive years that experienced extreme weather events, with 2016 being a hot and dry, 2017 being a dry, and 2018 being a hot year. The youngest stand became a net source of carbon for all three of these years and the oldest stand became a small source of carbon for the first time in 2018 since observations started in 2003. However, in 2019, all three stands reverted to annual net carbon sinks. Conclusions Our study results indicate that the timing, frequency and concurrent or consecutive occurrence of extreme weather events may have significant implications for carbon sequestration in temperate conifer forests in Eastern North America. This study is one of few globally available to provide long-term observational data on carbon exchanges in different-aged temperate plantation forests. It highlights interannual variability in carbon fluxes and enhances our understanding of the responses of these forest ecosystems to extreme weather events. Study results will help in developing climate resilient and sustainable forestry practices to offset atmospheric greenhouse gas emissions and improving simulation of carbon exchange processes in terrestrial ecosystem models.
Human activity is rapidly increasing the negative impact of artificial skyglow at even the most remote professional observatory sites. Assessment of the actual impact requires an understanding of the propagation as a function of source spectral energy distribution. The higher blue content of light-emitting diodes being widely used as replacement for sodium discharge lamps has greater impact closer to the source, and less impact for more distant mountain-top sites. All-sky cameras with moderate angular resolution provide data and metrics sufficient to model and remove celestial contributions and provide measures of artificial light contribution. The natural skyglow is significantly affected by solar activity, which must be accounted for in determining secular trends in the artificial component. With the availability of the New World Atlas of the Artificial Sky Brightness, a direct comparison is made of the modeled artificial contribution to the sites with the largest aperture telescopes, noting the possible systematic errors in individual cases. Population growth of the nearest urban centers allows a prediction of the change in that brightness over a decade. All site protections are effected primarily by national or regional regulation. A collection of worldwide regulations shows that most are leveraged off environmental protection statutes, while in the U.S., they are largely based on land-use zones. Particular examples are presented in more detail for Flagstaff, Arizona, and the Island of Hawai’i. The latest rapidly growing threat is that of reflected sunlight from large constellations of satellites in low-earth orbit. A snapshot is provided of that rapidly changing situation. In all cases, astronomers must become very proactive in educating the public about the cultural value of visual or naked eye astronomy as well as the science and the need for access to a dark night sky for astronomical research.
The accurate simulation of additional interactions at the ATLAS experiment for the analysis of proton–proton collisions delivered by the Large Hadron Collider presents a significant challenge to the computing resources. During the LHC Run 2 (2015–2018), there were up to 70 inelastic interactions per bunch crossing, which need to be accounted for in Monte Carlo (MC) production. In this document, a new method to account for these additional interactions in the simulation chain is described. Instead of sampling the inelastic interactions and adding their energy deposits to a hard-scatter interaction one-by-one, the inelastic interactions are presampled, independent of the hard scatter, and stored as combined events. Consequently, for each hard-scatter interaction, only one such presampled event needs to be added as part of the simulation chain. For the Run 2 simulation chain, with an average of 35 interactions per bunch crossing, this new method provides a substantial reduction in MC production CPU needs of around 20%, while reproducing the properties of the reconstructed quantities relevant for physics analyses with good accuracy.
We tested the ability of a novel DNA methylation biomarker set to distinguish metastatic pancreatic cancer cases from benign pancreatic cyst patients and to monitor tumor dynamics using quantitative DNA methylation analysis of cell-free DNA (cfDNA) from blood samples. The biomarkers were able to distinguish malignant cases from benign disease with high sensitivity and specificity (AUC = 0.999). Furthermore, the biomarkers detected a consistent decline in tumor-derived cfDNA in samples from patients undergoing chemotherapy. The study indicates that our liquid biopsy assay could be useful for management of pancreatic cancer patients.
Background Exercise training can positively impact the immune system and particularly natural killer (NK) cells, at least in healthy people. This effect would be of relevance in the context of cancer given the prominent role of these cells in antitumor immunity. In this systematic review and meta-analysis, we aimed to summarize current evidence on the effects of exercise training on the levels and function of NK cells in cancer survivors (i.e., from the time of diagnosis until the end of life). Methods Relevant articles were searched in PubMed, Scopus, Web of Science and Cochrane Central Register of Controlled Trials (until January 11, 2022). Randomized controlled trials (RCT) of exercise training (i.e., non-acute) interventions vs usual care conducted in cancer survivors and assessing NK number and/or cytotoxic activity (NKCA) before and upon completion of the intervention were included. Methodological quality of the studies was assessed with the PEDro scale, and results were meta-analyzed using a random effects (Dersimoian and Laird) model. Results Thirteen RCT including 459 participants (mean age ranging 11–63 years) met the inclusion criteria. Methodological quality of the studies was overall fair (median PEDro score = 5 out of 10). There was heterogeneity across studies regarding cancer types (breast cancer, non-small cell lung cancer and other solid tumors), treatment (e.g . , receiving vs having received chemotherapy), exercise modes (aerobic or resistance exercise, Tai Chi, Yoga) and duration (2–24 weeks). No consistent effects were observed for NK number in blood (mean difference [MD]: 1.47, 95% confidence interval [CI] − 0.35 to 3.29, p = 0.113) or NKCA as assessed in vitro (MD: − 0.02, 95%CI − 0.17 to 0.14, p = 0.834). However, mixed results existed across studies, and some could not be meta-analyzed due to lack of information or methodological heterogeneity. Conclusions Current evidence does not support a significant effect of exercise training intervention on NK cells in blood or on their ‘static response’ (as assessed in vitro) in cancer survivors. Several methodological issues and research gaps are highlighted in this review, which should be considered in future studies to draw definite conclusions on this topic.
The ATLAS experiment at the Large Hadron Collider has a broad physics programme ranging from precision measurements to direct searches for new particles and new interactions, requiring ever larger and ever more accurate datasets of simulated Monte Carlo events. Detector simulation with Geant4 is accurate but requires significant CPU resources. Over the past decade, ATLAS has developed and utilized tools that replace the most CPU-intensive component of the simulation—the calorimeter shower simulation—with faster simulation methods. Here, AtlFast3, the next generation of high-accuracy fast simulation in ATLAS, is introduced. AtlFast3 combines parameterized approaches with machine-learning techniques and is deployed to meet current and future computing challenges, and simulation needs of the ATLAS experiment. With highly accurate performance and significantly improved modelling of substructure within jets, AtlFast3 can simulate large numbers of events for a wide range of physics processes.
Obesity is highly prevalent in hospitalized patients admitted with COVID-19. Evidence based guidelines are available for COVID-19-related therapies but dosing information specific to patients with obesity is lacking. Failure to account for the pharmacokinetic alterations that exist in this population can lead to underdosing, and treatment failure, or overdosing, resulting in an adverse effect. The objective of this manuscript is to provide clinicians with guidance for making dosing decisions for medications used in the treatment of patients with COVID-19. A detailed literature search was conducted for medications listed in evidence-based guidelines from the National Institutes of Health with an emphasis on pharmacokinetics, dosing and obesity. Retrieved manuscripts were evaluated and the following prioritization strategy was used to form the decision framework for recommendations: clinical outcome data > pharmacokinetic studies > adverse effects > physicochemical properties. Most randomized controlled studies included a substantial number of patients who were obese but few had large numbers of patients more extreme forms of obesity. Pharmacokinetic data have described alterations with volume of distribution and clearance but this variability does not appear to warrant dosing modifications. Future studies should provide more information on size descriptors and stratification of data according to obesity and body habitus. Graphic Abstract
The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18–19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year’s focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1–5, and STEP 1–5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed. Trial registration The 8th Cardiovascular Outcome Trial Summit will be held virtually on November 10–11, 2022 ( http://www.cvot.org )
Land degradation, loss of access to land resources, climate variability, socio-economic changes, and population increase are among the factors that contribute to forage shortage among the pastoral communities. The loss of forage is critical, especially when droughts are frequent and prolonged. Interventions to improve pastoralists’ resilience include policies that encourage livelihood diversification, that is, promoting enterprises that are less impacted by climate variability. This paper evaluates a reseeding project among pastoralists from Lake Baringo, Kenya, with the goal of rehabilitating degraded lands. Field owners participated in a survey and answered both quantitative and qualitative questions relating to their field and household characteristics. We use livestock herd size to assess households’ conditions. We hypothesize that field characteristics including total land size reseeded, the total number of fields and the number of field locations, years of experience of working in reseeded fields, type of management, fencing, and the number of income-generating activities have an effect on herd size maintenance during drought. We find that the total number of fields and the number of income-generating activities have significant explanatory power in predicting a household’s ability to maintain its herd size during drought. These factors are related to fine-scale control over land use which contributes to maintaining herd size. These findings suggest that reseeding by local pastoralists could be replicated and up-scaled into other dryland counties of Kenya and sub-Saharan Africa as a promising intervention to improve resilience to climate variability, alleviate poverty, and improve environmental conditions.
We develop a protocol for entanglement generation in the quantum internet that allows a repeater node to use n -qubit Greenberger-Horne-Zeilinger (GHZ) projective measurements that can fuse n successfully entangled links , i.e., two-qubit entangled Bell pairs shared across n network edges, incident at that node. Implementing n -fusion, for n ≥ 3, is in principle not much harder than 2-fusions (Bell-basis measurements) in solid-state qubit memories. If we allow even 3-fusions at the nodes, we find—by developing a connection to a modified version of the site-bond percolation problem—that despite lossy (hence probabilistic) link-level entanglement generation, and probabilistic success of the fusion measurements at nodes, one can generate entanglement between end parties Alice and Bob at a rate that stays constant as the distance between them increases. We prove that this powerful network property is not possible to attain with any quantum networking protocol built with Bell measurements and multiplexing alone. We also design a two-party quantum key distribution protocol that converts the entangled states shared between two nodes into a shared secret, at a key generation rate that is independent of the distance between the two parties.
Background Right ventricular (RV) dilation has been used to predict adverse outcomes in acute pulmonary conditions. It has been used to categorize the severity of novel coronavirus infection (COVID-19) infection. Our study aimed to use chest CT-angiogram (CTA) to assess if increased RV dilation, quantified as an increased RV:LV (left ventricle) ratio, is associated with adverse outcomes in the COVID-19 infection, and if it occurs out of proportion to lung parenchymal disease. Results We reviewed clinical, laboratory, and chest CTA findings in COVID-19 patients ( n = 100), and two control groups: normal subjects ( n = 10) and subjects with organizing pneumonia ( n = 10). On a chest CTA, we measured basal dimensions of the RV and LV in a focused 4-chamber view, and dimensions of pulmonary artery (PA) and aorta (AO) at the PA bifurcation level. Among the COVID-19 cohort, a higher RV:LV ratio was correlated with adverse outcomes, defined as ICU admission, intubation, or death. In patients with adverse outcomes, the RV:LV ratio was 1.06 ± 0.10, versus 0.95 ± 0.15 in patients without adverse outcomes. Among the adverse outcomes group, compared to the control subjects with organizing pneumonia, the lung parenchymal damage was lower (22.6 ± 9.0 vs. 32.7 ± 6.6), yet the RV:LV ratio was higher (1.06 ± 0.14 vs. 0.89 ± 0.07). In ROC analysis, RV:LV ratio had an AUC = 0.707 with an optimal cutoff of RV:LV ≥ 1.1 as a predictor of adverse outcomes. In a validation cohort ( n = 25), an RV:LV ≥ 1.1 as a cutoff predicted adverse outcomes with an odds ratio of 76:1. Conclusions In COVID-19 patients, RV:LV ratio ≥ 1.1 on CTA chest is correlated with adverse outcomes. RV dilation in COVID-19 is out of proportion to parenchymal lung damage, pointing toward a vascular and/or thrombotic injury in the lungs.
Miscalculating the volumes of water withdrawn for irrigation, the largest consumer of freshwater in the world, jeopardizes sustainable water management. Hydrological models quantify water withdrawals, but their estimates are unduly precise. Model imperfections need to be appreciated to avoid policy misjudgements.
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16,131 members
Donald Myers
  • Department of Mathematics
Luwanika Mlera
  • BIO5 Institute
Tushar Kanti Bera
  • College of Medicine
Douglas G Stuart
  • Department of Physiology
Roberto Ramos
  • School of Plant Sciences
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