• Educación superior: ¿De masiva a universal... a obligatoria?

      Castiello-Gutiérrez, Santiago; Univ Arizona, Ctr Study Higher Educ (Universidad del Norte, 2019-07-12)
      Resumen: Aunque el costo de estudiar en una institución de educación superior pública en México es relativamente bajo, el acceso universal a la educación superior en este país aún está lejos de convertirse en una realidad. El gobierno federal, junto con las instituciones educativas públicas y privadas, ha implementado diferentes enfoques para aumentar la cobertura, sin embargo, la brecha continúa ampliándose entre los estratos más altos y bajos de la población con acceso a estudios terciarios. Recientemente, el gobierno federal impulsó una reforma constitucional que incluye la educación superior como un derecho, por lo tanto, la hace obligatoria. Este texto describe, de manera breve, el estado de la cobertura de la educación superior en México, así como las implicaciones de pasar a un sistema obligatorio. Abstract: Although Mexico has one of the less expensive costs of attendance, universal access to higher education is still far from becoming a reality. The federal government along with public and private educational institutions have implemented different approaches to increase access but the gap among higher and lower strata of the population reflected in HEIs seems to be widening. Recently, the federal government proposed to change the Constitution to include higher education as a right and compulsory. This essay presents an overview of access to higher education in México as well as the implications of moving to a compulsory system.
    • Indications and Clinical Results of Radial Head Replacement: Has Anything Changed?

      Eyberg, Blake A; McKee, Michael D; Univ Arizona, Coll Med Phoenix, Dept Orthopaed Surg (LIPPINCOTT WILLIAMS & WILKINS, 2019-12)
      Radial head fractures are common injuries comprising 1/3 of the fractures about the elbow. As a secondary valgus stabilizer of the elbow, radial head fractures can compromise elbow stability leading to long-term pain, dysfunction, and degenerative change. Furthermore, radial head fractures can be accompanied by associated injuries including ligamentous lesions that can further exacerbate elbow instability, leading to long-term sequelae. As fixation principles and technology have evolved, so has the ability to render surgical treatment for these fractures. In general, minimally displaced and some displaced fractures may be treated nonoperatively with early motion. Fractures with a block to rotation and displaced fragments with 3 or fewer fragments may be treated with open reduction and internal fixation. Comminuted fractures or those with greater than 3 fragments may be successfully treated with radial head replacement. Associated elbow instability will also influence treatment decisions.
    • ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway

      Wang, Nuozhou; Li, Ming-Yue; Liu, Yi; Yu, Jianqing; Ren, Jianwei; Zheng, Zhiyuan; Wang, Shanshan; Yang, Shucai; Yang, Sheng-Li; Liu, Li-Ping; et al. (ELSEVIER IRELAND LTD, 2019-12-23)
      Liver cancer stem cells (LCSCs) initiate hepatocellular carcinoma (HCC) and contribute to its recurrence and treatment resistance. Studies have suggested ZBP-89 as a candidate tumor suppressor in HCC. We explored the role of ZBP-89 in the regulation of LCSCs. This study was performed in liver tissue samples from 104 HCC patients, 2 cell lines and mouse tumor models. We demonstrated that ZBP-89 was weakly expressed in LCSCs. Patients with high expression of LCSC markers displayed reduced survivals and higher recurrence rates after curative surgical operation. The expression of ZBP-89 was predictive for decreased recurrence. LCSC markers were negatively correlated with ZBP-89 in HCC tissues and in enriched liver tumor spheres. The exogenous expression of ZBP-89 attenuated the tumor-sphere formation and secondary colony formation capabilities of LCSCs in vitro and tumorigenicity in vivo. Furthermore, the negative effect of ZBP-89 on cancer sternness was Notch1-dependent. Localized with Notch1 intracellular domain (NICD1) in the nucleus, ZBP-89 repressed the Notch1 signaling pathway by competitive binding to NICD1 with MAML1. Collectively, ZBP-89 negatively regulates HCC sternness via inhibiting the Notch1 signaling.
    • Chronic exposure to arsenite enhances influenza virus infection in cultured cells

      Amouzougan, Eva A; Lira, Ricardo; Klimecki, Walter T; Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol; Univ Arizona, Coll Vet Med (WILEY, 2020-01-20)
      Arsenic is a ubiquitous environmental toxicant that has been associated with human respiratory diseases. In humans, arsenic exposure has been associated with increased risk of respiratory infection. Considering the existing epidemiological evidence and the well-established impact of arsenic on epithelial cell biology, we posited that the effect of arsenic exposure in epithelial cells could enhance viral infection. In this study, we characterized influenza virus A/WSN/33 (H1N1) infection in Madin-Darby Canine Kidney (MDCK) cells chronically exposed to low levels of sodium arsenite (75 ppb). We observed a 27.3-fold increase in viral matrix (M2) protein (24 hours postinfection [p.i.]), a 1.35-fold increase in viral mRNA levels, and a 126% increase in plaque area in arsenite-exposed MDCK cells (48 hours p.i.). Arsenite exposure resulted in 114% increase in virus attachment-positive cells (2 hours p.i.) and 224% increase in alpha-2,3 sialic acid-positive cells. Interestingly, chronic exposure to arsenite reduced the effect of the antiviral drug, oseltamivir in MDCK cells. We also found that exposure to sodium arsenite resulted in a 4.4-fold increase in viral mRNA levels and significantly increased cytotoxicity in influenza A/Udorn/72 (H3N2) infected BEAS-2B cells. This study suggests that chronic arsenite exposure could result in enhanced influenza infection in epithelial cells, and that this may be mediated through increased sialic acid binding. Finally, the decreased effectiveness of the anti-influenza drug, oseltamivir, in arsenite-exposed cells raises substantial public health concerns if this effect translates to arsenic-exposed, influenza-infected people.
    • Modality and Interrelations Among Language, Reading, Spoken Phonological Awareness, and Fingerspelling

      Lederberg, Amy R; Branum-Martin, Lee; Webb, Mi-Young; Schick, Brenda; Antia, Shirin; Easterbrooks, Susan R; Connor, Carol McDonald; Univ Arizona (OXFORD UNIV PRESS, 2019-05-15)
      Better understanding of the mechanisms underlying early reading skills can lead to improved interventions. Hence, the purpose of this study was to examine multivariate associations among reading, language, spoken phonological awareness, and fingerspelling abilities for three groups of deaf and hard-of-hearing (DHH) beginning readers: those who were acquiring only spoken English (n = 101), those who were visual learners and acquiring sign (n = 131), and those who were acquiring both (n = 104). Children were enrolled in kindergarten, first, or second grade. Within-group and between-group confirmatory factor analysis showed that there were both similarities and differences in the abilities that underlie reading in these three groups. For all groups, reading abilities related to both language and the ability to manipulate the sublexical features of words. However, the groups differed on whether these constructs were based on visual or spoken language. Our results suggest that there are alternative means to learning to read. Whereas all DHH children learning to read rely on the same fundamental abilities of language and phonological processing, the modality, levels, and relations among these abilities differ.
    • Sorafenib in Hepatopulmonary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

      Kawut, Steven M; Ellenberg, Susan S; Krowka, Michael J; Goldberg, David; Vargas, Hugo; Koch, David; Sharkoski, Tiffany; Al-Naamani, Nadine; Fox, Alyson; Brown, Robert; et al. (WILEY, 2019-02-28)
      The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar-arterial oxygen gradient (AaPO2 ) at 3 months in patients with HPS. We performed a randomized, double-blind, placebo-controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, -3.8 to 7.0 mm Hg) and those allocated to placebo (-2.4 mm Hg; IQR, -4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2-expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.
    • Variation in the production of plant tissues bearing extrafloral nectaries explains temporal patterns of ant attendance in Amazonian understorey plants

      Nogueira, Anselmo; Baccaro, Fabricio B.; Leal, Laura C.; Rey, Pedro J.; Lohmann, Lúcia G.; Bronstein, Judith L.; Univ Arizona, Dept Ecol & Evolutionary Biol (WILEY, 2019-12-18)
      Information on direct and indirect drivers of temporal variation in ant-plant interactions is scarce, compromising our ability to predict the functioning of these ecologically important interactions. We investigated the roles of precipitation, ant activity, abundance of young plant tissues bearing extrafloral nectaries (EFNs) and EFN phenotypes in the establishment of EFN-mediated ant-plant interactions throughout the year in Amazonia, Brazil. We hypothesized that the frequency of ant-plant interactions follows a predictable seasonal pattern, being higher in wetter periods, during which plants invest more in the production of new plant tissues bearing EFNs, ultimately promoting ant attendance. We surveyed and tagged every understorey Bignonieae plant rooted inside 28,500-m(2) plots, and recorded ant-EFN interactions on each plant five times throughout the year. We also sampled ants with honey baits to estimate temporal variation in general ant activity. Contrary to our hypothesis, the proportion of plants tended by ants in each plot was higher in drier, not wetter, months. Ant attendance was indirectly and negatively related to precipitation, which was attributed to a decrease in the proportion of plants producing new EFN-bearing plant tissues during the wetter period. Additionally, seasonal variation in an ant activity did not explain temporal patterns of plant attendance. At the plant level, ant attendance increased strongly with the number of recently formed shoot nodes, and ants almost never attended plants with limited or no young tissue. Among the 12 most abundant Bignonieae species, the amount of young tissue was the most important predictor of ant attendance, secondarily explained by the EFN secretory area. Synthesis. Our results suggest that seasonal variation in the production of new plant tissues bearing EFNs is the primary driver of the temporal patterns of EFN-plant attendance by ants in this system. Contrary to our expectations, production of new plant tissue is higher in the drier months of the year, which in turn boosts the frequency of interactions between ants and EFN-bearing plants in the dry season. These results highlight the role of plant phenology in the remarkable variation encountered in ant visitation to EFN-bearing plants in both space and time.
    • Sealed Envelope Submissions Foster Research Integrity

      Dufwenberg, Martin; Martinsson, Peter; Univ Arizona (PRESSES FOND NAT SCI POLIT, 2019-08-05)
      Because journals favor clear stories, researchers may gain by engaging in scientific misconduct, ranging from shady practices like collecting more data hoping for significance to outright data fabrication. To set researchers' incentives straight, we propose sealed envelope submissions, where editors' and referees' evaluations are based only on the interest of the research question and on the proposed empirical method. We argue that researchers who are inherently honest and who would not have cheated anyway will not be hurt by our protocol, but rather be helped by being protected.
    • TNF-α mediated upregulation of Na1.7 currents in rat dorsal root ganglion neurons is independent of CRMP2 SUMOylation

      de Macedo, Flávio Henrique Pequeno; Aires, Rosária Dias; Fonseca, Esdras Guedes; Ferreira, Renata Cristina Mendes; Machado, Daniel Portela Dias; Chen, Lina; Zhang, Fang-Xiong; Souza, Ivana A; Lemos, Virgínia Soares; Romero, Thiago Roberto Lima; et al. (BMC, 2019-12-30)
      Clinical and preclinical studies have shown that patients with Diabetic Neuropathy Pain (DNP) present with increased tumor necrosis factor alpha (TNF-α) serum concentration, whereas studies with diabetic animals have shown that TNF-α induces an increase in NaV1.7 sodium channel expression. This is expected to result in sensitization of nociceptor neuron terminals, and therefore the development of DNP. For further study of this mechanism, dissociated dorsal root ganglion (DRG) neurons were exposed to TNF-α for 6 h, at a concentration equivalent to that measured in STZ-induced diabetic rats that developed hyperalgesia. Tetrodotoxin sensitive (TTXs), resistant (TTXr) and total sodium current was studied in these DRG neurons. Total sodium current was also studied in DRG neurons expressing the collapsin response mediator protein 2 (CRMP2) SUMO-incompetent mutant protein (CRMP2-K374A), which causes a significant reduction in NaV1.7 membrane cell expression levels. Our results show that TNF-α exposure increased the density of the total, TTXs and TTXr sodium current in DRG neurons. Furthermore, TNF-α shifted the steady state activation and inactivation curves of the total and TTXs sodium current. DRG neurons expressing the CRMP2-K374A mutant also exhibited total sodium current increases after exposure to TNF-α, indicating that these effects were independent of SUMOylation of CRMP2. In conclusion, TNF-α sensitizes DRG neurons via augmentation of whole cell sodium current. This may underlie the pronociceptive effects of TNF-α and suggests a molecular mechanism responsible for pain hypersensitivity in diabetic neuropathy patients.
    • Effect of a Virtual Patient Navigation Program on Behavioral Health Admissions in the Emergency Department: A Randomized Clinical Trial

      Roberge, Jason; McWilliams, Andrew; Zhao, Jing; Anderson, William E; Hetherington, Timothy; Zazzaro, Christine; Hardin, Elisabeth; Barrett, Amy; Castro, Manuel; Balfour, Margaret E; et al. (AMER MEDICAL ASSOC, 2020-01-29)
      This randomized clinical trial assesses whether the availability of a 45-day behavioral health-virtual patient navigation program decreases hospitalization among adult patients presenting to the emergency department with a behavioral health crisis or need. Importance The number of patients presenting to emergency departments (EDs) for psychiatric care continues to increase. Psychiatrists often make a conservative recommendation to admit patients because robust outpatient services for close follow-up are lacking. Objective To assess whether the availability of a 45-day behavioral health-virtual patient navigation program decreases hospitalization among patients presenting to the ED with a behavioral health crisis or need. Design, Setting, and Participants This randomized clinical trial enrolled 637 patients who presented to 6 EDs spanning urban and suburban locations within a large integrated health care system in North Carolina from June 12, 2017, through February 14, 2018; patients were followed up for up to 45 days. Eligible patients were aged 18 years or older, with a behavioral health crisis and a completed telepsychiatric ED consultation. The availability of the behavioral health-virtual patient navigation intervention was randomly allocated to specific days (Monday through Friday from 7 am to 7 pm) so that, in a 2-week block, there were 5 intervention days and 5 usual care days; 323 patients presented on days when the program was offered, and 314 presented on usual care days. Data analysis was performed from March 7 through June 13, 2018, using an intention-to-treat approach. Interventions The behavioral health-virtual patient navigation program included video contact with a patient while in the ED and telephonic outreach 24 to 72 hours after discharge and then at least weekly for up to 45 days. Main Outcomes and Measures The primary outcome was the conversion of an ED encounter to hospital admission. Secondary outcomes included 45-day follow-up encounters with a self-harm diagnosis and postdischarge acute care use. Results Among 637 participants, 358 (56.2%) were men, and the mean (SD) age was 39.7 (16.6) years. The conversion rates were 55.1% (178 of 323) in the intervention group vs 63.1% (198 of 314) in the usual care group (odds ratio, 0.74; 95% CI, 0.54-1.02; P = .06). The percentage of patient encounters with follow-up encounters having a self-harm diagnosis was significantly lower in the intervention group compared with the usual care group (36.8% [119 of 323] vs 45.5% [143 of 314]; P = .03). Conclusions and Relevance Although the primary result did not reach statistical significance, there is a strong signal of potential positive benefit in an area that lacks evidence, suggesting that there should be additional investment and inquiry into virtual behavioral health programs. Question Does offering virtual patient navigation reduce admission rates for patients presenting to the emergency department with a behavioral health crisis? Findings In this randomized clinical trial, there were fewer admissions on days when the navigation program was available (55.1%) vs on days with usual care (63.1%), although the difference was not statistically significant. Significantly fewer patients who used the navigation program had a follow-up encounter involving a self-harm diagnosis within 45 days compared with patients who received usual care (36.8% vs 45.5%). Meaning Although the primary result did not reach statistical significance, there is a strong signal of potential positive benefit in an area that lacks evidence, suggesting that there should be additional investment and inquiry into this area.
    • Chirality-enabled unidirectional light emission and nanoparticle detection in parity-time-symmetric microcavity

      Wang, Weihua; Liu, Shuai; Gu, Zhiyuan; Wang, Yue; Univ Arizona, Dept Mat Sci & Engn (AMER PHYSICAL SOC, 2020-01-29)
      Achieving unidirectional emission and manipulating waves in a microcavity are crucial for information processing and data transmission in next-generation photonic circuits (PCs). Here we show how to impose twin microcavities with opposite chirality by incorporating parity-time (PT) symmetry to realize unidirectional emission. Our numerical calculation results show that the opposite chirality in microcavities stems from the asymmetric coupling of the clockwise (CW) and counterclockwise (CCW) components carried by the attached waveguide to the left- or right-sided microcavities, respectively. Notably, by engineering PT symmetry in the coupled system via the gain-loss control, the clockwise component of the lossy cavity could be selectively suppressed, which leads to the unidirectional emission with an extinction ratio of up to -52 dB. Furthermore, the chirality and PT-symmetry breaking enabled unidirectional emission is extremely sensitive to external scatters, allowing the detection of nanoparticles with an ultrasmall radius of 5-50 nm by recording the extinction ratio change. The proposed system provides a simple yet general way to manipulate the standing waves in a microcavity and will be essential for advancing the potentials of the microcavity in PCs.
    • Influence of Substrate Concentration on the Culturability of Heterotrophic Soil Microbes Isolated by High-Throughput Dilution-to-Extinction Cultivation

      Bartelme, Ryan P; Custer, Joy M; Dupont, Christopher L; Espinoza, Josh L; Torralba, Manolito; Khalili, Banafshe; Carini, Paul; Univ Arizona, Dept Environm Sci (AMER SOC MICROBIOLOGY, 2020-01-29)
      The vast majority of microbes inhabiting oligotrophic shallow subsurface soil environments have not been isolated or studied under controlled laboratory conditions. In part, the challenges associated with isolating shallow subsurface microbes may persist because microbes in deeper soils are adapted to low nutrient availability or quality. Here, we use high-throughput dilution-to-extinction culturing to isolate shallow subsurface microbes from a conifer forest in Arizona, USA. We hypothesized that the concentration of heterotrophic substrates in microbiological growth medium would affect which microbial taxa were culturable from these soils. To test this, we diluted cells extracted from soil into one of two custom-designed defined growth media that differed by 100-fold in the concentration of amino acids and organic carbon. Across the two media, we isolated a total of 133 pure cultures, all of which were classified as Actinobacteria or Alphaproteobacteria The substrate availability dictated which actinobacterial phylotypes were culturable but had no significant effect on the culturability of Alphaproteobacteria We isolated cultures that were representative of the most abundant phylotype in the soil microbial community (Bradyrhizobium spp.) and representatives of five of the top 10 most abundant Actinobacteria phylotypes, including Nocardioides spp., Mycobacterium spp., and several other phylogenetically divergent lineages. Flow cytometry of nucleic acid-stained cells showed that cultures isolated on low-substrate medium had significantly lower nucleic acid fluorescence than those isolated on high-substrate medium. These results show that dilution-to-extinction is an effective method to isolate abundant soil microbes and that the concentration of substrates in culture medium influences the culturability of specific microbial lineages.IMPORTANCE Isolating environmental microbes and studying their physiology under controlled conditions are essential aspects of understanding their ecology. Subsurface ecosystems are typically nutrient-poor environments that harbor diverse microbial communities-the majority of which are thus far uncultured. In this study, we use modified high-throughput cultivation methods to isolate subsurface soil microbes. We show that a component of whether a microbe is culturable from subsurface soils is the concentration of growth substrates in the culture medium. Our results offer new insight into technical approaches and growth medium design that can be used to access the uncultured diversity of soil microbes.
    • Category-specific effects in Welsh mutation

      Hammond, Michael; Bell, Elise; Anderson, Skye; Webb-Davies, Peredur; Ohala, Diane; Carnie, Andrew; Brooks, Heddwen; Univ Arizona (UBIQUITY PRESS LTD, 2020-01-03)
      In this paper we investigate category-specific effects through the lens of Welsh mutation. Smith (2011) and Moreton et al. (2017) show that English distinguishes nouns and proper nouns in an experimental blending task. Here we show that Welsh distinguishes nouns, verbs, personal names, and place names in the mutation system. We demonstrate these effects experimentally in a translation task designed to elicit mutation intuitions and in several corpus studies. In addition, we show that these effects correlate with lexical frequency. Deeper statistical analysis and a review of the English data suggests that frequency is a more explanatory factor than part of speech in both languages. We therefore argue that these category-specific effects can be reduced to lexical frequency effects.
    • Development of Practical Design Approaches for Water Distribution Systems

      Choi, Young Hwan; Lee, Ho Min; Choi, Jiho; Yoo, Do Guen; Kim, Joong Hoon; Univ Arizona, Dept Civil & Architectural Engn & Mech (MDPI, 2019-11-26)
      The optimal design of water distribution systems (WDSs) should be economical, consider practical field applicability, and satisfy hydraulic constraints such as nodal pressure and flow velocity. However, the general optimal design of a WDSs approach using a metaheuristic algorithm was difficult to apply for achieving pipe size continuity at the confluence point. Although some studies developed the design approaches considering the pipe continuity, these approaches took many simulation times. For these reasons, this study improves the existing pipe continuity search method by reducing the computation time and enhancing the ability to handle pipe size continuity at complex joints that have more than three nodes. In addition to more practical WDSs designs, the approach considers various system design factors simultaneously in a multi-objective framework. To verify the proposed approach, the three well-known WDSs to apply WDS design problems are applied, and the results are compared with the previous design method, which used a pipe continuity research algorithm. This study can reduce the computation time by 87% and shows an ability to handle complex joints. Finally, the application of this practical design technique, which considers pipe continuity and multiple design factors, can reduce the gap between the theoretical design and the real world because it considers construction conditions and abnormal situations.
    • Joint Probabilistic-Nyquist Pulse Shaping for an LDPC-Coded 8-PAM Signal in DWDM Data Center Communications

      Han, Xiao; Yang, Mingwei; Djordjevic, Ivan B; Yue, Yang; Wang, Qiang; Qu, Zhen; Anderson, Jon; Univ Arizona, ECE Dept (MDPI, 2019-11-20)
      M-ary pulse-amplitude modulation (PAM) meets the requirements of data center communication because of its simplicity, but coarse entropy granularity cannot meet the dynamic bandwidth demands, and there is a large capacity gap between uniform formats and the Shannon limit. The dense wavelength division multiplexing (DWDM) system is widely used to increase the channel capacity, but low spectral efficiency of the intensity modulation/direct detection (IM/DD) solution restricts the throughput of the modern DWDM data center networks. Probabilistic shaping distribution is a good candidate to offer us a fine entropy granularity and efficiently reduce the gap to the Shannon limit, and Nyquist pulse shaping is widely used to increase the spectral efficiency. We aim toward the joint usage of probabilistic shaping and Nyquist pulse shaping with low-density parity-check (LDPC) coding to improve the bit error rate (BER) performance of 8-PAM signal transmission. We optimized the code rate of the LDPC code and compared different Nyquist pulse shaping parameters using simulations and experiments. We achieved a 0.43 dB gain using Nyquist pulse shaping, and a 1.1 dB gain using probabilistic shaping, while the joint use of probabilistic shaping and Nyquist pulse shaping achieved a 1.27 dB gain, which offers an excellent improvement without upgrading the transceivers.
    • Single-cell ATAC-Seq in human pancreatic islets and deep learning upscaling of rare cells reveals cell-specific type 2 diabetes regulatory signatures

      Rai, Vivek; Quang, Daniel X; Erdos, Michael R; Cusanovich, Darren A; Daza, Riza M; Narisu, Narisu; Zou, Luli S; Didion, John P; Guan, Yuanfang; Shendure, Jay; et al. (ELSEVIER, 2019-12-20)
      Objective: Type 2 diabetes (T2D) is a complex disease characterized by pancreatic islet dysfunction, insulin resistance, and disruption of blood glucose levels. Genome-wide association studies (GWAS) have identified > 400 independent signals that encode genetic predisposition. More than 90% of associated single-nucleotide polymorphisms (SNPs) localize to non-coding regions and are enriched in chromatin-defined islet enhancer elements, indicating a strong transcriptional regulatory component to disease susceptibility. Pancreatic islets are a mixture of cell types that express distinct hormonal programs, so each cell type may contribute differentially to the underlying regulatory processes that modulate T2D-associated transcriptional circuits. Existing chromatin profiling methods such as ATAC-seq and DNase-seq, applied to islets in bulk, produce aggregate profiles that mask important cellular and regulatory heterogeneity. Methods: We present genome-wide single-cell chromatin accessibility profiles in >1,600 cells derived from a human pancreatic islet sample using single-cell combinatorial indexing ATAC-seq (sci-ATAC-seq). We also developed a deep learning model based on U-Net architecture to accurately predict open chromatin peak calls in rare cell populations. Results: We show that sci-ATAC-seq profiles allow us to deconvolve alpha, beta, and delta cell populations and identify cell-type-specific regulatory signatures underlying T2D. Particularly, T2D GWAS SNPs are significantly enriched in beta cell-specific and across cell-type shared islet open chromatin, but not in alpha or delta cell-specific open chromatin. We also demonstrate, using less abundant delta cells, that deep learning models can improve signal recovery and feature reconstruction of rarer cell populations. Finally, we use co-accessibility measures to nominate the cell-specific target genes at 104 non-coding T2D GWAS signals. Conclusions: Collectively, we identify the islet cell type of action across genetic signals of T2D predisposition and provide higher-resolution mechanistic insights into genetically encoded risk pathways. Published by Elsevier GmbH.
    • MiR130b from Schlafen4+ MDSCs stimulates epithelial proliferation and correlates with preneoplastic changes prior to gastric cancer

      Ding, Lin; Li, Qian; Chakrabarti, Jayati; Munoz, Andres; Faure-Kumar, Emmanuelle; Ocadiz-Ruiz, Ramon; Razumilava, Nataliya; Zhang, Guiying; Hayes, Michael H; Sontz, Ricky A; et al. (BMJ, 2020-01-24)
      The myeloid differentiation factor Schlafen4 (Slfn4) marks a subset of myeloid-derived suppressor cells (MDSCs) in the stomach during Helicobacter-induced spasmolytic polypeptide-expressing metaplasia (SPEM). OBJECTIVE: To identify the gene products expressed by Slfn4+-MDSCs and to determine how they promote SPEM. DESIGN: We performed transcriptome analyses for both coding genes (mRNA by RNA-Seq) and non-coding genes (microRNAs using NanoString nCounter) using flow-sorted SLFN4+ and SLFN4- cells from Helicobacter-infected mice exhibiting metaplasia at 6 months postinfection. Thioglycollate-elicited myeloid cells from the peritoneum were cultured and treated with IFNα to induce the T cell suppressor phenotype, expression of MIR130b and SLFN4. MIR130b expression in human gastric tissue including gastric cancer and patient sera was determined by qPCR and in situ hybridisation. Knockdown of MiR130b in vivo in Helicobacter-infected mice was performed using Invivofectamine. Organoids from primary gastric cancers were used to generate xenografts. ChIP assay and Western blots were performed to demonstrate NFκb p65 activation by MIR130b. RESULTS: MicroRNA analysis identified an increase in MiR130b in gastric SLFN4+ cells. Moreover, MIR130b colocalised with SLFN12L, a human homologue of SLFN4, in gastric cancers. MiR130b was required for the T-cell suppressor phenotype exhibited by the SLFN4+ cells and promoted Helicobacter-induced metaplasia. Treating gastric organoids with the MIR130b mimic induced epithelial cell proliferation and promoted xenograft tumour growth. CONCLUSION: Taken together, MiR130b plays an essential role in MDSC function and supports metaplastic transformation.
    • Gastric Cardia Adenocarcinoma with Metastasis to the Scalp: A Case Report

      Menghani, Sanjay V; Barbosa, Alexandra; Sagerman, Paul; Beal, Matthew W; Scott, Aaron; Univ Arizona, Coll Med, Dermatol; Univ Arizona, Coll Med, Internal Med; Univ Arizona, Ctr Canc, Oncol (CUREUS INC, 2020-01-27)
      Cutaneous metastasis is a rare manifestation of advanced gastrointestinal (GI) cancers. Gastric adenocarcinoma rarely presents with cutaneous metastasis, as cutaneous manifestations occur in less than 1% of upper GI tract malignancies. Here, we present the case of a patient with advanced gastric cardia adenocarcinoma with metastasis to the right occipital region of the scalp. Following shave biopsy, the immunohistochemistry (IHC) and molecular profile of the scalp lesion were analyzed, both of which confirmed metastasis and guided the treatment approach. The lesion demonstrated programmed death ligand-1 (PD-L1), an immune checkpoint protein, positivity by IHC, which led to the recommendation for treatment with immunotherapy as per the National Comprehensive Cancer Network (NCCN) guidelines. Clinicians should conduct dermatologic examinations in patients with a history of gastric cancer or who are currently undergoing chemotherapy for gastric cancer in order to monitor for disease progression or metastatic lesions. The aim of this report is to increase awareness of scalp metastasis as an indicator of advanced internal visceral carcinoma for earlier diagnosis and improved management of the condition.
    • Mass Loss From Calving in Himalayan Proglacial Lakes

      Watson, C. Scott; Kargel, Jeffrey S.; Shugar, Dan H.; Haritashya, Umesh K.; Schiassi, Enrico; Furfaro, Roberto; Univ Arizona, Dept Hydrol & Atmospher Sci; Univ Arizona, Coll Engn, Dept Syst & Ind Engn; Univ Arizona, Coll Engn, Dept Aerosp & Mech Engn (FRONTIERS MEDIA SA, 2020-01-08)
      The formation and expansion of Himalayan glacial lakes has implications for glacier dynamics, mass balance and glacial lake outburst floods (GLOFs). Subaerial and subaqueous calving is an important component of glacier mass loss but they have been difficult to track due to spatiotemporal resolution limitations in remote sensing data and few field observations. In this study, we used near-daily 3 m resolution PlanetScope imagery in conjunction with an uncrewed aerial vehicle (UAV) survey to quantify calving events and derive an empirical area-volume relationship to estimate calved glacier volume from planimetric iceberg areas. A calving event at Thulagi Glacier in 2017 was observed by satellite from before and during the event to nearly complete melting of the icebergs, and was observed in situ midway through the melting period, thus giving insights into the melting processes. In situ measurements of Thulagi Lake's surface and water column indicate that daytime sunlight absorption heats mainly just the top metre of water, but this heat is efficiently mixed downwards through the top tens of metres due to forced convection by wind-blown icebergs; this heat then is retained by the lake and is available to melt the icebergs. Using satellite data, we assess seasonal glacier velocities, lake thermal regime and glacier surface elevation change for Thulagi, Lower Barun and Lhotse Shar glaciers and their associated lakes. The data reveal widely varying trends, likely signifying divergent future evolution. Glacier velocities derived from 1960/70s declassified Corona satellite imagery revealed evidence of glacier deceleration for Thulagi and Lhotse Shar glaciers, but acceleration at Lower Barun Glacier following lake development. We used published modelled ice thickness data to show that upon reaching their maximum extents, Imja, Lower Barun and Thulagi lakes will contain, respectively, about 90 x 10(6), 62 x 10(6) and 5 x 10(6) m(3) of additional water compared to their 2018 volumes. Understanding lake-glacier interactions is essential to predict future glacier mass loss, lake formation and associated hazards.
    • Theoretical Evaluation of Anisotropic Reflectance Correction Approaches for Addressing Multi-Scale Topographic Effects on the Radiation-Transfer Cascade in Mountain Environments

      Bishop, Michael P.; Young, Brennan W.; Colby, Jeffrey D.; Furfaro, Roberto; Schiassi, Enrico; Chi, Zhaohui; Univ Arizona, Dept Syst & Ind Engn (MDPI, 2019-11-20)
      Research involving anisotropic-reflectance correction (ARC) of multispectral imagery to account for topographic effects has been ongoing for approximately 40 years. A large body of research has focused on evaluating empirical ARC methods, resulting in inconsistent results. Consequently, our research objective was to evaluate commonly used ARC methods using first-order radiation-transfer modeling to simulate ASTER multispectral imagery over Nanga Parbat, Himalaya. Specifically, we accounted for orbital dynamics, atmospheric absorption and scattering, direct- and diffuse-skylight irradiance, land cover structure, and surface biophysical variations to evaluate their effectiveness in reducing multi-scale topographic effects. Our results clearly reveal that the empirical methods we evaluated could not reasonably account for multi-scale topographic effects at Nanga Parbat. The magnitude of reflectance and the correlation structure of biophysical properties were not preserved in the topographically-corrected multispectral imagery. The CCOR and SCS+C methods were able to remove topographic effects, given the Lambertian assumption, although atmospheric correction was required, and we did not account for other primary and secondary topographic effects that are thought to significantly influence spectral variation in imagery acquired over mountains. Evaluation of structural-similarity index images revealed spatially variable results that are wavelength dependent. Collectively, our simulation and evaluation procedures strongly suggest that empirical ARC methods have significant limitations for addressing anisotropic reflectance caused by multi-scale topographic effects. Results indicate that atmospheric correction is essential, and most methods failed to adequately produce the appropriate magnitude and spatial variation of surface reflectance in corrected imagery. Results were also wavelength dependent, as topographic effects influence radiation-transfer components differently in different regions of the electromagnetic spectrum. Our results explain inconsistencies described in the literature, and indicate that numerical modeling efforts are required to better account for multi-scale topographic effects in various radiation-transfer components.