bluuebunny/crossref_metadata_2025 huggingface dataset:
Dead level contour technical design parameters required for sustainable crop production in semi-arid areas of Zimbabwe
Authors: Gumbo Douglas , Wuta Menas , Nyagumbo Isaiah
Published: May 2021

Smallholder farmers in sub-Saharan Africa are increasingly exposed to risks such as erratic rainfall, prolonged dry spells, and frequent droughts that threaten sustainable crop production. This study assessed the effectiveness of dead level contours with innovations (DLC INN), dead level contours with infiltration pits (DLC INFIL), dead level contours with open channels (DLC OPEN) and standard graded contours (SGCs) in harvesting and storing water in the channel, and improving crop conditions during the critical stages of maize growth on different soil textural groups in the Zvishavane District of Zimbabwe. The DLC INFIL, DLC OPEN and DLC INN outperformed the SGC under medium- and heavy-textured soils, with yields ranging between 1.7 and 2.36 t/ha compared to 0.9 t/ha for the SGC. For light textured soils, the DLC INN had the highest maize yield, averaging 0.8 t/ha. On heavy textured soils using DLC INN, DLC INFIL and DLC OPEN, smallholder farmers may use a spacing interval of 24–27 m. On medium textured soils, DLC INN and DLC INFIL can be used at a spacing interval of 18–21 m and 12 to 15 m with DLC OPEN. On light textured soils, farmers are advised to invest in DLC INN only, using a spacing interval of 12–15 m.
Management outcome and its associated factors among surgically treated intestinal obstruction cases in Dilla University Referral Hospital, Southern Ethiopia. A cross-sectional study
Authors: Girma Hailemichael , Negesso Miesso , Tadese Jarso , Hussen Robel , Aweke Zemedu
Published: May 2021

ABSTRACT

Background:

Intestinal obstruction is the most common surgical emergency worldwide. Intestinal obstruction continues to remain a challenge to surgeons despite advances in the field of medicine, surgical technique and accounts for high mortality ranges from 3% to 30% all over the world.

Objective:

The study aimed to assess management outcome and its associated factors among surgically treated intestinal obstruction cases, at Dilla University Referral Hospital 2020 GC.

Method:

Hospital-based cross-sectional study was conducted on all cases surgically managed for intestinal obstruction, at Dilla University Referral Hospital from November, 1/2016 up to November, 30/2019. Data were collected using a structured questionnaire by trained data collectors. The collected data was checked for its completeness and entered into epidata version 3.1 then exported to SPSS version 26 for cleaning and analysis. The odds ratio along with 95%CI was estimated to measure the strength of the association. Statistical significance was declared at p-value < 0.05.

Result:

258 cases were included in this study. From these, 223 (86.4%) cases have favorable surgical management outcomes of intestinal obstruction. Of 35 cases with unfavorable outcome, the most common postoperative complication occurred was surgical site Infection followed by post-operative pneumonia. A total of 4.7% of postoperative deaths were documented as unfavorable surgical management outcomes. Fever, length of illness, comorbidity, intraoperative bowel condition, bowel resection was done and length of hospital stay after operation were independent significantly associated factors with the surgical management outcome of intestinal obstruction.

Conclusion:

The unfavorable management outcome of patients with IO who treated surgically at the study area was high. Assessing co-morbidity, fluid resuscitation, administration of prophylactic antibiotics before operation and properly applying infection prevention protocol are some of the activities that need emphasis in intestinal obstruction management.

Highlights
Coopetition
Authors: Zhu Ling
Published: May 2021

Public service innovation, defined as the adoption of new technology and methods of service delivery, is at the heart of public management research. Scholars have long studied public and private sector innovation as distinctive phenomena, arguing that private sector innovation aims to increase firms' competitive advantage, while public sector innovation purports to improve governance and performance. The public-private dichotomy overlooks the complex way how organizations interact with each other for service delivery. Public services are increasingly delivered through the web of collaborative networks, in which organizations compete and cooperate simultaneously. This Element explores how coopetition, namely the simultaneous presence of competition and collaboration, shapes innovation in the health care sector. Analyzing panel data of 4,000+ American hospitals from 2008 to 2017, this Element finds evidence that coopetition catalyzes the technology and service process innovation and offers practical implications on managing innovation in competitive environments.
On sofic approximations of
Authors: IOANA ADRIAN
Published: May 2021

We construct a sofic approximation of

${\mathbb F}_2\times {\mathbb F}_2$
that is not essentially a ‘branched cover’ of a sofic approximation by homomorphisms. This answers a question of L. Bowen.
Topological and geometric hyperbolicity criteria for polynomial automorphisms of
Authors: BEDFORD ERIC , DUJARDIN ROMAIN
Published: May 2021

We prove that uniform hyperbolicity is invariant under topological conjugacy for dissipative polynomial automorphisms of

$\mathbb {C}^2$
. Along the way we also show that a sufficient condition for hyperbolicity is that local stable and unstable manifolds of saddle points have uniform geometry.
A characterization of a map whose inverse limit is an arc
Authors: GREENWOOD SINA , ŠTIMAC SONJA
Published: May 2021

For a continuous function
$f:[0,1] \to [0,1]$
we define a splitting sequence admitted by f and show that the inverse limit of f is an arc if and only if f does not admit a splitting sequence.
The peri-urban leopards of Kathmandu: assessing determinants of presence and predation on domestic animals
Authors: Bista Ashish , Chanchani Pranav , Subedi Naresh , Bajracharya Siddhartha B.
Published: May 2021

The conservation of large carnivores in human-dominated landscapes needs to be reconciled with the safety of humans and domestic animals. This is especially true for the leopard Panthera pardus, which occurs extensively in agricultural landscapes and remnant forest tracts embedded within peri-urban areas such as Kathmandu district in Nepal. We carried out interviews in 321 households in this district to determine the extent of leopard habitat use and predation on domestic animals (dogs and goats) during October 2015–April 2016. We used multi-state occupancy models, and estimated probabilities of leopard habitat use (Ψ1) and predation on domestic animals (Ψ2) as a function of covariates, while accounting for imperfect detection. Our findings indicate that the rapidly urbanizing outskirts of Kathmandu city are used extensively by leopards. The estimated probability of fine-scale habitat use in 2 km2 sample units was 0.96 ± SE 0.05 and the probability of predation on domestic animals was 0.76 ± SE 0.15. Leopard attacks occurred in areas with high vegetation cover and abundant goats. Addressing the problem of leopard attacks on domestic animals will require developing a comprehensive mitigation plan that includes educational activities to raise awareness, measures to address grievances of affected local communities, interventions to prevent attacks on livestock, compensation programmes, and rapid response teams to ensure human and animal welfare in conflict-prone areas. Land-use planning in these peri-urban landscapes needs to facilitate the safe sharing of space between people and leopards.
The Martyrdom of Konon (BHG 2077): the construction of a realm of memory
Authors: Pilhofer Philipp
Published: May 2021

This article focuses on a local martyr from a village close to Isaura in the Taurus mountains: Konon of Bidana. The Martyrdom of Konon is a late antique Greek hagiographical text centred on this rural saint, and, in particular, its inter-connection of space and time is analysed. Through the employment of this literary strategy, the region around Bidana is used as a backdrop to a realm of memory. The epigraphical and archaeological remains show that the regional population respected Konon as their local patron.
FREEDOM OF THOUGHT
Authors: Schmidtz David
Published: May 2021

This essay introduces basic issues that make up the topic of freedom of thought, including newly emerging issues raised by the current proliferation of Internet search algorithms.
IN PRAISE OF EVIL THOUGHTS
Authors: Koppelman Andrew
Published: May 2021

Freedom of thought means freedom from social tyranny, the capacity to think for oneself, to encounter even shocking ideas without shrinking away from them. That aspiration is a core concern of the free speech tradition. It is not specifically concerned with law, but it explains some familiar aspects of the First Amendment law we actually have—aspects that the most prevalent theories of free speech fail to capture. It explains the prohibition of compelled speech, and can clarify the perennial puzzle of why freedom of speech extends to art and literature. It also tells us something about the limits of legal regulation, and about the ethical obligations of private actors.
THE NONRANDOM WALK OF KNOWLEDGE
Authors: Bambauer Jane R. , Masconale Saura , Sepe Simone M.
Published: May 2021

A person’s epistemic goals sometimes clash with pragmatic ones. At times, rational agents will degrade the quality of their epistemic process in order to satisfy a goal that is knowledge-independent (for example, to gain status or at least keep the peace with friends.) This is particularly so when the epistemic quest concerns an abstract political or economic theory, where evidence is likely to be softer and open to interpretation. Before wide-scale adoption of the Internet, people sought out or stumbled upon evidence related to a proposition in a more random way. And it was difficult to aggregate the evidence of friends and other similar people to the exclusion of others, even if one had wanted to. Today, by contrast, the searchable Internet allows people to simultaneously pursue social and epistemic goals.

This essay shows that the selection effect caused by a merging of social and epistemic activities will cause both polarization in beliefs and devaluation of expert testimony. This will occur even if agents are rational Bayesians and have moderate credences before talking to their peers. What appears to be rampant dogmatism could be just as well explained by the nonrandom walk in evidence-gathering. This explanation better matches the empirical evidence on how people behave on social media platforms. It also helps clarify why media outlets (not just the Internet platforms) might have their own pragmatic reasons to compromise their epistemic goals in today’s competitive and polarized information market. Yet, it also makes policy intervention much more difficult, since we are unlikely to neatly separate individuals’ epistemic goals from their social ones.
Diaphragmatic eventration as a first sign of Scimitar syndrome
Authors: Vieira Martins Miguel , Martins Duarte S , Oliveira Graça
Published: May 2021

Diaphragmatic eventration is an anomaly of the diaphragm. In Scimitar syndrome, a curved-shaped anomalous pulmonary venous drainage is seen. Association between these conditions is rare. We present a newborn with diaphragmatic eventration, whose diagnosis of Scimitar syndrome was made after surgical repair. Scimitar syndrome is a congenital disorder often associated with other heart and lungs anomalies. Diagnosis can be fortuitous but with important prognostic features.
No More Strategical Neutrality on Technological Neutrality: Technological Neutrality as a Bridge Between the Analogue Trading Regime and Digital Trade
Authors: Kwak Dongchul
Published: May 2021

The World Trade Organization (WTO), a unique multilateral trading regime, has failed to establish its relevance to the digital nature of trade. This article revisits the ‘principle of technological neutrality’ to make the cross-border supply of services by electronic means subject to the current rules-based trading regime. I argue that the principle of technological neutrality could help resolve a number of thorny legal issues: confirming the applicability of the General Agreement on Trade in Services (GATS) rules to the delivery of services by electronic means; providing a guideline to determine the likeness of services in the era of digital trade; and backing up an evolutionary approach to interpreting the GATS schedules of commitments. However, the WTO adjudicatory bodies have been reluctant to rely on the principle of technological neutrality, which is referred to as strategic neutrality in this article. This article urges the WTO adjudicatory bodies to abandon their strategically neutral position on technological neutrality immediately. It also explores ways to incorporate the principle of technological neutrality into the world trading system at the bilateral, plurilateral, and multilateral levels.
End-of-life decision making in critical illness: Perspectives of Asian parents
Authors: Fu Kristy Xinghan , Chiong Yee Keow , Ngiam Nicola
Published: May 2021

Objective

To explore parents’ perspectives regarding end-of-life (EOL) decisions, factors and possible barriers that influence the EOL decision making process, and to understand parental preferences for communication about EOL care in an Asian population.

Method

A prospective questionnaire cohort study conducted in a university-based tertiary care hospital. 30 parents of children who had been admitted to general pediatric wards for acute ailments and/or were being followed up in general pediatric outpatient clinics after inpatient admissions or emergency department visits completed 30 interviewer-administered questionnaires. With the first 10 completed questionnaires, we sought feedback on the design of the four case vignettes and related questions. Responses to specific questions related to each case vignette were rated on a Likert scale.

Results

The majority of parents were able to comprehend and identify with the issues in the case vignettes, which allowed them to respond appropriately. Parents tended to avoid active withdrawal or withholding of life-sustaining treatment. The top three priorities for parents making EOL decisions for their children were: the chance of improvement, the presence of pain or discomfort, and information provided by healthcare staff. Parents reported that they would prefer to know immediately if their child is at risk of dying; they also preferred to get as much information as possible from the healthcare team and thought that meeting with the healthcare team before making EOL decisions was pivotal.

Significance of results

Parents place highest priorities on their child's likelihood of improvement, perception of their child's pain, and information provided by healthcare professionals in making EOL decisions.
Urban Forests as Main Regulator of the Evaporative Cooling Effect in Cities
Authors: Paschalis Athanasios , Chakraborty TC , Fatichi Simone , Meili Naika , Manoli Gabriele
Published: May 2021

Higher temperatures in urban areas expose a large fraction of the human population to potentially dangerous heat stress. Green spaces are promoted worldwide as local and city‐scale cooling strategies but the amount, type, and functioning of vegetation in cities lack quantification and their interaction with urban climate in different settings remains a matter of debate. Here we use state‐of‐the‐art remote sensing data from 145 city clusters to disentangle the drivers of surface urban heat islands (SUHI) intensity and quantify urban‐rural differences in vegetation cover, species composition, and evaporative cooling. We show that nighttime SUHIs are affected mostly by abiotic factors, while daytime SUHIs are highly correlated with vegetation characteristics and the wetness of the background climate. Magnitude and seasonality of daytime SUHIs are controlled by urban‐rural differences in plant transpiration and leaf area, which explain the dependence of SUHIs on wetness conditions. Leaf area differences are caused primarily by changes in vegetation type and a loss of in‐city forested areas, highlighting the importance of maintaining “natural reserves” as a sustainable heat mitigation policy.
Rapid Reduction of pH and CaCO3 Saturation State in the Tsugaru Strait by the Intensified Tsugaru Warm Current During 2012–2019
Authors: Wakita M. , Sasaki K. , Nagano A. , Abe H. , Tanaka T. , Nagano K. , Sugie K. , Kaneko H. , Kimoto K. , Okunishi T. , Takada M. , Yoshino J. , Watanabe S.
Published: May 2021

To examine the ocean acidification of coastal water as the result of the oceanic uptake of anthropogenic atmospheric CO2, we initiated acidification monitoring in the eastern part of the Tsugaru Strait, through which the Tsugaru Warm Current flows eastward from the Sea of Japan to the North Pacific. Annual mean pH and CaCO3 saturation state during 2012–2019 decreased considerably throughout all depths at rates of 0.0030–0.0051 and 0.017–0.036 years−1, respectively. These rates of decrease are faster than those caused by increasing atmospheric CO2 and faster than those observed during previous research. These fast rates are attributed to an enhanced increase in dissolved inorganic carbon concurrently with increases in salinity and density caused by elevated mixing of the upper and deeper waters from the Sea of Japan at the western part of the strait. The elevated mixing is attributable to the strengthening of the Tsugaru Warm Current.
Fast and Localized Temperature Measurements During Simulated Earthquakes in Carbonate Rocks
Authors: Aretusini Stefano , Núñez‐Cascajero Arántzazu , Spagnuolo Elena , Tapetado Alberto , Vázquez Carmen , Di Toro Giulio
Published: May 2021

The understanding of earthquake physics is hindered by the poor knowledge of fault strength and temperature evolution during seismic slip. Experiments reproducing seismic velocity (∼1 m/s) allow us to measure both the evolution of fault strength and the associated temperature increase due to frictional heating. However, temperature measurements were performed with techniques having insufficient spatial and temporal resolution. Here we conduct high velocity friction experiments on Carrara marble rock samples sheared at 20 MPa normal stress, velocity of 0.3 and 6 m/s, and 20 m of total displacement. We measured the temperature evolution of the fault surface at the acquisition rate of 1 kHz and over a spatial resolution of ∼40 µm with an optical fiber conveying the infrared radiation to a two‐color pyrometer. Temperatures up to 1,250°C and low coseismic fault shear strength are compatible with the activation of grain size dependent viscous creep.
Underestimated MJO Variability in CMIP6 Models
Authors: Le Phong V. V. , Guilloteau Clément , Mamalakis Antonios , Foufoula‐Georgiou Efi
Published: May 2021

The Madden‐Julian Oscillation (MJO) is the leading mode of intraseasonal climate variability, having profound impacts on a wide range of weather and climate phenomena. Here, we use a wavelet‐based spectral Principal Component Analysis (wsPCA) to evaluate the skill of 20 state‐of‐the‐art CMIP6 models in capturing the magnitude and dynamics of the MJO. By construction, wsPCA has the ability to focus on desired frequencies and capture each propagative physical mode with one principal component (PC). We show that the MJO contribution to the total intraseasonal climate variability is substantially underestimated in most CMIP6 models. The joint distribution of the modulus and angular frequency of the wavelet PC series associated with MJO is used to rank models relatively to the observations through the Wasserstein distance. Using Hovmöller phase‐longitude diagrams, we also show that precipitation variability associated with MJO is underestimated in most CMIP6 models for the Amazonia, Southwest Africa, and Maritime Continent.
Preliminary Analysis of Source Physics Experiment Explosion‐Triggered Microseismicity Using the Back‐Projection Method
Authors: Ichinose G. A. , Ford S. R. , Kroll K. , Dodge D. , Pyle M. , Pitarka A. , Walter W. R.
Published: May 2021

A series of four chemical explosions were detonated in a deep borehole within the Yucca Flat Dry Alluvium Geology (DAG) at the Nevada National Security Site between 2018 and 2019. The two larger chemical explosions of 50 tons (DAG‐2) and 10 tons (DAG‐4) TNT equivalent yield triggered energetic aftershock sequences numbering 1392 and 347 microearthquakes, respectively, within the first 10 days. No significant aftershock activity was observed for the two smaller 1‐ton explosions (DAG‐1 and DAG‐3). We used a back‐projection method based on travel‐time migration and stacking of signal‐to‐noise ratio traces to detect, associate and locate aftershocks from a subset of 22‐geophones within a larger 2  2 km seismic array surrounding the borehole. The aftershocks located within 300 m of the borehole and the depths were above the working points of 300 and 50 m depths of DAG‐2 and DAG‐4, respectively, ruling out triggering slip on geologic faults or disturbances beneath neighboring collapse craters. DAG‐2 and DAG‐4 aftershocks decayed at similar rates, with power‐law exponents of p = 1.48 and p = 1.49, respectively. These decay rates are comparable to aftershocks sequences triggered by earthquakes and historical nuclear explosions at Yucca Flat. A smooth power‐law aftershock decay within the first 10 days suggests a triggering mechanism from explosion generated stress relaxation due to the diffusion of high gas pressures in the cavity and radial fractures. A more random and episodic aftershock rate would be expected due to cavity collapse or falling rubble in chimney formation.
Diffusivity and Solubility of H2 in Ice Ih: Implications for the Behavior of H2 in Polar Ice
Authors: Patterson John D. , Saltzman Eric S.
Published: May 2021

Reconstructions of paleoatmospheric H2 using polar firn air and ice cores would lead to a better understanding of the H2 biogeochemical cycle and how it is influenced by climate change and human activity. In this study, the permeability, diffusivity, and solubility of H2 are determined experimentally in ice Ih at temperatures relevant to polar ice sheets (199–253 K). The experimental data are used in conjunction with simplified diffusion models to assess the implications for: (a) Diffusion of H2 from pressurized closed bubbles to open pores in polar firn, (b) diffusive smoothing of H2 gradients in the ice sheet, and (c) post‐coring diffusive losses of H2 from ice core samples. The results indicate that diffusive equilibrium between open and closed pores is likely achieved in the firn lock‐in zone. Diffusive smoothing of atmospheric variations is significant and should be accounted for in atmospheric reconstructions on millennial time scales. Diffusive losses from a bubbly ice sample are sufficiently slow that samples may be meaningfully analyzed for H2 after storage on the order of a year. These results suggest that the mobility of H2 in ice should not preclude the reconstruction of paleoatmospheric H2 from firn air and ice cores.
Observations of Lightning NOx Production From Tropospheric Monitoring Instrument Case Studies Over the United States
Authors: Allen Dale , Pickering Kenneth E. , Bucsela Eric , Van Geffen Jos , Lapierre Jeff , Koshak William , Eskes Henk
Published: May 2021

Nitrogen oxides produced by lightning (LNOx) play an important role in determining mid‐ and upper‐tropospheric concentrations of the hydroxyl radical (OH), methane (CH4), and ozone (O3). The moles of NOx produced per flash was examined using nitrogen dioxide (NO2) columns and cloud properties from the Tropospheric Monitoring Instrument (TROPOMI) and flash counts from the Geostationary Lightning Mapper (GLM) aboard the Geostationary Operational Environmental Satellite‐16 (GOES‐16) and Earth Networks Total Lightning Network (ENTLN) for 29 convective systems over the United States that occurred during 2018 and 2019. For each of the case studies, the LNOx production efficiency (PE) was estimated using TROPOMI pixels over deep convection. First, the NOx columns associated with the TROPOMI NO2 columns were estimated using a specially derived air mass factor (AMF). The tropospheric column due to recent lightning was then determined by subtracting from the median NOx column a background representative of the NOx column due to sources other than recent lightning. Then, the PE was calculated by multiplying the LNOx column by the storm area and dividing by the number of flashes contributing to the column. For a three‐hour chemical lifetime, the mean PE was found to be 175 ± 100 mol per flash for optical flashes from GLM and 120 ± 65 mol per flash for radio‐wave‐detected flashes from ENTLN. The uncertainty associated with these values is mostly due to uncertainties in tropospheric background, AMF, and detection efficiency. GLM PE for individual systems was found to be positively correlated with optical energy.
Years After the Pacific Marine Heat Wave, Ecosystem Shifts Persist
Authors: Thomasy Hannah
Published: May 2021

Researchers question whether Gulf of Alaska species will return to pre–heat wave conditions.
US COVID‐19 Shutdown Demonstrates Importance of Background NO2 in Inferring NOx Emissions From Satellite NO2 Observations
Authors: Qu Zhen , Jacob Daniel J. , Silvern Rachel F. , Shah Viral , Campbell Patrick C. , Valin Lukas C. , Murray Lee T.
Published: May 2021

Satellite nitrogen dioxide (NO2) measurements are used extensively to infer nitrogen oxide emissions and their trends, but interpretation can be complicated by background contributions to the NO2 column sensed from space. We use the step decrease of US anthropogenic emissions from the COVID‐19 shutdown to compare the responses of NO2 concentrations observed at surface network sites and from satellites (Ozone Monitoring Instrument [OMI], Tropospheric Ozone Monitoring Instrument [TROPOMI]). After correcting for differences in meteorology, surface NO2 measurements for 2020 show decreases of 20% in March–April and 10% in May–August compared to 2019. The satellites show much weaker responses in March–June and no decrease in July–August, consistent with a large background contribution to the NO2 column. Inspection of the long‐term OMI trend over remote US regions shows a rising summertime NO2 background from 2010 to 2019 potentially attributable to wildfires.
Mineral Magnetic Characterization of High‐Latitude Sediments From Lake Levinson‐Lessing, Siberia
Authors: Scheidt Stephanie , Egli Ramon , Lenz Matthias , Rolf Christian , Fabian Karl , Melles Martin
Published: May 2021

Levinson‐Lessing Lake in northern Central Siberia is a sedimentary archive characterized by continuous, widely constant sedimentation at high rates (0.7 m ka−1 for >32 ka). This study provides the first evidence of the suitability of the lake′s sediments for paleomagnetic analyses using the 46‐m‐long core Co1401. Although the lowermost 8 m are disturbed, the upper 38 m of Co1401 provide the preconditions for an exceptional, high‐resolution paleomagnetic record located within the tangent cylinder of the inner core. High‐resolution analyses of magnetic susceptibility, anhysteretic remanent magnetization, isothermal remanent magnetization, and hysteresis parameters show largely uniform mineral magnetic properties. First‐order reversal curves indicate magnetite particles in pseudo‐single domain state are the main remanence carrier, supplemented by single‐domain particles, originating likely from magnetotactic bacteria. Above 6.7 m, the bulk magnetic mineralogy is slightly harder than below and initial greigite formation occurs. However, the main remanence carriers are still of detrital origin.
Seismic Diffusivity and the Influence of Heterogeneity on Injection‐Induced Seismicity
Authors: Haagenson Ryan , Rajaram Harihar
Published: May 2021

The spatiotemporal patterns of injection‐induced seismicity (IIS) are commonly interpreted with the concept of a triggering front, which propagates in a diffusion‐like manner with an associated diffusivity parameter. Here, we refer to this diffusivity as the “seismic diffusivity.” Several previous studies implicitly assume that seismic diffusivity is equivalent to the effective hydraulic diffusivity of the subsurface, which describes the behavior of the mean pressure field in heterogeneous porous media. Seismicity‐based approaches for hydraulic characterization or simulations of IIS using domains of homogeneous equivalent porous media are implicitly based on this assumed equivalence. However, seismicity is expected to propagate with the threshold triggering pressure, and thus not be controlled by the evolution of the mean pressure field. We present numerical simulations of fluid injection to compare the seismic and effective hydraulic diffusivities in heterogeneous formations (including fractured rock). The numerical model combines uncoupled, linear pressure diffusion with the Mohr‐Coulomb failure criterion to simulate IIS. We demonstrate that connected pathways of relatively high hydraulic diffusivity in heterogeneous media (particularly in fractured rock domains) allow the threshold triggering pressure to propagate more rapidly than predicted by the effective hydraulic diffusivity. As a result, the seismic diffusivity is greater than the effective hydraulic diffusivity in heterogeneous porous media, possibly by an order of magnitude or more. Additionally, we present a case study of IIS near Soultz‐sous‐Forêts where seismic diffusivity is found to be at least one order of magnitude larger than the effective hydraulic diffusivity.
ST6Gal1 targets the ectodomain of ErbB2 in a site-specific manner and regulates gastric cancer cell sensitivity to trastuzumab
Authors: Duarte Henrique O. , Rodrigues Joana G. , Gomes Catarina , Hensbergen Paul J. , Ederveen Agnes L. Hipgrave , de Ru Arnoud H. , Mereiter Stefan , Polónia António , Fernandes Elisabete , Ferreira José A. , van Veelen Peter A. , Santos Lúcio L. , Wuhrer Manfred , Gomes Joana , Reis Celso A.
Published: May 2021

The clinical performance of the therapeutic monoclonal antibody trastuzumab in the treatment of ErbB2-positive unresectable gastric cancer (GC) is severely hampered by the emergence of molecular resistance. Trastuzumab’s target epitope is localized within the extracellular domain of the oncogenic cell surface receptor tyrosine kinase (RTK) ErbB2, which is known to undergo extensive N-linked glycosylation. However, the site-specific glycan repertoire of ErbB2, as well as the detailed molecular mechanisms through which specific aberrant glycan signatures functionally impact the malignant features of ErbB2-addicted GC cells, including the acquisition of trastuzumab resistance, remain elusive. Here, we demonstrate that ErbB2 is modified with both α2,6- and α2,3-sialylated glycan structures in GC clinical specimens. In-depth mass spectrometry-based glycomic and glycoproteomic analysis of ErbB2’s ectodomain disclosed a site-specific glycosylation profile in GC cells, in which the ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites occurring within the receptor’s trastuzumab-binding domain. Abrogation of ST6Gal1 expression reshaped the cellular and ErbB2-specific glycomes, expanded the cellular half-life of the ErbB2 receptor, and sensitized ErbB2-dependent GC cells to trastuzumab-induced cytotoxicity through the stabilization of ErbB dimers at the cell membrane, and the decreased activation of both ErbB2 and EGFR RTKs. Overall, our data demonstrates that ST6Gal1-mediated aberrant α2,6-sialylation actively tunes the resistance of ErbB2-driven GC cells to trastuzumab.
LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance
Authors: Billing Ola , Holmgren Ylva , Nosek Daniel , Hedman Håkan , Hemmingsson Oskar
Published: May 2021

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma.
YWHAE-NUTM2 oncoprotein regulates proliferation and cyclin D1 via RAF/MAPK and Hippo pathways
Authors: Ou Wen-Bin , Lundberg Meijun Z. , Zhu Shuihao , Bahri Nacef , Kyriazoglou Anastasios , Xu Liangliang , Chen Ting , Mariño-Enriquez Adrian , Fletcher Jonathan A.
Published: May 2021

Endometrial stromal sarcoma (ESS) is the second most common subtype of uterine mesenchymal cancer, after leiomyosarcoma, and oncogenic fusion proteins are found in many ESS. Our previous studies demonstrated transforming properties and diagnostic relevance of the fusion oncoprotein YWHAE–NUTM2 in high-grade endometrial stromal sarcoma (HG-ESS) and showed that cyclin D1 is a diagnostic biomarker in these HG-ESS. However, YWHAE–NUTM2 mechanisms of oncogenesis and roles in cyclin D1 expression have not been characterized. In the current studies, we show YWHAE-NUTM2 complexes with both BRAF/RAF1 and YAP/TAZ in HG-ESS. These interactions are functionally relevant because YWHAE-NUTM2 knockdown in HG-ESS and other models inhibits RAF/MEK/MAPK phosphorylation, cyclin D1 expression, and cell proliferation. Further, cyclin D1 knockdown in HG-ESS dephosphorylates RB1 and inhibits proliferation. In keeping with these findings, we show that MEK and CDK4/6 inhibitors have anti-proliferative effects in HG-ESS, and combinations of these inhibitors have synergistic activity. These findings establish that YWHAE-NUTM2 regulates cyclin D1 expression and cell proliferation by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling pathways. Recent studies demonstrate Hippo/YAP-TAZ pathway aberrations in many sarcomas, but this is among the first studies to demonstrate a well-defined oncogenic mechanism as the cause of Hippo pathway dysregulation.
Moderation of the transgenerational transference of antenatal stress-induced anxiety
Authors: Burstein Or , Simon Noam , Simchon-Tenenbaum Yaarit , Rehavi Moshe , Franko Motty , Shamir Alon , Doron Ravid
Published: May 2021

Maternal stress has debilitating implications for both mother and child, including increased risk for anxiety. The current COVID-19 pandemic escalates these phenomena, thus, urging the need to further explore and validate feasible therapeutic options. Unlike the protracted nature of clinical studies, animal models could offer swift evidence. Prominent candidates for treatment are selective serotonin reuptake inhibitors (SSRIs) to the mother, that putatively accommodate maternal functioning, and, thereby, also protect the child. However, SSRIs might have deleterious effects. It is important to assess whether SSRIs and other pharmacotherapies can moderate the transference of anxiety by soothing maternal anxiety and to examine the extent of offspring’s exposure to the drugs via lactation. To our knowledge, the possibility that antenatal stress exacerbates lactation-driven exposure to SSRIs has not been tested yet. Thirty ICR-outbred female mice were exposed to stress during gestation and subsequently administered with either the SSRI, escitalopram, or the novel herbal candidate, shan-zha, during lactation. Upon weaning, both dams’ and pups’ anxiety-like behavior and serum escitalopram levels were assessed. The major findings of the current study show that both agents moderated the antenatal stress-induced transgenerational transference of anxiety by ameliorating dams’ anxiety. Interestingly though, pups’ exposure to escitalopram via lactation was exacerbated by antenatal stress. The latter finding provides a significant insight into the mechanism of lactation-driven exposure to xenobiotics and calls for a further consideration vis-à-vis the administration of other drugs during breastfeeding.
The role of the orbitofrontal cortex and the nucleus accumbens for craving in alcohol use disorder
Authors: Bracht Tobias , Soravia Leila , Moggi Franz , Stein Maria , Grieder Matthias , Federspiel Andrea , Tschümperlin Raphaela , Batschelet Hallie M. , Wiest Roland , Denier Niklaus
Published: May 2021

This study aimed to investigate structural and functional alterations of the reward system and the neurobiology of craving in alcohol use disorder (AUD). We hypothesized reduced volume of the nucleus accumbens (NAcc), reduced structural connectivity of the segment of the supero-lateral medial forebrain bundle connecting the orbitofrontal cortex (OFC) with the NAcc (OFC-NAcc), and reduced resting-state OFC-NAcc functional connectivity (FC). Furthermore, we hypothesized that craving is related to an increase of OFC-NAcc FC. Thirty-nine recently abstinent patients with AUD and 18 healthy controls (HC) underwent structural (T1w-MP2RAGE, diffusion-weighted imaging (DWI)) and functional (resting-state fMRI) MRI-scans. Gray matter volume of the NAcc, white matter microstructure (fractional anisotropy (FA)) and macrostructure (tract length) of the OFC-NAcc connection and OFC-NAcc FC were compared between AUD and HC using a mixed model MANCOVA controlling for age and gender. Craving was assessed using the thoughts subscale of the obsessive-compulsive drinking scale (OCDS) scale and was correlated with OFC-NAcc FC. There was a significant main effect of group. Results were driven by a volume reduction of bilateral NAcc, reduced FA in the left hemisphere, and reduced tract length of bilateral OFC-NAcc connections in AUD patients. OFC-NAcc FC did not differ between groups. Craving was associated with increased bilateral OFC-NAcc FC. In conclusion, reduced volume of the NAcc and reduced FA and tract length of the OFC-NAcc network suggest structural alterations of the reward network in AUD. Increased OFC-NAcc FC is associated with craving in AUD, and may contribute to situational alcohol-seeking behavior in AUD.
Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis
Authors: Zhang Sensen , Yuan Baolei , Lam Jordy Homing , Zhou Jun , Zhou Xuan , Ramos-Mandujano Gerardo , Tian Xueyuan , Liu Yang , Han Renmin , Li Yu , Gao Xin , Li Mo , Yang Maojun
Published: May 2021

Pannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.
Unique reactivity of nanoporous cellulosic materials mediated by surface-confined water
Authors: Beaumont Marco , Jusner Paul , Gierlinger Notburga , King Alistair W. T. , Potthast Antje , Rojas Orlando J. , Rosenau Thomas
Published: May 2021

The remarkable efficiency of chemical reactions is the result of biological evolution, often involving confined water. Meanwhile, developments of bio-inspired systems, which exploit the potential of such water, have been so far rather complex and cumbersome. Here we show that surface-confined water, inherently present in widely abundant and renewable cellulosic fibres can be utilised as nanomedium to endow a singular chemical reactivity. Compared to surface acetylation in the dry state, confined water increases the reaction rate and efficiency by 8 times and 30%, respectively. Moreover, confined water enables control over chemical accessibility of selected hydroxyl groups through the extent of hydration, allowing regioselective reactions, a major challenge in cellulose modification. The reactions mediated by surface-confined water are sustainable and largely outperform those occurring in organic solvents in terms of efficiency and environmental compatibility. Our results demonstrate the unexploited potential of water bound to cellulosic nanostructures in surface esterifications, which can be extended to a wide range of other nanoporous polymeric structures and reactions.
Bandwidth-control orbital-selective delocalization of 4f electrons in epitaxial Ce films
Authors: Wu Yi , Fang Yuan , Li Peng , Xiao Zhiguang , Zheng Hao , Yuan Huiqiu , Cao Chao , Yang Yi-feng , Liu Yang
Published: May 2021

The 4f-electron delocalization plays a key role in the low-temperature properties of rare-earth metals and intermetallics, and it is normally realized by the Kondo coupling between 4f and conduction electrons. Due to the large Coulomb repulsion of 4f electrons, the bandwidth-control Mott-type delocalization, commonly observed in d-electron systems, is difficult in 4f-electron systems and remains elusive in spectroscopic experiments. Here we demonstrate that the bandwidth-control orbital-selective delocalization of 4f electrons can be realized in epitaxial Ce films by thermal annealing, which results in a metastable surface phase with reduced layer spacing. The quasiparticle bands exhibit large dispersion with exclusive 4f character near $$\bar{{{\Gamma }}}$$

Γ

¯

and extend reasonably far below the Fermi energy, which can be explained from the Mott physics. The experimental quasiparticle dispersion agrees well with density-functional theory calculation and also exhibits unusual temperature dependence, which could arise from the delicate interplay between the bandwidth-control Mott physics and the coexisting Kondo hybridization. Our work opens up the opportunity to study the interaction between two well-known localization-delocalization mechanisms in correlation physics, i.e., Kondo vs Mott, which can be important for a fundamental understanding of 4f-electron systems.
Intrinsic functional neuron-type selectivity of transcranial focused ultrasound neuromodulation
Authors: Yu Kai , Niu Xiaodan , Krook-Magnuson Esther , He Bin
Published: May 2021

Transcranial focused ultrasound (tFUS) is a promising neuromodulation technique, but its mechanisms remain unclear. We hypothesize that if tFUS parameters exhibit distinct modulation effects in different neuron populations, then the mechanism can be understood through identifying unique features in these neuron populations. In this work, we investigate the effect of tFUS stimulation on different functional neuron types in in vivo anesthetized rodent brains. Single neuron recordings were separated into regular-spiking and fast-spiking units based on their extracellular spike shapes acquired through intracranial electrophysiological recordings, and further validated in transgenic optogenetic mice models of light-excitable excitatory and inhibitory neurons. We show that excitatory and inhibitory neurons are intrinsically different in response to ultrasound pulse repetition frequency (PRF). The results suggest that we can preferentially target specific neuron types noninvasively by tuning the tFUS PRF. Chemically deafened rats and genetically deafened mice were further tested for validating the directly local neural effects induced by tFUS without potential auditory confounds.
Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection
Authors: Diao Bo , Wang Chenhui , Wang Rongshuai , Feng Zeqing , Zhang Ji , Yang Han , Tan Yingjun , Wang Huiming , Wang Changsong , Liu Liang , Liu Ying , Liu Yueping , Wang Gang , Yuan Zilin , Hou Xiaotao , Ren Liang , Wu Yuzhang , Chen Yongwen
Published: May 2021

It is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly infect human kidney, thus leading to acute kidney injury (AKI). Here, we perform a retrospective analysis of clinical parameters from 85 patients with laboratory-confirmed coronavirus disease 2019 (COVID-19); moreover, kidney histopathology from six additional COVID-19 patients with post-mortem examinations was performed. We find that 27% (23/85) of patients exhibited AKI. The elderly patients and cases with comorbidities (hypertension and heart failure) are more prone to develop AKI. Haematoxylin & eosin staining shows that the kidneys from COVID-19 autopsies have moderate to severe tubular damage. In situ hybridization assays illustrate that viral RNA accumulates in tubules. Immunohistochemistry shows nucleocapsid and spike protein deposits in the tubules, and immunofluorescence double staining shows that both antigens are restricted to the angiotensin converting enzyme-II-positive tubules. SARS-CoV-2 infection triggers the expression of hypoxic damage-associated molecules, including DP2 and prostaglandin D synthase in infected tubules. Moreover, it enhances CD68+ macrophages infiltration into the tubulointerstitium, and complement C5b-9 deposition on tubules is also observed. These results suggest that SARS-CoV-2 directly infects human kidney to mediate tubular pathogenesis and AKI.
Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures
Authors: Franciosa Giulia , Smits Jos G. A. , Minuzzo Sonia , Martinez-Val Ana , Indraccolo Stefano , Olsen Jesper V.
Published: May 2021

Notch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.