bluuebunny/crossref_metadata_2025 huggingface dataset:
Levothyroxine treatment and gastric juice pH in humans: the proof of concept
Authors: Virili Camilla , Bruno Giovanni , Santaguida Maria Giulia , Gargano Lucilla , Stramazzo Ilaria , De Vito Corrado , Cicenia Alessia , Scalese Giulia , Porowska Barbara , Severi Carola , Centanni Marco
Published: April 2022

Purpose

Despite the absorption of oral thyroxine (T4) occurs in the small bowel, several patients with gastric disorders show an increased need for T4. In vitro evidence suggested that medium pH variations interfere with T4 dissolution. This study was aimed at finding the proof of concept of a direct relationship between the minimal effective dose of T4 and the actual gastric juice pH.

Patients and methods

Among 311 consecutively thyroxine-treated patients, 61 bearing Hashimoto’s thyroiditis (52 F/9 M; median age = 51 years) who complained persistent dyspepsia and/or upper abdominal symptoms following a noninvasive workup for gastrointestinal disorders, underwent EGDS with multiple biopsies and gastric juice pH measurement. All patients accepted to take thyroxine in fasting conditions, abstaining from eating or drinking for one hour.

Results

Thyroxine requirement increased along with the rising gastric pH (ρ = 0.4229; p = 0.0007). A multivariate analysis revealed that gastric pH was, beside body mass index, the far more important independent variable in determining the effective dose of T4 (p = 0.001). The ROC curve revealed that the pH threshold for an increased thyroxine requirement was at 2.28, being the AUC by 78%. Subdividing patients by the histologic findings, it appeared a significant increase (p = 0.0025) along with the progressive damage of gastric mucosa.

Conclusion

The in vivo measurement of gastric pH highlighted its key role in determining the minimal effective dose of oral T4 and may explain the interference of food, of some drugs and gut disorders on levothyroxine treatment
On control measures of multimeasures
Authors: Rodríguez José
Published: April 2022

Let M be a multimeasure defined on a $$\sigma $$
σ
-algebra and taking values in the family of bounded non-empty subsets of a Banach space X. We prove that M admits a control measure whenever X contains no subspace isomorphic to $$c_0(\omega _1)$$

c
0

(

ω
1

)

. The additional assumption on X is shown to be essential.
A new method for image processing using generalized linguistic neutrosophic cubic aggregation operator
Authors: Kaur Gagandeep , Garg Harish
Published: April 2022

Image processing is a technique of scrutinizing an image and extricating important information. Indecisive situations are generally undergone when the picture processes with profuse noise. Neutrosophic set (NS), a part of neutrosophy theory, studies the scope of neutralities and is essential to reasoning with incomplete and uncertain information. However, the linguistic neutrosophic cubic set (LNCS) is one of the extensions of the NS. In LNCS, each element is characterized by the interval-valued and single-valued neutrosophic numbers to handle the data uncertainties. Keeping these features in mind, we apply LNCS for image processing after defining their aggregation operators and operations. In this study, noisy grey-scale images were transformed into the LNCS domain using three membership degrees, then aggregated using aggregation operators. The proposed method clarifies the noise in the Lena image and three other test images. It has justified the utilization of operators based on visual clarity obtained. Suitable comparison analysis and efficiency testing is performed on the proposed theory by considering noise types, such as Gaussian, Poisson, and Speckle. In addition, we have also compared the computational efficiency of our proposed method with existing ones. The results show that our approach consumes less memory and executes quicker than the existing methods. A decision-maker can select a more effective operator to segment the images more effectively using the obtained results.
Impact of Cryopreservation and Freeze-Thawing on Therapeutic Properties of Mesenchymal Stromal/Stem Cells and Other Common Cellular Therapeutics
Authors: Cottle Chasen , Porter Amanda Paige , Lipat Ariel , Turner-Lyles Caitlin , Nguyen Jimmy , Moll Guido , Chinnadurai Raghavan
Published: April 2022

Purpose of Review

Cryopreservation and its associated freezing and thawing procedures–short “freeze-thawing”–are among the final steps in economically viable manufacturing and clinical application of diverse cellular therapeutics. Translation from preclinical proof-of-concept studies to larger clinical trials has indicated that these processes may potentially present an Achilles heel to optimal cell product safety and particularly efficacy in clinical trials and routine use.

Recent Findings

We review the current state of the literature on how cryopreservation of cellular therapies has evolved and how the application of this technique to different cell types is interlinked with their ability to engraft and function upon transfer in vivo, in particular for hematopoietic stem and progenitor cells (HSPCs), their progeny, and therapeutic cell products derived thereof. We also discuss pros and cons how this may differ for non-hematopoietic mesenchymal stromal/stem cell (MSC) therapeutics. We present different avenues that may be crucial for cell therapy optimization, both, for hematopoietic (e.g., effector, regulatory, and chimeric antigen receptor (CAR)-modified T and NK cell based products) and for non-hematopoietic products, such as MSCs and induced pluripotent stem cells (iPSCs), to achieve optimal viability, recovery, effective cell dose, and functionality of the cryorecovered cells.

Summary

Targeted research into optimizing the cryopreservation and freeze-thawing routines and the adjunct manufacturing process design may provide crucial advantages to increase both the safety and efficacy of cellular therapeutics in clinical use and to enable effective market deployment strategies to become economically viable and sustainable medicines.
Bayesian Inference on the Bimodality of the Generalized von Mises Distribution
Authors: Gatto Riccardo , Salvador Sara
Published: April 2022

This article introduces Bayesian inference on the bimodality of the generalized von Mises (GvM) distribution for planar directions (Gatto and Jammalamadaka in Stat Methodol 4(3):341–353, 2007). The GvM distribution is a flexible model that can be axial symmetric or asymmetric, unimodal or bimodal. Two inferential approaches are analysed. The first is the test of null hypothesis of bimodality and Bayes factors are obtained. The second approach provides a two-dimensional highest posterior density (HPD) credible set for two parameters relevant to bimodality. Based on the identification of the two-dimensional parametric region associated with bimodality, the inclusion of the HPD credible set in that region allows us to infer on the bimodality of the underlying GvM distribution. A particular implementation of the Metropolis–Hastings algorithm allows for the computation of the Bayes factors and the HPD credible sets. A Monte Carlo study reveals that, whenever the samples are generated under a bimodal GvM, the Bayes factors and the HPD credible sets do clearly confirm the underlying bimodality.
Deep Optimisation: Transitioning the Scale of Evolutionary Search by Inducing and Searching in Deep Representations
Authors: Caldwell Jamie , Knowles Joshua , Thies Christoph , Kubacki Filip , Watson Richard
Published: April 2022

We investigate the optimisation capabilities of an algorithm inspired by the Evolutionary Transitions in Individuality. In these transitions, the natural evolutionary process is repeatedly rescaled through successive levels of biological organisation. Each transition creates new higher-level evolutionary units that combine multiple units from the level below. We call the algorithm Deep Optimisation (DO) to recognise both its use of deep learning methods and the multi-level rescaling of biological evolutionary processes. The evolutionary model used in DO is a simple hill-climber, but, as higher-level representations are learned, the hill-climbing process is repeatedly rescaled to operate in successively higher-level representations. The transition process is based on a deep learning neural network (NN), specifically a deep auto-encoder. Our experiments with DO start with a study using the NP-hard problem, multiple knapsack (MKP). Comparing with state-of-the-art model-building optimisation algorithms (MBOAs), we show that DO finds better solutions to MKP instances and does so without using a problem-specific repair operator. A second, much more in-depth investigation uses a class of configurable problems to understand more precisely the distinct problem characteristics that DO can solve that other MBOAs cannot. Specifically, we observe a polynomial vs exponential scaling distinction where DO is the only algorithm to show polynomial scaling for all problems. We also demonstrate that some problem characteristics need a deep network in DO. In sum, our findings suggest that the use of deep learning principles have significant untapped potential in combinatorial optimisation. Moreover, we argue that natural evolution could be implementing something like DO, and the evolutionary transitions in individuality are the observable result.
Central-line–associated bloodstream infections and central-line–associated non-CLABSI complications among pediatric oncology patients
Authors: Kelada Aml S. , Foster Timothy B. , Gagliano Gregory C. , Worley Sarah , Tang Anne , Arakoni Venkatraman A. , Foster Charles B.
Published: April 2022

Objective:

To assess central venous catheter (CVC) harm in pediatric oncology patients, we explored risks for central-line–associated bloodstream infections (CLABSIs) and central-line–associated non-CLABSI complications (CLANCs).

Design:

Retrospective cohort study.

Setting:

Midwestern US pediatric oncology program.

Patients:

The study cohort comprised 592 pediatric oncology patients seen between 2006 and 2016.

Methods:

CLABSIs were defined according to Centers for Disease Control and Prevention (CDC)/National Health Safety Network (NHSN) definitions. CLANCs were classified using a novel definition requiring CVC removal. Patient-level and central-line–level risks were calculated using a negative binomial model to adjust for correlations between total events and line numbers.

Results:

CVCs were inserted in 62% of patients, with 175,937 total catheter days. The inpatient CLABSI and CLANC rates were 5.8 and 8.5 times higher than outpatient rates. At the patient level, shared risks included acute myeloid leukemia (AML) and age <1 year at diagnosis. At the line level, shared risks included age <1 year at diagnosis, non-mediports, and >1 lumen. AML was a CLABSI-specific risk. CLANC-specific risks included non–brain-tumor diagnosis, younger age at diagnosis or central-line placement, and age <1 year at diagnosis or line placement. Multivariable risks were for CLABSI >1 lumen and for CLANC age <1 year at placement.

Conclusions:

Among patients with CVCs, CLABSI and CLANC rates were similar, higher among inpatients than outpatients. For both CLABSIs and CLANCs, infants and patients with AML were at higher risk. In both univariate and multivariate models, lines with >1 lumen were associated with CLABSIs and placement during infancy with CLANCs.
Asymptotic theory of a flapping wing of a circular cross-section
Authors: Nuriev Artem N. , Egorov Andrey G.
Published: April 2022

The paper is devoted to the study of the propulsive motion of a flapping wing of a circular cross-section performing translational–rotational oscillations in a viscous incompressible fluid. To describe the flow past the wing, the unsteady Navier–Stokes equation is solved. Using the method of asymptotic expansions for the case of small amplitudes of oscillations, an analytical solution of the problem is constructed in the first two terms. It is shown that the nonlinear interaction of time harmonics of translational and rotational oscillations causes secondary flows (steady streaming) that make the wing move in the direction perpendicular to the axis of translational oscillations. For the case of cruising motion, when the average hydrodynamic force acting on the wing is equal to zero, the dependence of the average speed on the dimensionless oscillation parameters is found. The results show that for relatively large angles of rotation the cruising speed of a flapping wing can be as high as the velocity amplitude of translational oscillations. The limits of applicability of the asymptotic theory are investigated using direct numerical simulations. Numerical data demonstrate that the theory well describes the flow past the wing in a wide range of dimensionless amplitudes, frequencies and angles of rotation. In conclusion, the efficiency of the propulsion system is evaluated. It is shown that in terms of relative energy consumption, a cylindrical flapping wing can be attributed to the most efficient propulsors in the range of Reynolds numbers

$Re \sim 10^2\text {--}10^3$

.
Acoustic emission of a vortex ring near a porous edge. Part 1: theory
Authors: Chen Huansheng , Yoas Zachary W. , Jaworski Justin W. , Krane Michael H.
Published: April 2022

The sound of a vortex ring passing near a semi-infinite porous edge is investigated analytically. A Green's function approach solves the associated vortex sound problem and determines the time-dependent pressure signal and its directivity in the acoustic far field as a function of a single dimensionless porosity parameter. At large values of this parameter, the radiated acoustic power scales on the vortex ring speed

$U$

and the nearest distance between the edge and the vortex ring

$L$

as

$U^6 L^{-5}$

, in contrast to the

$U^5 L^{-4}$

scaling recovered in the impermeable edge limit. Results for the vortex ring configuration in a quiescent fluid furnish an analogue to scaling results from standard turbulence noise generation analyses, and permit a direct comparison to experiments described in Part 2 that circumvent contamination of the weak sound from porous edges by background noise sources that exist as a result of a mean flow.
Urannah
Authors: McCallum Peter
Published: April 2022

Photographer Jeff Tan dropped into the Mackay Environment Centre back in 2015. He had been on an expedition to Urannah Creek, where he had the chance to photograph some delightful landscapes. Jeff showed me one of his photos, evocatively named ‘Urannah_landscapes_24’, which was taken as the sun set over the river. The deep shadows created an eerie, dark scene but, even in the dying light, the colours of the river rocks were easily visible through the clear, fast-flowing water. I wanted to learn more about the place.
The Daintree Blockade
Authors: Wilkie Bill
Published: April 2022

Radio log 11/8/84

D5 crossing creek under Timbertop’s tree ::: continues to fill the creek crossing ::: If he continues to fill it high enough the D10 should go through. Looks like a moonscape where the dozers are working.

Timbertop’s other alias is Gummy, a well-known rainforest warrior of many campaigns. The radio log gives a live blow-by-blow account of the Daintree Blockade, of police heavy-handedness and council bulldozers destroying the fragile ecosystem. The blockade was started in response to Douglas Shire Council building a road through some of the last tropical lowland rainforest in Australia.
'Tourist Fiction'
Authors: Andy Leonard
Published: April 2022

My name is Leonard Andy and I’m a Djiru Traditional Owner of the Mission Beach area.

Where I live today and where my Ancestors have lived is not the same place. Today the Mission Beach area has become a tourism destination and it has changed the people, our culture. Presently, there are twelve Traditional Owners living in the area, off these twelve, five are still at school.
Aquariums and Human–Animal Relations at the Great Barrier Reef
Authors: Elias Ann
Published: April 2022

In the early twentieth century, great delight in the unique tropical beauty of the Great Barrier Reef, coupled with an opportunistic spirit for commercial development, inspired the commission of eye-catching posters and advertisements by Australian tourist organisations. The aim of this article is to discuss a pictorial device that developed alongside the rise of modern tourist advertising images of Great Barrier Reef – a split-level viewpoint that approximates the effect of looking at the Reef through the glass sides of an aquarium. Building on my earlier research published in 2019 on wildlife photography and the construction of the Great Barrier Reef as a modern visual spectacle, and combining art history with environmental history, this article also turns to coloured advertising lithographs. It argues that split-level visualisations separate human from non-human and elevate the idea of human superiority. With the Great Barrier Reef facing unprecedented ecological pressures, the historical images at the centre of this article are instructive for understanding the deleterious effects of anthropogenic impact, as well as early twentieth-century attitudes towards human–non-human relations.
Great Barrier Reef World Heritage
Authors: Pocock Celmara
Published: April 2022

The Great Barrier Reef is inscribed on the World Heritage List for its natural values, including an abundance of marine life and extraordinary aesthetic qualities. These and the enormous scale of the Reef make it unique and a place of ‘Outstanding Universal Value’. In the twentieth century, protection of the Great Barrier Reef shifted from limiting mechanical and physical impacts on coral reefs to managing agricultural runoff from adjacent mainland to minimise environmental impacts. By the early twenty-first century, it was apparent that threats to the Great Barrier Reef were no longer a local issue. Global warming, more frequent extreme weather events and increased ocean temperatures have destroyed vast swathes of coral reefs. Conservation scientists have begun trialling radical new methods of reseeding areas of bleached coral and creating more resilient coral species. The future of the Great Barrier Reef may depend on genetically engineered corals, and reefs that are seeded, weeded and cultured. This article asks whether the Great Barrier Reef can remain a natural World Heritage site or whether it might become World Heritage in Danger as its naturalness is questioned.
CHRONOLOGY OF THE GOLDEN HORDE IN KAZAKHSTAN: 14C DATING OF JOCHI KHAN MAUSOLEUM
Authors: Panyushkina Irina P , Usmanova Emma R , Uskenbay Kanat Z , Kozha Mukhtar B , Dzhumabekov Dzhambul A , Akhatov Gaziz A , Jull A J Timothy
Published: April 2022

We present accelerator mass spectrometry radiocarbon (AMS 14C) dating results of the “Jochi Khan Mausoleum”—the proposed burial place of the oldest son of Gengghis Khan in Ulytau, Kazakhstan. The Ulytau region retains 34 burial complexes of Islamic tradition associated with the Golden Horde history (1221–1438 CE). However, there is no calendar-dated chronology of the medieval mausoleums in this region, which complicates their historical interpretation. Three 14C dates from construction timbers and burial of the Jochi Khan mausoleum are calibrated to 1220–1400 CE interval (95.4% range) with the mid-point at 1245 CE for the coffin, 1330 CE for the entry door, and 1350 CE for a masonry wall. The 14C-calibration suggests that the mausoleum was built about 100 years after the death of Jochi (1225 CE) and renovated at least once in the middle of the 14th century. Apparently, the wood for the coffin was harvested sometime in the interval 1220–1270 CE. The calendar ages of the coffin and the mausoleum are ca. 75 years apart. It is possible that the old coffin was placed into a newly constructed mausoleum. However, there is no historical evidence confirming this important re-burial of Jochi. The dating results challenge the attribution of the mausoleum to Jochi Khan. This study demonstrates that the age of the Islamic mausoleums in Ulytau can be successfully dated with 14C. While requiring further data assembly, this first 14C dataset can form the basis of the calendar chronology of the Golden Horde in Kazakhstan. Historical attribution of the mausoleums must be collaborated with the calendar chronology.
Metabolic adaptation to high-starch diet in largemouth bass (Micropterus salmoides) was associated with the restoration of metabolic functions via inflammation, bile acid synthesis and energy metabolism
Authors: Chen Pei , Zhu Yaping , Wu Xiufeng , Gu Xu , Xue Min , Liang Xiaofang
Published: April 2022

A short-term 2-week (2w) and long-term 8-week (8w) feeding trial was conducted to investigate the effects of low-starch (LS) and high-starch (HS) diets on the growth performance, metabolism and liver health of largemouth bass (Micropterus salmoides). Two isonitrogenous and isolipidic diets containing two levels of starch (LS, 9·06 %; HS, 13·56 %) were fed to largemouth bass. The results indicated that HS diet had no significant effects on specific growth rate during 2w, whereas significantly lowered specific growth rate at 8w. HS diet significantly increased hepatic glycolysis and gluconeogenesis at postprandial 24 h in 2w. The hepatosomatic index, plasma alkaline phosphatase, total bile acid (TBA) levels, and hepatic glycogen, TAG, total cholesterol, TBA, and NEFA contents were significantly increased in the HS group at 2w. Moreover, HS diet up-regulated fatty acid and TAG synthesis-related genes and down-regulated TAG hydrolysis andβ-oxidation-related genes. Therefore, the glucolipid metabolism disorders resulted in metabolic liver disease induced by HS diet at 2w. However, the up-regulation of bile acid synthesis, inflammation and energy metabolism-related genes in 2w indicated that largemouth bass was still in a state of ‘self-repair’ response. Interestingly, all the metabolic parameters were returned to homoeostasis, with up-regulation of intestinal glucose uptake and transport-related genes, even hepatic histopathological analysis showed no obvious abnormality in the HS group in 8w. In conclusion, HS feed induced short-term acute metabolic disorder, but long-term metabolic adaptation to HS diet was related to repairing metabolism disorders via improving inflammatory responses, bile acid synthesis and energy metabolism. These results strongly indicated that the largemouth bass owned certain adaptability to HS diet.
Cardiac features of Noonan syndrome in Japanese patients
Authors: Ichikawa Yasuhiro , Kuroda Hiroyuki , Ikegawa Takeshi , Kawai Shun , Ono Shin , Kim Ki-Sung , Yanagi Sadamitsu , Kurosawa Kenji , Aoki Yoko , Ueda Hideaki
Published: April 2022

Background:

Cardiovascular disease is one of the most important problems in long-term follow-up for Noonan syndrome. We examined cardiovascular issues and clinical manifestations, with a focus on the cardiovascular disease and prognosis of patients with Noonan syndrome.

Methods:

This single-centre study evaluated patients who were clinically and genetically diagnosed with Noonan syndrome.

Results:

Forty-three patients diagnosed with Noonan syndrome were analysed. The most prevalent responsible mutation was found inPTPN11(25/43). The second and third most prevalent causative genes wereSOS1(6/43) and RIT1 (5/43), respectively, and 67.4% of genetically diagnosed patients with Noonan syndrome had structural cardiovascular abnormalities. Pulmonary valve stenosis was prevalent in patients with mutations inPTPN11(8/25),SOS1(4/6), andRIT1(4/5). Hypertrophic cardiomyopathy was found in two of three patients with mutations inRAF1. There was no difference in the cardiovascular events or cardiovascular disease prevalence in patients with or withoutPTPN11mutations. The proportion ofRIT1mutation-positive patients who underwent intervention due to cardiovascular disease was significantly higher than that of patients withPTPN11mutations. Patients who underwent any intervention for pulmonary valve stenosis exhibited significantly higher pulmonary flow velocity than patients who did not undergo intervention, when they visited our hospital for the first time. All patients who underwent intervention for pulmonary valve stenosis had a pulmonary flow velocity of more than 3.0 m/s at first visit.

Conclusions:

These findings suggest that genetic information can provide a clinical prognosis for cardiovascular disease and may be part of genotype-based follow-up in Noonan syndrome.
Preserving a Liberal International Order: The EU’s Unity and Economic Strength as a Means of Limiting the Corrosive Effects of China’s Sharp Power
Authors: Leal de Faria Luís
Published: April 2022

This article studies the mechanics through which the EU’s relations with China may harm its values and institutions, providing specific examples that precisely illustrate the Chinese Communist Party’s malign influence in Europe. It also intends to reflect on the extent to which the two distinct political and economic models are compatible with the preservation of a liberal international order. Accordingly, we aim to assess whether the EU has the capacity to counteract China’s sharp power, highlighting concrete policy actions that help strengthen the EU’s position while also identifying persisting shortcomings. It is argued that the EU has considerable economic deterrence to push China into respecting global defined rules and arrangements. Indeed, recent reforms, such as the investment screening mechanism and the global sanctions regime, were an important step towards the affirmation of an EU committed to its values. However, the unanimity requirement in the Common Foreign and Security Policy’s decision-making will likely remain a relevant obstacle for a coherent and efficient EU’s external action.
Interdisciplinary and Psychiatric Treatment of Anabolic Androgenic Steroids Users
Authors: Butzke Ingo , Iff Samuel , Zitzmann Michael , Quednow Boris B. , Claussen Malte Christian
Published: April 2022

Abstract. The prevalence of anabolic androgenic steroid (AAS; anabolic steroids) use in recreational sports is underestimated. Due to the influence of social media, an increase in AAS use in recreational sports and in the general population is to be expected. AAS use is associated with significant physical and mental health consequences, and the psychiatric consequences include the risk of developing addictive behaviour. The widespread stigmatization of AAS use also by professionals often undermines users’ trust in physicians and drives them into the arms of so-called “gurus.” The tightening of anti-doping practices in sports and an exclusively prohibitive stance have so far failed to convincingly curb the problem in recreational sports. Harm reduction strategies could help patients to get the help they need from primary care providers.
First Observations of E‐Region Near Range Echoes Partially Modulated by F‐Region Traveling Ionospheric Disturbances Observed by the Same SuperDARN HF Radar
Authors: Hiyadutuje Alicreance , Kosch Michael J. , Stephenson Judy A. E.
Published: April 2022

We present the first observations from SuperDARN HF radar data of E‐region Near Range Echoes (NREs) whose amplitudes are partially modulated by Medium‐Scale Traveling Ionospheric Disturbances (MSTIDs) propagating in the F‐region overhead that have been observed by the same radar in the far ranges. SuperDARN NREs occur normally ∼180–315 km downrange from the radar at ∼95–125 km altitude. Selected observations of TID‐modulated NREs are presented from SANAE and Zhongshan Antarctic SuperDARN radars for both summer and winter seasons as well as geomagnetic active and quiet times. We show that the most likely mechanism is partial modulation of the Gradient Drift Instability (GDI), which is responsible for producing the NREs. GDI is driven by the velocity difference between neutrals and ions and may appear in the E‐region ionosphere wherever suitable plasma density gradients exist. GDI already present in the E‐region can be partially modulated by an MSTID passing overhead in the F‐region via the additional MSTID polarization electric field mapped down in altitude along the equipotential magnetic field lines, thereby partially modulating the NRE amplitudes as observed.
4D‐Var Inversion of European NH3 Emissions Using CrIS NH3 Measurements and GEOS‐Chem Adjoint With Bi‐Directional and Uni‐Directional Flux Schemes
Authors: Cao Hansen , Henze Daven K. , Zhu Liye , Shephard Mark W. , Cady‐Pereira Karen , Dammers Enrico , Sitwell Michael , Heath Nicholas , Lonsdale Chantelle , Bash Jesse O. , Miyazaki Kazuyuki , Flechard Christophe , Fauvel Yannick , Kruit Roy Wichink , Feigenspan Stefan , Brümmer Christian , Schrader Frederik , Twigg Marsailidh M. , Leeson Sarah , Tang Yuk S. , Stephens Amy C. M. , Braban Christine , Vincent Keith , Meier Mario , Seitler Eva , Geels Camilla , Ellermann Thomas , Sanocka Agnieszka , Capps Shannon L.
Published: April 2022

We conduct the first 4D‐Var inversion of NH3 accounting for NH3 bi‐directional flux, using CrIS satellite NH3 observations over Europe in 2016. We find posterior NH3 emissions peak more in springtime than prior emissions at continental to national scales, and annually they are generally smaller than the prior emissions over central Europe, but larger over most of the rest of Europe. Annual posterior anthropogenic NH3 emissions for 25 European Union members (EU25) are 25% higher than the prior emissions and very close (<2% difference) to other inventories. Our posterior annual anthropogenic emissions for EU25, the UK, the Netherlands, and Switzerland are generally 10%–20% smaller than when treating NH3 fluxes as uni‐directional emissions, while the monthly regional difference can be up to 34% (Switzerland in July). Compared to monthly mean in‐situ observations, our posterior NH3 emissions from both schemes generally improve the magnitude and seasonality of simulated surface NH3 and bulk NHx wet deposition throughout most of Europe, whereas evaluation against hourly measurements at a background site shows the bi‐directional scheme better captures observed diurnal variability of surface NH3. This contrast highlights the need for accurately simulating diurnal variability of NH3 in assimilation of sun‐synchronous observations and also the potential value of future geostationary satellite observations. Overall, our top‐down ammonia emissions can help to examine the effectiveness of air pollution control policies to facilitate future air pollution management, as well as helping us understand the uncertainty in top‐down NH3 emissions estimates associated with treatment of NH3 surface exchange.
Understanding and Utilizing the Fractured Earth
Authors: Viswanathan Hari , Hyman Jeffrey
Published: April 2022

The prediction of flow and transport in fractured rock is one of the great challenges in the Earth and energy sciences with far-reaching economic and environmental impacts.
An aptamer agonist of the insulin receptor acts as a positive or negative allosteric modulator, depending on its concentration
Authors: Yunn Na-Oh , Lee Jimin , Lee Hye Sun , Oh Eun Ju , Park Mangeun , Park Seongeun , Jin Seo Yeon , Shin Euisu , Lee Jo woon yi , Kim Youndong , Bae Sun Sik , Ryu Sung Ho
Published: April 2022

Aptamers are widely used as binders that interact with targets with high affinity or as inhibitors of the function of target molecules. However, they have also been used to modulate target protein function, which they achieve by activating the target or stabilizing its conformation. Here, we report a unique aptamer modulator of the insulin receptor (IR), IR-A62. Alone, IR-A62 acts as a biased agonist that preferentially induces Y1150 monophosphorylation of IR. However, when administered alongside insulin, IR-A62 shows variable binding cooperativity depending on the ligand concentration. At low concentrations, IR-A62 acts as a positive allosteric modulator (PAM) agonist that enhances insulin binding, but at high concentrations, it acts as a negative allosteric modulator (NAM) agonist that competes with insulin for IR. Moreover, the concentration of insulin affects the binding of IR-A62 to IR. Finally, the subcutaneous administration of IR-A62 to diabetic mice reduces blood glucose levels with a longer-lasting effect than insulin administration. These findings imply that aptamers can elicit various responses from receptors beyond those of a simple agonist or inhibitor. We expect further studies of IR-A62 to help reveal the mechanism of IR activation and greatly expand the range of therapeutic applications of aptamers.
Ultrashort pulse laser ablation in liquids: probing the first nanoseconds of underwater phase explosion
Authors: Chen Chaobo , Zhigilei Leonid V.
Published: April 2022

The ultrafast pump-probe microscopy has shed new light on the complex dynamics of laser-induced explosive phase transformations and highlighted the importance of close integration of experimental, computational, and theoretical efforts.
Nucleus accumbens D1-receptors regulate and focus transitions to reward-seeking action
Authors: Grima Laura L. , Panayi Marios C. , Härmson Oliver , Syed Emilie C. J. , Manohar Sanjay G. , Husain Masud , Walton Mark E.
Published: April 2022

It is well established that dopamine transmission is integral in mediating the influence of reward expectations on reward-seeking actions. However, the precise causal role of dopamine transmission in moment-to-moment reward-motivated behavioral control remains contentious, particularly in contexts where it is necessary to refrain from responding to achieve a beneficial outcome. To examine this, we manipulated dopamine transmission pharmacologically as rats performed a Go/No-Go task that required them to either make or withhold action to gain either a small or large reward. D1R Stimulation potentiated cue-driven action initiation, including fast impulsive actions on No-Go trials. By contrast, D1R blockade primarily disrupted the successful completion of Go trial sequences. Surprisingly, while after global D1R blockade this was characterized by a general retardation of reward-seeking actions, nucleus accumbens core (NAcC) D1R blockade had no effect on the speed of action initiation or impulsive actions. Instead, fine-grained analyses showed that this manipulation decreased the precision of animals’ goal-directed actions, even though they usually still followed the appropriate response sequence. Strikingly, such “unfocused” responding could also be observed off-drug, particularly when only a small reward was on offer. These findings suggest that the balance of activity at NAcC D1Rs plays a key role in enabling the rapid activation of a focused, reward-seeking state to enable animals to efficiently and accurately achieve their goal.
YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity
Authors: Lee Gwan-Jun , Kim Youn Ju , Park Bongju , Yim Sujin , Park Chansang , Roh Hyunsoo , Moon Yunwon , Seong Je Kyung , Park Hyunsung
Published: April 2022

Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy.
α-Clustering in atomic nuclei from first principles with statistical learning and the Hoyle state character
Authors: Otsuka T. , Abe T. , Yoshida T. , Tsunoda Y. , Shimizu N. , Itagaki N. , Utsuno Y. , Vary J. , Maris P. , Ueno H.
Published: April 2022

A long-standing crucial question with atomic nuclei is whether or not α clustering occurs there. An α particle (helium-4 nucleus) comprises two protons and two neutrons, and may be the building block of some nuclei. This is a very beautiful and fascinating idea, and is indeed plausible because the α particle is particularly stable with a large binding energy. However, direct experimental evidence has never been provided. Here, we show whether and how α(-like) objects emerge in atomic nuclei, by means of state-of-the-art quantum many-body simulations formulated from first principles, utilizing supercomputers including K/Fugaku. The obtained physical quantities exhibit agreement with experimental data. The appearance and variation of the α clustering are shown by utilizing density profiles for the nuclei beryllium-8, -10 and carbon-12. With additional insight by statistical learning, an unexpected crossover picture is presented for the Hoyle state, a critical gateway to the birth of life.
No general stability conditions for marine ice-sheet grounding lines in the presence of feedbacks
Authors: Sergienko Olga V.
Published: April 2022

The “marine ice-sheet instability” hypothesis continues to be used to interpret the observed mass loss from the Antarctic and Greenland ice sheets. This hypothesis has been developed for conditions that do not account for feedbacks between ice sheets and environmental conditions. However, snow accumulation and the ice-sheet surface melting depend on the surface temperature, which is a strong function of elevation. Consequently, there is a feedback between precipitation, atmospheric surface temperature and ice-sheet surface elevation. Here, we investigate stability conditions of a marine-based ice sheet in the presence of such a feedback. Our results show that no general stability condition similar to one associated with the “marine ice-sheet instability” hypothesis can be determined. Stability of individual configurations can be established only on a case-by-case basis. These results apply to a wide range of feedbacks between marine ice sheets and atmosphere, ocean and lithosphere.
The formation of Haumea and its family via binary merging
Authors: Proudfoot Benjamin , Ragozzine Darin
Published: April 2022

Dozens of families of asteroids in the asteroid belt have similar orbits and compositions because they formed through a collision. However, the icy debris beyond the orbit of Neptune, called the Kuiper Belt, contains only one known family, the Haumea family. So far, no self-consistent explanation for the formation of the Haumea family can match all geophysical and orbital characteristics of the family without invoking extremely improbable events. Here, we show that the family is adequately explained as the product of a merging binary near the end of Neptune’s orbital migration. The unique orbital signature of a merging binary, which was not found in extensive searches, is effectively erased during the final stages of migration, providing an explanation for all aspects of the Haumea family. By placing the formation of the Haumea family in the broader context of solar system formation, we demonstrate a proof-of-concept model for the formation of Haumea.
Three-dimensional structure determination of protein complexes using matrix-landing mass spectrometry
Authors: Westphall Michael S. , Lee Kenneth W. , Salome Austin Z. , Lodge Jean M. , Grant Timothy , Coon Joshua J.
Published: April 2022

Native mass spectrometry (MS) is increasingly used to provide complementary data to electron microscopy (EM) for protein structure characterization. Beyond the ability to provide mass measurements of gas-phase biomolecular ions, MS instruments offer the ability to purify, select, and precisely control the spatial location of these ions. Here we present a modified Orbitrap MS system capable of depositing a native MS ion beam onto EM grids. We further describe the use of a chemical landing matrix that preserves the structural integrity of the deposited particles. With this system we obtain a three-dimensional reconstruction of the 800 kDa protein complex GroEL from gas-phase deposited GroEL ions. These data provide direct evidence that non-covalent protein complexes can indeed retain their condensed-phase structures following ionization and vaporization. Finally, we describe how further developments of this technology could pave the way to an integrated MS-EM technology with promise to provide improved cryo-EM sample preparation over conventional plunge-freezing techniques.
L-tyrosine-bound ThiH structure reveals C–C bond break differences within radical SAM aromatic amino acid lyases
Authors: Amara Patricia , Saragaglia Claire , Mouesca Jean-Marie , Martin Lydie , Nicolet Yvain
Published: April 2022

2-iminoacetate synthase ThiH is a radical S-adenosyl-L-methionine (SAM) L-tyrosine lyase and catalyzes the L-tyrosine Cα–Cβ bond break to produce dehydroglycine and p-cresol while the radical SAM L-tryptophan lyase NosL cleaves the L-tryptophan Cα–C bond to produce 3-methylindole-2-carboxylic acid. It has been difficult to understand the features that condition one C–C bond break over the other one because the two enzymes display significant primary structure similarities and presumably similar substrate-binding modes. Here, we report the crystal structure of L-tyrosine bound ThiH from Thermosinus carboxydivorans revealing an unusual protonation state of L-tyrosine upon binding. Structural comparison of ThiH with NosL and computational studies of the respective reactions they catalyze show that substrate activation is eased by tunneling effect and that subtle structural changes between the two enzymes affect, in particular, the hydrogen-atom abstraction by the 5´-deoxyadenosyl radical species, driving the difference in reaction specificity.
Gene co-expression architecture in peripheral blood in a cohort of remitted first-episode schizophrenia patients
Authors: Rodríguez Natalia , Gassó Patricia , Martínez-Pinteño Albert , Segura Àlex-González , Mezquida Gisela , Moreno-Izco Lucia , González-Peñas Javier , Zorrilla Iñaki , Martin Marta , Rodriguez-Jimenez Roberto , Corripio Iluminada , Sarró Salvador , Ibáñez Angela , Butjosa Anna , Contreras Fernando , Bioque Miquel , Cuesta Manuel-Jesús , Parellada Mara , González-Pinto Ana , Berrocoso Esther , Bernardo Miquel , Mas Sergi ,   2EPS group, Amoretti S Silvia , Moren Constanza , Stella Carol , Gurriarán Xaquin , Alonso-Solís Anna , Grasa Eva , Fernandez Jessica , Gonzalez-Ortega Itxaso , Casanovas Francesc , Bulbuena Antoni , Núñez-Doyle Ágatha , Jiménez-Rodríguez Olga , Pomarol-Clotet Edith , Feria-Raposo Isabel , Usall Judith , Muñoz-Samons Daniel , Ilundain Jose L. , Sánchez-Torres Ana Maria , Saiz-Ruiz Jeronimo , López-Torres Isabel , Nacher Juan , De-la-Cámara Concepción , Gutiérrez Miguel , Sáiz Pilar Alejandra
Published: April 2022

A better understanding of schizophrenia subtypes is necessary to stratify the patients according to clinical attributes. To explore the genomic architecture of schizophrenia symptomatology, we analyzed blood co-expression modules and their association with clinical data from patients in remission after a first episode of schizophrenia. In total, 91 participants of the 2EPS project were included. Gene expression was assessed using the Clariom S Human Array. Weighted-gene co-expression network analysis (WGCNA) was applied to identify modules of co-expressed genes and to test its correlation with global functioning, clinical symptomatology, and premorbid adjustment. Among the 25 modules identified, six modules were significantly correlated with clinical data. These modules could be clustered in two groups according to their correlation with clinical data. Hub genes in each group showing overlap with risk genes for schizophrenia were enriched in biological processes related to metabolic processes, regulation of gene expression, cellular localization and protein transport, immune processes, and neurotrophin pathways. Our results indicate that modules with significant associations with clinical data showed overlap with gene sets previously identified in differential gene-expression analysis in brain, indicating that peripheral tissues could reveal pathogenic mechanisms. Hub genes involved in these modules revealed multiple signaling pathways previously related to schizophrenia, which may represent the complex interplay in the pathological mechanisms behind the disease. These genes could represent potential targets for the development of peripheral biomarkers underlying illness traits in clinical remission stages after a first episode of schizophrenia.
Insight into impact of sewage discharge on microbial dynamics and pathogenicity in river ecosystem
Authors: Xie Yuyang , Liu Xiaolin , Wei Haiwei , Chen Xue , Gong Ningji , Ahmad Shakeel , Lee Taeho , Ismail Sherif , Ni Shou-Qing
Published: April 2022

Direct sewage discharge could cause copious numbers of serious and irreversible harm to the environment. This study investigated the impacts of treated and raw sewage on the river ecosystem. Through our analysis, sewage carried various nutrients into the river, leading to changes in the microbial community in the river and reducing the diversity and richness of bacteria. The relative abundances of Hydrogenophaga, Thauera, Planctomyces, Zoogloea, and Pseudomonas boosted from 0.25, 0.01, 0.00, 0.05, and 0.08% to 3.33, 3.43, 0.02, 6.28, and 2.69%, before and after raw sewage discharge, respectively. The gene abundance of pathogenic bacteria significantly increased after raw sewage discharge. For instance, the gene abundance of Vibrio, Helicobacter, Tuberculosis, and Staphylococcus augmented from 4055, 3797, 13,545, 33 reads at Site-1 to 23,556, 13,163, 19,887, 734 reads at Site-2, respectively. In addition, according to the redundancy analysis (RDA), the infectious pathogens were positively related to the environmental parameters, in which COD showed the highest positive correlation with Mycobacterium tuberculosis. Additionally, river self-purification may contribute to improving water quality and reducing pathogenicity. The outcomes of this study showed that direct discharge brought pathogens and changed microbial community structure of the river.