bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging adults’ intersecting experiences of food insecurity, unsafe neighbourhoods and discrimination during the coronavirus disease 2019 (COVID-19) outbreak
Authors: Larson Nicole , Slaughter-Acey Jaime , Alexander Tricia , Berge Jerica , Harnack Lisa , Neumark-Sztainer Dianne
Published: October 2020

Objective:

To examine how food insecurity is related to emerging adults’ food behaviours and experiences of neighbourhood safety and discrimination and to identify resources needed to support their health during the COVID-19 outbreak.

Design:

Rapid response online survey. Participants completed the six-item US Household Food Security Survey Module, a brief measure of food insufficiency, and measures of food behaviours, neighbourhood safety and discrimination. Open-ended questions were used to assess changes in eating behaviours during COVID-19 and needed resources.

Setting:

C-EAT (COVID-19 Eating and Activity over Time) study invitations were sent by email and text message to a longitudinal cohort.

Participants:

A total of 218 emerging adults (mean age = 24·6 (sd 2·0) years, 70·2 % female) completed a survey in April–May 2020 during a stay-at-home order in Minnesota.

Results:

The past year prevalence of food insecurity was 28·4 %. Among food-insecure respondents, 41·0 % reported both eating less and experiencing hunger due to lack of money in the past month. Food-insecure respondents were less likely than those who were food secure to have fruits/vegetables at home and more likely to have frequent fast-food restaurant meals, feel unsafe in their neighbourhood and experience discrimination during the stay-at-home order. Food-insecure adults reported changes including eating more food prepared at home, eating more take-out restaurant meals and purchasing more energy-dense snacks as a result of events related to COVID-19. Resources most needed to support their health included eligibility for more food assistance and relief funds.

Conclusions:

Food-insecure emerging adults experience many barriers to maintaining healthful eating patterns during COVID-19.
Exploiting a perchlorate-tolerant desert cyanobacterium to support bacterial growth for in situ resource utilization on Mars
Authors: Billi Daniela , Gallego Fernandez Beatriz , Fagliarone Claudia , Chiavarini Salvatore , Rothschild Lynn Justine
Published: October 2020

The presence of perchlorate in the Martian soil may limit in-situ resource utilization (ISRU) technologies to support human outposts. In order to exploit the desiccation, radiation-tolerant cyanobacterium Chroococcidopsis in Biological Life Support Systems based on ISRU, we investigated the perchlorate tolerance of Chroococcidopsis sp. CCMEE 029 and its derivative CCMEE 029 P-MRS. This strain was obtained from dried cells mixed with Martian regolith simulant and exposed to Mars-like conditions during the BIOMEX space experiment. After a 55-day exposure of up to 200 mM perchlorate ions, a tolerance threshold value of 100 mM perchlorate ions was identified for both Chroococcidopsis strains. After 40-day incubation, a Mars-relevant perchlorate concentration of 2.4 mM perchlorate ions, provided as a 60 and 40% mixture of Mg- and Ca-perchlorate, had no negative effect on the growth rate of the two strains. A proof-of-concept experiment was conducted using Chroococcidopsis lysate in ISRU technologies to feed a heterotrophic bacterium, i.e. an Escherichia coli strain capable of metabolizing sucrose. The sucrose content was fivefold increased in Chroococcidopsis cells through air-drying and the yielded lysate successfully supported the bacterial growth. This suggested that Chroococcidopsis is a suitable candidate for ISRU technologies to support heterotrophic BLSS components in a Mars-relevant perchlorate environment that would prove challenging to many other cyanobacteria, allowing a ‘live off the land’ approach on Mars.
Study of plant height as a dynamic trait by multistage phenotyping in chickpea under heat stress identifies common as well as stage specific marker–trait associations
Authors: Bohare Tinkeshwari V. , Kulwal Pawan L. , Mhase Laxman B. , Jadhav Ashok S.
Published: October 2020

Plant height in chickpea is a multivariate, dynamic trait, and shows differences in growth rate at different stages of plant development in different genotypes. In the majority of plant-breeding experiments, the phenotypic data on a quantitative trait measured at a fixed time point (generally at maturity) are used for quantitative trait loci (QTL) mapping. However, this method can result in missing important/major QTLs which are expressed at different time points and are not expressed at maturity. In the current study, using a set of 49 desi chickpea genotypes sown at three different durations for two successive years, we observed that heritability for plant height was highest at the 2 month stage in the normal sown trial, and at the 1 month stage in late-sown trials. However, heritability drastically declines at maturity, particularly due to heat stress with an increase in temperatures during the growing period. In the association analysis, it was also observed that almost all the marker–trait associations (MTAs) identified using endpoint phenotypes were identified using data obtained at different intervals. In addition, some novel and stage-specific MTAs were identified using phenotypic data recorded at monthly intervals. The results highlight the importance of multistage phenotyping for dynamic traits like plant height in germplasm characterization programmes.
The Iowa Bird That Inspired Antonín Dvořák's American String Quartet in 1893: Controversy over the Species’ Identity and Why It Matters
Authors: McKone Mark J. , Beccue David A.
Published: October 2020

Antonín Dvořák composed the String Quartet in F major (op. 96, the ‘American’) in June 1893 while visiting the town of Spillville, Iowa, USA. Based on accounts from Dvořák's secretary Josef Kovařík, portions of the quartet's Scherzo movement were inspired by birdsong Dvořák heard in Spillville. Kovařík's account included both Dvořák's visual description of the bird that inspired him and a transcribed fragment of the birdsong Dvořák reportedly used. In 1954, Clapham identified the bird as a scarlet tanager (Piranga olivacea), based mainly on the visual description. This widely accepted identification was questionable because of the poor match of the tanager's song to musical material in the Scherzo. In 2016, Floyd proposed the red-eyed vireo (Vireo olivaceus) as Dvořák's inspiration, based on song rather than appearance. The vireo's song is clearly identifiable in the Scherzo as well in the birdsong fragment recorded by Kovařík. The mismatch between the visual description and the transcribed song fragment could have occurred when Dvořák heard and recorded the persistent singing of a cryptic red-eyed vireo, but misidentified the song's source when he caught sight of a brightly coloured tanager. Correct identification of the birdsong changes the interpretation of the movement. Previously, birdsong has been considered the source of a short secondary motif. But red-eyed vireo songs are highly variable, and a slight variation of Kovařík's song fragment could be the basis of the main theme of the Scherzo. Therefore, Dvořák may have used American birdsong in the movement considerably more than previously appreciated.
An inquiry into the blurring boundaries between professionals and paraprofessionals in Dutch courts and the public prosecution service
Authors: Holvast N.L. , Lindeman J.M.W.
Published: October 2020

The autonomous position of legal professionals is no longer self-evident. Professionals are under increased pressure to reform. This phenomenon is not only true for legal professionals. A broader trend – which is recognised for the medical profession, academic profession and alike – is that paraprofessionals are gaining a more prominent position. In this paper, we focus on the developments in the Dutch public justice system. We conduct a case-study on the role of paraprofessionals in courts and in the public prosecution service – two understudied legal institutions in this regard. By drawing on empirical data unfolding the working routine of the judiciary and the prosecution service, we find two paradigms that define the thinking about professionalism: a traditional ‘pure professional’ paradigm and a new, more hybrid paradigm that includes (policy-based) managerial thinking. The latter appears to be enhanced by a New Public Management (NPM) approach within these institutions. Although we observe resistance among (para)professionals towards professional changes and ambiguity in the relationships between professionals and paraprofessionals, we also observe that managerialism has changed the work processes and the division of labour between professionals and paraprofessionals.
Acceptability of Assisted Suicide in Patients With Severe and Persistent Mental Illness
Authors: Gloeckler Sophie , Trachsel Manuel
Published: October 2020

Abstract. In Switzerland, assisted suicide (AS) may be granted on the basis of a psychiatric diagnosis. This pilot study explored the moral attitudes and beliefs of nurses regarding these practices through a quantitative survey of 38 psychiatric nurses. The pilot study, which serves to inform hypothesis development and future studies, showed that participating nurses supported AS and valued the reduction of suffering in patients with severe persistent mental illness. Findings were compared with those from a previously published study presenting the same questions to psychiatrists. The key differences between nurses’ responses and psychiatrists, may reflect differences in the burden of responsibility, while similarities might capture shared values worth considering when determining treatment efforts. More information is needed to determine whether these initial findings represent nurses’ views more broadly.
To Save Low-Lying Atolls, Adaptive Measures Need to Start Now
Authors: Fritts Rachel
Published: October 2020

New research uses 5,000 years of geological data to understand how and when sea level rise will affect the livability of low-lying reef islands.
Fine‐Scale Structure of Earth's Deep Mantle Resolved Through Statistical Analysis of Hawaiian Basalt Geochemistry
Authors: Weis Dominique , Harrison Lauren N. , McMillan Rhy , Williamson Nicole M. B.
Published: October 2020

Hawaiian volcanoes belong to two geographically and geochemically distinct trends, the Loa and Kea trends. The cause of this dichotomy is still strongly debated. One of the prevailing hypotheses is that the two trends originate in the deep mantle where the Hawaiian mantle plume straddles two geophysically and geochemically distinct domains at the core‐mantle boundary (CMB). New high‐precision multi‐isotopic (Pb, Hf, Nd, and Sr) compositions of lavas from three key volcanoes, Lō‘ihi, Kohala, and Haleakalā, show transitional signatures between Loa and Kea compositions that call into question the degree of physical independence between the two trends. Statistical analysis of multi‐collector inductively coupled plasma mass spectrometer or triple‐spike Pb (n > 800) and Sr, Nd, and Hf data (n > 400) for shield tholeiites from the entire Hawaiian Islands (<5.5 Ma) identifies six unique geochemical groups, and for the first time, documents large‐scale heterogeneities in the Kea trend. The spatial orientation of the six geochemical groups shows that the bilateral zonation of the plume source at the CMB is gradational, and that the Hawaiian mantle plume periodically entrains large‐scale ephemeral geochemical heterogeneities on million‐year, regional timescales. These geochemical heterogeneities are stretched vertically during transit of the plume to the surface and are observed in the lavas from the Hawaiian Islands. These results provide evidence that the large low shear velocity province in the deep Pacific is thermochemical and highly heterogeneous.
Hysteresis of Natural Magnetite Ensembles: Micromagnetics of Silicate‐Hosted Magnetite Inclusions Based on Focused‐Ion‐Beam Nanotomography
Authors: Nikolaisen Even S. , Harrison Richard J. , Fabian Karl , McEnroe Suzanne A.
Published: October 2020

Three‐dimensional geometries of silicate‐hosted magnetic inclusions from the Harcus intrusion, South Australia have been determined using focused‐ion‐beam nanotomography (FIB‐nt). By developing an effective workflow, the geometries were reconstructed for magnetic particles in a plagioclase (162) and a pyroxene (282), respectively. For each inclusion, micromagnetic modeling using Micromagnetic Earth Related Rapid Interpreted Language Laboratory provided averaged hysteresis loops and backfield remanence curves of 20 equidistributed field directions together with average Ms, Mrs, Hc, and Hcr. The micromagnetic structures within each silicate are single‐domain (SD), single‐vortex (SV), multivortex (MV) and multidomain states. They have been analyzed using domain‐state diagnostic plots, such as the Day plot and the Néel plot. SD particles can be subdivided into groups with dominant uniaxial anisotropy (Mrs/Ms ∼0.5 and 10 < Hc < 100 mT) and mixed uniaxial/multiaxial anisotropy (Mrs/Ms ∼0.7 and 10 < Hc < 30 mT). Most SV particles lie on a trend with 0 < Mrs/Ms < 0.1 and 0 < Hc < 10 mT, while others display a broad range of intermediate Mrs/Ms and Hc values. SV and MV states do not plot on systematic grain‐size trends. Instead, the multicomponent mixture of domain states within each silicate spans the entire range of natural variability seen in bulk samples. This questions the interpretation of bulk average hysteresis parameters in terms of grain size alone. FIB‐nt combined with large‐scale micromagnetic simulations provides a more complete characterization of silicate‐hosted carriers of stable magnetic remanence. This approach will improve the understanding of single‐crystal paleomagnetism and enable primary paleomagnetic data to be extracted from ancient rocks.
Spatial Fingerprint of Younger Dryas Cooling and Warming in Eastern North America
Authors: Fastovich David , Russell James M. , Jackson Stephen T. , Krause Teresa R. , Marcott Shaun A. , Williams John W.
Published: October 2020

The Younger Dryas (YD, 12.9–11.7 ka) is the most recent, near‐global interval of abrupt climate change with rates similar to modern global warming. Understanding the causes and biodiversity effects of YD climate changes requires determining the spatial fingerprints of past temperature changes. Here we build pollen‐based and branched glycerol dialkyl glycerol tetraether‐based temperature reconstructions in eastern North America (ENA) to better understand deglacial temperature evolution. YD cooling was pronounced in the northeastern United States and muted in the north central United States. Florida sites warmed during the YD, while other southeastern sites maintained a relatively stable climate. This fingerprint is consistent with an intensified subtropical high during the YD and demonstrates that interhemispheric responses were more complex spatially in ENA than predicted by the bipolar seesaw model. Reduced‐amplitude or antiphased millennial‐scale temperature variability in the southeastern United States may support regional hotspots of biodiversity and endemism.
Empirical Distribution of Conditional Errors in Radar Rainfall Products
Authors: Ciach Grzegorz J. , Gebremichael Mekonnen
Published: October 2020

Efficient quantification of conditional errors in radar rainfall (RR) products requires a realistic model of random error distribution. Nonparametric estimate of the probability density function (pdf) of standardized RR errors is obtained using a large data sample. The standardization is based on a second‐order separation of systematic and random effects. The estimated empirical distribution is skewed and has exponential shapes of its tails with two different scales. It cannot be modeled with the Gaussian law that was used in several previous studies. A good representation of the tails of the empirical distribution of RR errors is obtained with a three‐parameter modified Laplace model with a shift and unequal slopes of its two sides.
Resource partitioning of phytoplankton metabolites that support bacterial heterotrophy
Authors: Ferrer-González Frank Xavier , Widner Brittany , Holderman Nicole R , Glushka John , Edison Arthur S , Kujawinski Elizabeth B , Moran Mary Ann
Published: October 2020

The communities of bacteria that assemble around marine microphytoplankton are predictably dominated by Rhodobacterales, Flavobacteriales, and families within the Gammaproteobacteria. Yet whether this consistent ecological pattern reflects the result of resource-based niche partitioning or resource competition requires better knowledge of the metabolites linking microbial autotrophs and heterotrophs in the surface ocean. We characterized molecules targeted for uptake by three heterotrophic bacteria individually co-cultured with a marine diatom using two strategies that vetted the exometabolite pool for biological relevance by means of bacterial activity assays: expression of diagnostic genes and net drawdown of exometabolites, the latter detected with mass spectrometry and nuclear magnetic resonance using novel sample preparation approaches. Of the more than 36 organic molecules with evidence of bacterial uptake, 53% contained nitrogen (including nucleosides and amino acids), 11% were organic sulfur compounds (including dihydroxypropanesulfonate and dimethysulfoniopropionate), and 28% were components of polysaccharides (including chrysolaminarin, chitin, and alginate). Overlap in phytoplankton-derived metabolite use by bacteria in the absence of competition was low, and only guanosine, proline, and N-acetyl-d-glucosamine were predicted to be used by all three. Exometabolite uptake pattern points to a key role for ecological resource partitioning in the assembly marine bacterial communities transforming recent photosynthate.
Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells
Authors: Wang Kang , Zhang Zhengyang , Tsai Hsiang-i , Liu Yanfang , Gao Jie , Wang Ming , Song Lian , Cao Xiongfeng , Xu Zhanxue , Chen Hongbo , Gong Aihua , Wang Dongqing , Cheng Fang , Zhu Haitao
Published: October 2020

Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc– activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.
CSF1R signaling is a regulator of pathogenesis in progressive MS
Authors: Hagan Nellwyn , Kane John L. , Grover Deepak , Woodworth Lisa , Madore Charlotte , Saleh Jacqueline , Sancho Jose , Liu Jinyu , Li Yi , Proto Jonathan , Zelic Matija , Mahan Amy , Kothe Michael , Scholte Andrew A. , Fitzgerald Maria , Gisevius Barbara , Haghikia Aiden , Butovsky Oleg , Ofengeim Dimitry
Published: October 2020

Microglia serve as the innate immune cells of the central nervous system (CNS) by providing continuous surveillance of the CNS microenvironment and initiating defense mechanisms to protect CNS tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming their morphology, and producing pro-inflammatory cytokines. These activated microglia initially serve a beneficial role, but their continued activation drives neuroinflammation and neurodegeneration. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, and activated microglia and macrophages play a significant role in mediating disease pathophysiology and progression. Colony-stimulating factor-1 receptor (CSF1R) and its ligand CSF1 are elevated in CNS tissue derived from MS patients. We performed a large-scale RNA-sequencing experiment and identified CSF1R as a key node of disease progression in a mouse model of progressive MS. We hypothesized that modulating microglia and infiltrating macrophages through the inhibition of CSF1R will attenuate deleterious CNS inflammation and reduce subsequent demyelination and neurodegeneration. To test this hypothesis, we generated a novel potent and selective small-molecule CSF1R inhibitor (sCSF1Rinh) for preclinical testing. sCSF1Rinh blocked receptor phosphorylation and downstream signaling in both microglia and macrophages and altered cellular functions including proliferation, survival, and cytokine production. In vivo, CSF1R inhibition with sCSF1Rinh attenuated neuroinflammation and reduced microglial proliferation in a murine acute LPS model. Furthermore, the sCSF1Rinh attenuated a disease-associated microglial phenotype and blocked both axonal damage and neurological impairments in an experimental autoimmune encephalomyelitis (EAE) model of MS. While previous studies have focused on microglial depletion following CSF1R inhibition, our data clearly show that signaling downstream of this receptor can be beneficially modulated in the context of CNS injury. Together, these data suggest that CSF1R inhibition can reduce deleterious microglial proliferation and modulate microglial phenotypes during neuroinflammatory pathogenesis, particularly in progressive MS.
Epigenetic silencing of ZIC4 contributes to cancer progression in hepatocellular carcinoma
Authors: Chen Wenbiao , Tang Donge , Tang Dongxin , Dai Yong
Published: October 2020

Inactivation of tumor suppressor gene played critical roles in the development and progression of human hepatocellular carcinoma (HCC). Zic family member 4 (ZIC4) is transcription factor and plays an important role in the developmental process. However, the expression and biological role of ZIC4 in HCC is poorly understood. Here, bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database revealed an aberrant hypermethylation of ZIC4 in HCC. ZIC4 is frequently hypermethylated in promoter region and down expressed in HCC cells and tissues. Functionally, ZIC4 inhibition facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, ZIC4 overexpression reduced proliferation and invasiveness of HCC cells. In addition, ZIC4 inhibition rescued the antitumor effect induced by enhancer of zeste homolog 2 (EZH2) knockdown or EZH2 inhibitor. Mechanistically, EZH2 knockdown or EZH2 inhibitor reduced the enrichment of EZH2 and H3K27me3 in ZIC4 promoter region and leading to the upregulation of ZIC4. Altogether, these data indicate that epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in HCC and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.
Prime editing for functional repair in patient-derived disease models
Authors: Schene Imre F. , Joore Indi P. , Oka Rurika , Mokry Michal , van Vugt Anke H. M. , van Boxtel Ruben , van der Doef Hubert P. J. , van der Laan Luc J. W. , Verstegen Monique M. A. , van Hasselt Peter M. , Nieuwenhuis Edward E. S. , Fuchs Sabine A.
Published: October 2020

Prime editing is a recent genome editing technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct the vast majority of genetic defects. Here, we develop prime editing for primary adult stem cells grown in organoid culture models. First, we generate precise in-frame deletions in the gene encoding β‐catenin (CTNNB1) that result in proliferation independent of Wnt-stimuli, mimicking a mechanism of the development of liver cancer. Moreover, prime editing functionally recovers disease-causing mutations in intestinal organoids from patients with DGAT1-deficiency and liver organoids from a patient with Wilson disease (ATP7B). Prime editing is as efficient in 3D grown organoids as in 2D grown cell lines and offers greater precision than Cas9-mediated homology directed repair (HDR). Base editing remains more reliable than prime editing but is restricted to a subgroup of pathogenic mutations. Whole-genome sequencing of four prime-edited clonal organoid lines reveals absence of genome-wide off-target effects underscoring therapeutic potential of this versatile and precise gene editing strategy.
Pattern recognition based on machine learning identifies oil adulteration and edible oil mixtures
Authors: Lim Kevin , Pan Kun , Yu Zhe , Xiao Rong Hui
Published: October 2020

Previous studies have shown that each edible oil type has its own characteristic fatty acid profile; however, no method has yet been described allowing the identification of oil types simply based on this characteristic. Moreover, the fatty acid profile of a specific oil type can be mimicked by a mixture of 2 or more oil types. This has led to fraudulent oil adulteration and intentional mislabeling of edible oils threatening food safety and endangering public health. Here, we present a machine learning method to uncover fatty acid patterns discriminative for ten different plant oil types and their intra-variability. We also describe a supervised end-to-end learning method that can be generalized to oil composition of any given mixtures. Trained on a large number of simulated oil mixtures, independent test dataset validation demonstrates that the model has a 50th percentile absolute error between 1.4–1.8% and a 90th percentile error of 4–5.4% for any 3-way mixtures of the ten oil types. The deep learning model can also be further refined with on-line training. Because oil-producing plants have diverse geographical origins and hence slightly varying fatty acid profiles, an online-training method provides also a way to capture useful knowledge presently unavailable. Our method allows the ability to control product quality, determining the fair price of purchased oils and in-turn allowing health-conscious consumers the future of accurate labeling.
Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains
Authors: Kim Jinuk , Han Wonhee , Park Taeyong , Kim Eun Jin , Bang Injin , Lee Hyun Sik , Jeong Yejin , Roh Kyeonghwan , Kim Jeesoo , Kim Jong-Seo , Kang Chanhee , Seok Chaok , Han Jin-Kwan , Choi Hee-Jung
Published: October 2020

Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the β-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 (E1) is known to interact with SOST, several unresolved questions remain, such as the reason why SOST binds to LRP6 E1E2 with higher affinity than to the E1 domain alone. Here, we present the crystal structure of the LRP6 E1E2–SOST complex with two interaction sites in tandem. The unexpected additional binding site was identified between the C-terminus of SOST and the LRP6 E2 domain. This interaction was confirmed by in vitro binding and cell-based signaling assays. Its functional significance was further demonstrated in vivo using Xenopus laevis embryos. Our results provide insights into the inhibitory mechanism of SOST on Wnt signaling.
Polymerization and editing modes of a high-fidelity DNA polymerase are linked by a well-defined path
Authors: Dodd Thomas , Botto Margherita , Paul Fabian , Fernandez-Leiro Rafael , Lamers Meindert H. , Ivanov Ivaylo
Published: October 2020

Proofreading by replicative DNA polymerases is a fundamental mechanism ensuring DNA replication fidelity. In proofreading, mis-incorporated nucleotides are excised through the 3′-5′ exonuclease activity of the DNA polymerase holoenzyme. The exonuclease site is distal from the polymerization site, imposing stringent structural and kinetic requirements for efficient primer strand transfer. Yet, the molecular mechanism of this transfer is not known. Here we employ molecular simulations using recent cryo-EM structures and biochemical analyses to delineate an optimal free energy path connecting the polymerization and exonuclease states of E. coli replicative DNA polymerase Pol III. We identify structures for all intermediates, in which the transitioning primer strand is stabilized by conserved Pol III residues along the fingers, thumb and exonuclease domains. We demonstrate switching kinetics on a tens of milliseconds timescale and unveil a complete pol-to-exo switching mechanism, validated by targeted mutational experiments.
The nucleotide pGpp acts as a third alarmone in Bacillus, with functions distinct from those of (p)ppGpp
Authors: Yang Jin , Anderson Brent W. , Turdiev Asan , Turdiev Husan , Stevenson David M. , Amador-Noguez Daniel , Lee Vincent T. , Wang Jue D.
Published: October 2020

The alarmone nucleotides guanosine tetraphosphate and pentaphosphate, commonly referred to as (p)ppGpp, regulate bacterial responses to nutritional and other stresses. There is evidence for potential existence of a third alarmone, guanosine-5′-monophosphate-3′-diphosphate (pGpp), with less-clear functions. Here, we demonstrate the presence of pGpp in bacterial cells, and perform a comprehensive screening to identify proteins that interact respectively with pGpp, ppGpp and pppGpp inBacillusspecies. Both ppGpp and pppGpp interact with proteins involved in inhibition of purine nucleotide biosynthesis and with GTPases that control ribosome assembly or activity. By contrast, pGpp interacts with purine biosynthesis proteins but not with the GTPases. In addition, we show that hydrolase NahA (also known as YvcI) efficiently produces pGpp by hydrolyzing (p)ppGpp, thus modulating alarmone composition and function. Deletion ofnahAleads to reduction of pGpp levels, increased (p)ppGpp levels, slower growth recovery from nutrient downshift, and loss of competitive fitness. Our results support the existence and physiological relevance of pGpp as a third alarmone, with functions that can be distinct from those of (p)ppGpp.
Unravelling the room-temperature atomic structure and growth kinetics of lithium metal
Authors: Liang Chao , Zhang Xun , Xia Shuixin , Wang Zeyu , Wu Jiayi , Yuan Biao , Luo Xin , Liu Weiyan , Liu Wei , Yu Yi
Published: October 2020

Alkali metals are widely studied in various fields such as medicine and battery. However, limited by the chemical reactivity and electron/ion beam sensitivity, the intrinsic atomic structure of alkali metals and its fundamental properties are difficult to be revealed. Here, a simple and versatile method is proposed to form the alkali metals in situ inside the transmission electron microscope. Taking alkali salts as the starting materials and electron beam as the trigger, alkali metals can be obtained directly. With this method, atomic resolution imaging of lithium and sodium metal is achieved at room temperature, and the growth of alkali metals is visualized at atomic-scale with millisecond temporal resolution. Furthermore, our observations unravel the ambiguities in lithium metal growth on garnet-type solid electrolytes for lithium-metal batteries. Finally, our method enables a direct study of physical contact property of lithium metal as well as its surface passivation oxide layer, which may contribute to better understanding of lithium dendrite and solid electrolyte interphase issues in lithium ion batteries.
The desensitization pathway of GABAA receptors, one subunit at a time
Authors: Gielen Marc , Barilone Nathalie , Corringer Pierre-Jean
Published: October 2020

GABAA receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following GABA binding and fast activation, these receptors undergo a slower desensitization, the conformational pathway of which remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1β2γ2 GABAA receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.
Chemical trends of deep levels in van der Waals semiconductors
Authors: Ci Penghong , Tian Xuezeng , Kang Jun , Salazar Anthony , Eriguchi Kazutaka , Warkander Sorren , Tang Kechao , Liu Jiaman , Chen Yabin , Tongay Sefaattin , Walukiewicz Wladek , Miao Jianwei , Dubon Oscar , Wu Junqiao
Published: October 2020

Properties of semiconductors are largely defined by crystal imperfections including native defects. Van der Waals (vdW) semiconductors, a newly emerged class of materials, are no exception: defects exist even in the purest materials and strongly affect their electrical, optical, magnetic, catalytic and sensing properties. However, unlike conventional semiconductors where energy levels of defects are well documented, they are experimentally unknown in even the best studied vdW semiconductors, impeding the understanding and utilization of these materials. Here, we directly evaluate deep levels and their chemical trends in the bandgap of MoS2, WS2 and their alloys by transient spectroscopic study. One of the deep levels is found to follow the conduction band minimum of each host, attributed to the native sulfur vacancy. A switchable, DX center - like deep level has also been identified, whose energy lines up instead on a fixed level across different hosts, explaining a persistent photoconductivity above 400 K.
Immediate and transgenerational effects of thymol supplementation, inactivated Salmonella and chronic heat stress on representative immune variables of Japanese quail
Authors: Videla E. A. , Giayetto O. , Fernández M. E. , Chacana P. A. , Marín R. H. , Nazar F. N.
Published: October 2020

Environmental challenges are integrated in the inmunoneuroendocrine interplay, impacting the immune system of the challenged individuals, and potentially implying transgenerational effects on their offspring. This study addressed whether dietary supplementation with thymol can modulate the immune response of adult Japanese quail when simultaneously exposed to an inoculum of inactivated Salmonella Enteritidis and a chronic heat stress (CHS). We also evaluated whether the experienced situations by adults can affect the immune response of their undisturbed offspring. In the parental generation, supplemented quail exposed to CHS had a higher inflammatory response and similar values of the heterophil/lymphocyte (H/L) ratio than those that were not supplemented. In their offspring, those chicks whose parents were exposed to CHS showed higher inflammatory response and lower antibody production. Regarding the H/L ratio, chicks whose parents were supplemented showed lower H/L ratio values. Dietary supplementation with thymol partially and positively modulated the inflammatory response and avoided H/L ratio alteration in the parental generation exposed to high environmental temperatures, suggesting these adults were better at dealing with the challenge. The lower H/L ratio values in the offspring suggests that chicks are more capable to deal with potential stressful situations associated with conventional breeding conditions.
A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone
Authors: Zhang Baoshan , Chao Cara W. , Tsybovsky Yaroslav , Abiona Olubukola M. , Hutchinson Geoffrey B. , Moliva Juan I. , Olia Adam S. , Pegu Amarendra , Phung Emily , Stewart-Jones Guillaume B. E. , Verardi Raffaello , Wang Lingshu , Wang Shuishu , Werner Anne , Yang Eun Sung , Yap Christina , Zhou Tongqing , Mascola John R. , Sullivan Nancy J. , Graham Barney S. , Corbett Kizzmekia S. , Kwong Peter D.
Published: October 2020

Antigens displayed on self-assembling nanoparticles can stimulate strong immune responses and have been playing an increasingly prominent role in structure-based vaccines. However, the development of such immunogens is often complicated by inefficiencies in their production. To alleviate this issue, we developed a plug-and-play platform using the spontaneous isopeptide-bond formation of the SpyTag:SpyCatcher system to display trimeric antigens on self-assembling nanoparticles, including the 60-subunit Aquifex aeolicus lumazine synthase (LuS) and the 24-subunit Helicobacter pylori ferritin. LuS and ferritin coupled to SpyTag expressed well in a mammalian expression system when an N-linked glycan was added to the nanoparticle surface. The respiratory syncytial virus fusion (F) glycoprotein trimer—stabilized in the prefusion conformation and fused with SpyCatcher—could be efficiently conjugated to LuS-SpyTag or ferritin-SpyTag, enabling multivalent display of F trimers with prefusion antigenicity. Similarly, F-glycoprotein trimers from human parainfluenza virus-type 3 and spike-glycoprotein trimers from SARS-CoV-2 could be displayed on LuS nanoparticles with decent yield and antigenicity. Notably, murine vaccination with 0.08 µg of SARS-CoV-2 spike-LuS nanoparticle elicited similar neutralizing responses as 2.0 µg of spike, which was ~ 25-fold higher on a weight-per-weight basis. The versatile platform described here thus allows for multivalent plug-and-play presentation on self-assembling nanoparticles of trimeric viral antigens, with SARS-CoV-2 spike-LuS nanoparticles inducing particularly potent neutralizing responses.
Improving ultrasound images with elevational angular compounding based on acoustic refraction
Authors: Afshari Parastoo , Zakian Christian , Ntziachristos Vasilis
Published: October 2020

Ultrasound imaging is affected by coherent noise or speckle, which reduces contrast and overall image quality and degrades the diagnostic precision of the collected images. Elevational angular compounding (EAC) is an attractive means of addressing this limitation, since it reduces speckle noise while operating in real-time. However, current EAC implementations rely on mechanically rotating a one-dimensional (1D) transducer array or electronically beam steering of two-dimensional (2D) arrays to provide different elevational imaging angles, which increases the size and cost of the systems. Here we present a novel EAC implementation based on a 1D array, which does not necessitate mechanically rotating the transducer. The proposed refraction-based elevational angular compounding technique (REACT) instead utilizes a translating cylindrical acoustic lens that steers the ultrasound beam along the elevational direction. Applying REACT to investigate phantoms and excised tissue samples demonstrated superior suppression of ultrasound speckle noise compared to previous EAC methods, with up to a two-fold improvement in signal- and contrast-to-noise ratios. The effects of elevational angular width on speckle reduction was further investigated to determine the appropriate conditions for applying EAC. This study introduces acoustic refractive elements as potential low cost solutions to noise reduction, which could be integrated into current medical ultrasound devices.
Comparison of transoral robotic surgery with other surgeries for obstructive sleep apnea
Authors: Tsou Yung-An , Chang Wen-Dien
Published: October 2020

This study compared the characteristic surgical parameters and clinical effects of transoral robotic surgery (TORS) and other available methods used to alleviate obstructive sleep apnea. Articles on TORS and other surgeries for obstructive sleep apnea were identified in the PubMed and EMBASE databases. Two investigators independently reviewed the articles and classified the data for meta-analysis. The pooled effect sizes of TORS (standardized mean difference; SMD = − 2.38), coblation tongue base resection (CTBR; SMD = − 2.00) and upper airway stimulation (UAS; SMD = − 0.94) revealed significant improvement in the apnea–hypopnea index (AHI; p < 0.05). The lowest O2 saturation reported was significantly increased following TORS (SMD = 1.43), CTBR (SMD = 0.86) and UAS (SMD = 1.24, p < 0.05). Furthermore, TORS (SMD = − 2.91) and CTBR (SMD = − 1.51, p < 0.05) significantly reduced the Epworth Sleepiness Scale (ESS) score. No significant difference in operation time, success rate, or instances of complication were observed between TORS and the other compared interventions. The use of TORS in obstructive sleep apnea has the same rate of success and failure as other methods of surgical intervention for obstructive sleep apnea with no statistical difference in operation times. The reported clinical effects on the AHI, lowest O2 saturation, and ESS scores of TORS were similar to those of other surgeries.
Colour matters more than shape for chimpanzees’ recognition of developmental face changes
Authors: Kawaguchi Yuri , Nakamura Koyo , Tomonaga Masaki
Published: October 2020

Social primates must recognise developmental stages of other conspecifics in order to behave appropriately. Infant faces have peculiar morphological characteristics—relatively large eyes, a small nose, and small mouth—known as baby schema. In addition, the infant faces of many primate species have unique skin coloration. However, it is unclear which features serve as critical cues for chimpanzees to recognise developmental changes in their faces. The present study aimed to investigate the relative contributions of facial shape and colour to age categorisation in chimpanzees. We used a symbolic matching-to-sample task in which chimpanzees were trained to discriminate between adult and infant faces. Then, we tested how their age category judgments transferred to a series of morphed faces which systematically differed in facial shape and colour. Statistical image quantification analysis revealed significant differences both in shape and colour between adult and infant faces. However, we found that facial coloration contributed to age categorisation in chimpanzees more than facial shape. Our results showed that chimpanzees use unique infantile facial coloration as a salient cue when discriminating between adult and infant faces. The display of their developmental stages through facial colour may help chimpanzees to induce appropriate behaviour from other individuals.
A causal role for the cerebellum in semantic integration: a transcranial magnetic stimulation study
Authors: Gatti Daniele , Van Vugt Floris , Vecchi Tomaso
Published: October 2020

Mounting evidence suggests that the cerebellum, a structure previously linked to motor function, is also involved in a wide range of non-motor processes. It has been proposed that the cerebellum performs the same computational processes in both motor and non-motor domains. Within motor functions, the cerebellum is involved in the integration of signals from multiple systems. Here we hypothesized that cerebellum may be involved in integration within semantic memory as well. Specifically, understanding a noun-adjective combination (e.g. red apple) requires combining the meaning of the adjective (red) with the meaning of the noun (apple). In two experiments, participants were asked to judge whether noun-adjective word-pairs were semantically related (e.g., red apple) or not (e.g., lucky milk) while online transcranial magnetic stimulation (TMS) was administered over the right cerebellum or over a control site (vertex in Experiment 1 and visual cortex in Experiment 2). Cerebellar TMS caused a decrease in participants’ accuracy for related word-pairs while accuracy for unrelated stimuli was not affected. A third experiment using a control task where subjects compared pairs of random letters showed no effect of TMS. Taken together these results indicate that the right cerebellum is involved specifically in the processing of semantically related stimuli. These results are consistent with theories that proposed the existence of a unified cerebellar function within motor and non-motor domains, as well with recent perspectives about cerebellar involvement in semantic memory and predictive cognition.
Urinary podocyte mRNAs precede microalbuminuria as a progression risk marker in human type 2 diabetic nephropathy
Authors: Fukuda Akihiro , Minakawa Akihiro , Kikuchi Masao , Sato Yuji , Nagatomo Masanao , Nakamura Shuji , Mizoguchi Tetsu , Fukunaga Naoya , Shibata Hirotaka , Naik Abhijit S. , Wiggins Roger C. , Fujimoto Shouichi
Published: October 2020

Earlier detection of progression risk in diabetic nephropathy will allow earlier intervention to reduce progression. The hypothesis that urinary pellet podocyte mRNA is a more sensitive progression risk marker than microalbuminuria was tested. A cross sectional cohort of 165 type 2 diabetics and 41 age and sex-matched controls were enrolled. Podocyte stress (Urinary pellet podocin:nephrin mRNA ratio), podocyte detachment (Urinary pellet podocin mRNA:creatinine ratio: UPPod:CR) and a tubular marker (Urinary pellet aquaporin 2:creatinine ratio) were measured in macro-albuminuric, micro-albuminuric and norm-albuminuric groups. eGFR was reassessed after 4 years in 124 available diabetic subjects. Urinary pellet podocyte and tubular mRNA markers were increased in all diabetic groups in cross-sectional analysis. After 4 years of follow-up univariable and multivariate model analysis showed that the only urinary markers significantly related to eGFR slope were UPPod:CR (P < 0.01) and albuminuria (P < 0.01). AUC analysis using K-fold cross validation to predict eGFR loss of ≥ 3 ml/min/1.73m2/year showed that UPPod:CR and albuminuria each improved the AUC similarly such that combined with clinical variables they gave an AUC = 0.70. Podocyte markers and albuminuria had overlapping AUC contributions, as expected if podocyte depletion causes albuminuria. In the norm-albuminuria cohort (n = 75) baseline UPPod:CR was associated with development of albuminuria (P = 0.007) and, in the tertile with both normal kidney function (eGFR 84 ± 11.7 ml/min/1.73m2) and norm-albuminuria at baseline, UPPod:CR was associated with eGFR loss rate (P = 0.003). In type 2 diabetics with micro- or macro-albuminuria UPPod:CR and albuminuria were equally good at predicting eGFR loss. For norm-albuminuric type 2 diabetics UPPod:CR predicted both albuminuria and eGFR loss.