bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibiotic breakdown by susceptible bacteria enhances the establishment of β-lactam resistant mutants
Authors: Saebelfeld Manja , Das Suman G. , Brink Jorn , Hagenbeek Arno , Krug Joachim , de Visser J. Arjan G.M.
Published: April 2021

For a better understanding of the evolution of antibiotic resistance, it is imperative to study the factors that determine the initial establishment of mutant resistance alleles. In addition to the antibiotic concentration, the establishment of resistance alleles may be affected by interactions with the surrounding susceptible cells from which they derive, for instance via the release of nutrients or removal of the antibiotic. Here, we investigate the effects of social interactions with surrounding susceptible cells on the establishment ofEscherichia colimutants with increasing β-lactamase activity (i.e. the capacity to hydrolyze β-lactam antibiotics) from single cells under the exposure of the antibiotic cefotaxime on agar plates. We find that mutant establishment probability is increased in the presence of susceptible cells due to the active breakdown of the antibiotic, but the rate of breakdown by the susceptible strain is much higher than expected based on its low enzymatic activity. A detailed theoretical model suggests that this observation can be explained by cell filamentation causing delayed lysis. While susceptible cells may hamper the spread of higher-resistant β-lactamase mutants at relatively high frequencies, our findings show that they could promote establishment during their emergence.
Sphingolipid-Induced Programmed Cell Death Is a Salicylic Acid and EDS1-Dependent Phenotype in Arabidopsis
Authors: König Stefanie , Gömann Jasmin , Zienkiewicz Agnieszka , Zienkiewicz Krzysztof , Meldau Dorothea , Herrfurth Cornelia , Feussner Ivo
Published: April 2021

Ceramides and long chain bases (LCBs) are plant sphingolipids involved in the induction of plant programmed cell death (PCD). Thefatty acid hydroxylasemutantfah1 fah2exhibits high ceramide levels and moderately elevated LCB levels. Salicylic acid (SA) is strongly induced in these mutants, but no cell death is visible. To determine the effect of ceramides with different chain lengths,fah1 fah2was crossed withceramide synthasemutantslongevity assurance gene one homologue1-3(loh1,loh2andloh3). Surprisingly, only triple mutants withloh2show a cell death phenotype under the selected conditions. Sphingolipid profiling revealed that the greatest differences between the triple mutant plants are in the LCB and LCB-phosphate (LCB-P) fraction.fah1 fah2 loh2plants accumulate LCB d18:0 and LCB-P d18:0. Crossingfah1 fah2 loh2with the SA synthesis mutantsid2-2, and with the SA signaling mutantsenhanced disease susceptibility 1-2(eds1-2) andphytoalexin deficient 4-1(pad4-1), revealed that lesions are SA- and EDS1-dependent. These quadruple mutants also suggest that there may be a feedback loop between SA and sphingolipid metabolism as they accumulated less ceramides and LCBs. In conclusion, PCD infah1 fah2 loh2is a SA and EDS1-dependent phenotype, which is likely due to accumulation of LCB d18:0.
Alzheimer’s disease-associatedTM2Dgenes regulate Notch signaling and neuronal function inDrosophila
Authors: Salazar Jose L. , Yang Sheng-An , Lin Yong Qi , Li-Kroeger David , Marcogliese Paul C. , Deal Samantha L. , Neely G. Gregory , Yamamoto Shinya
Published: April 2021

TM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each species. Rare variants inTM2D3are associated with Alzheimer’s disease (AD) and its fly orthologalmondexis required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all threeTM2Dgenes (almondex, CG11103/amaretto,CG10795/biscotti) inDrosophilaand found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive electrophysiological defects. The functional links between all threeTM2Dgenes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD.
Post-weaning social isolation increases reward-seeking behavior in a sex-specific manner in mice
Authors: Noback Michael , Barrow James C. , Carr Gregory V.
Published: April 2021

Social isolation is a growing concern in public health. Although isolation at any age is harmful, previous studies have shown that isolation during adolescence, correlating with critical periods of brain development, can impair cognitive function and increase the risk for psychiatric illness later in life. In this study, we utilized a mouse model of adolescent social isolation (SI) and compared performance of isolated and group-housed mice on touchscreen-based continuous performance test (CPT) and fixed ratio/progressive ratio (FR/PR) tasks in adulthood. SI increased sensitivity in the CPT in male mice and had no effect in female mice. The increase in sensitivity was consistent across time bins within the 45-minute testing session and there were no SI effects on reaction times or reward retrieval latencies. A possible confound for performance in the CPT would be SI-induced changes in reward-seeking or motivation for the strawberry milk reward. We next compared the SI mice to their group-housed littermate controls on both FR and PR schedules of reinforcement and found that male SI mice earned significantly more reinforcers on FR schedules of reinforcement and had higher breakpoints on PR schedules compared to their group-housed littermates. SI had no effect on FR or PR performance in female mice. These data indicate that SI during adolescence has striking, sex-specific effects on reward-seeking behavior in adult mice and may provide a useful behavioral model for studying the link between SI and risk for neuropsychiatric disorders.
Continuous multiplexed population representations of task context in the mouse primary visual cortex
Authors: Hajnal Márton Albert , Tran Duy , Einstein Michael , Martelo Mauricio Vallejo , Safaryan Karen , Polack Pierre-Olivier , Golshani Peyman , Orbán Gergő
Published: April 2021

Primary visual cortex (V1) neurons integrate motor and multisensory information with visual inputs during sensory processing. However, whether V1 neurons also integrate and encode higher-order cognitive variables is less understood. We trained mice to perform a context-dependent cross-modal decision task where the interpretation of identical audio-visual stimuli depends on task context. We performed silicon probe population recordings of neuronal activity in V1 during task performance and showed that task context (whether the animal should base its decision on visual or auditory stimuli) can be decoded during both intertrial intervals and stimulus presentations. Context and visual stimuli were represented in overlapping populations but were orthogonal in the population activity space. Context representation was not static but displayed distinctive dynamics upon stimulus onset and offset. Thus, activity patterns in V1 independently represent visual stimuli and cognitive variables relevant to task execution.
A Synthetic, Closed-Looped Gene Circuit for the Autonomous Regulation of RUNX2 Activity during Chondrogenesis
Authors: Kaur Gurcharan , Wu Biming , Murali Sunjana , Lanigan Thomas , Coleman Rhima M.
Published: April 2021

The transcription factor RUNX2 is a key regulator of chondrocyte phenotype during development, making it an ideal target for prevention of undesirable chondrocyte maturation in cartilage tissue engineering strategies. Here, we engineered an autoregulatory gene circuit (cisCXp-shRunx2) that negatively controls RUNX2 activity in chondrogenic cells via RNA interference initiated by a tunable syntheticCol10a1-like promoter (cisCXp). ThecisCXp-shRunx2gene circuit is designed based on the observation that induced RUNX2 silencing after early chondrogenesis enhances the accumulation of cartilaginous matrix in ATDC5 cells. We show that thecisCXp-shRunx2initiates RNAi of RUNX2 in maturing chondrocytes in response to the increasing intracellular RUNX2 activity without interfering with early chondrogenesis. The induced loss of RUNX2 activity in turn negatively regulates the gene circuit itself. Moreover, the efficacy of RUNX2 suppression fromcisCXp-shRunx2can be controlled by modifying the sensitivity ofcisCXp promoter. Finally, we show the efficacy of inhibiting RUNX2 in preventing matrix loss in human MSC-derived cartilage under conditions that induce chondrocyte hypertrophic differentiation, including inflammation. Overall, our results demonstrated that the negative modulation of RUNX2 activity with our autoregulatory gene circuit enhanced matrix synthesis and resists ECM degradation by reprogrammed MSC-derived chondrocytes in response to the microenvironment of the degenerative joint.
Trade-offs in biosensor optimization for dynamic pathway engineering
Authors: Verma Babita K. , Mannan Ahmad A. , Zhang Fuzhong , Oyarzún Diego A.
Published: April 2021

Recent progress in synthetic biology allows the construction of dynamic control circuits for metabolic engineering. This technology promises to overcome many challenges encountered in traditional pathway engineering, thanks to their ability to self-regulate gene expression in response to bioreactor perturbations. The central components in these control circuits are metabolite biosensors that read out pathway signals and actuate enzyme expression. However, the construction of metabolite biosensors is a major bottleneck for strain design, and a key challenge is to understand the relation between biosensor dose-response curves and pathway performance. Here we employ multiobjective optimization to quantify performance trade-offs that arise in the design and calibration of metabolite biosensors. Our approach reveals strategies for tuning dose-response curves along an optimal trade-off between production flux and the cost of an increased expression burden on the host. We explore properties of control architectures built in the literature, and identify their advantages and caveats in terms of performance and robustness to growth conditions and leaky promoters. We demonstrate the optimality of a control circuit for glucaric acid production inEscherichia coli, which has been shown to increase titer by 2.5-fold as compared to static designs. Our results lay the groundwork for the automated design of control circuits for pathway engineering, with applications in the food, energy and pharmaceutical sectors.
Anaerobic growth ofListeria monocytogeneson rhamnose is stimulated by Vitamin B12 and bacterial microcompartment dependent 1,2-propanediol utilization
Authors: Zeng Zhe , Li Siming , Boeren Sjef , Smid Eddy J. , Notebaart Richard A. , Abee Tjakko
Published: April 2021

The food-borne pathogenListeria monocytogenesis able to form proteinaceous organelles called bacterial microcompartments (BMCs) that optimize the utilization of substrates, such as 1,2-propanediol, and confer an anaerobic growth advantage. Rhamnose is a deoxyhexose sugar abundant in a range of environments including the human intestine, and can be degraded in anaerobic conditions into 1,2-propanediol, next to acetate and lactate. Rhamnose-derived 1,2-propanediol has been found to link with BMCs in a limited number of commensal human colonic species and some human pathogens such asSalmonella enterica, but the involvement of BMCs in rhamnose metabolism and potential physiological effects onL. monocytogenesare still unknown. In this study, we firstly test the effect of rhamnose uptake and utilization on anaerobic growth ofL. monocytogenesEGDe without and with added vitamin B12, followed by metabolic analysis. We unveil that the vitamin B12-dependent activation ofpdustimulates metabolism and anaerobic growth ofL. monocytogenesEGDe on rhamnose via 1,2-propanediol degradation into 1-propanol and propionate. Transmission electron microscopy ofpdu-induced cells shows that BMCs are formed and additional proteomics experiments confirm expression ofpduBMC shell proteins and enzymes. Finally, we discuss physiological effects and energy efficiency ofL. monocytogenes pduBMC-driven anaerobic rhamnose metabolism and impact on competitive fitness in environments such as the human intestine.
Heterologous reporter expression in the planarianSchmidtea mediterraneathrough somatic mRNA transfection
Authors: Hall Richard Nelson , Weill Uri , Drees Leonard , Leal-Ortiz Sergio , Li Hongquan , Chai Chew , Alvarado Alejandro Sánchez , Melosh Nicholas A. , Fire Andrew Z. , Rink Jochen C. , Wang Bo
Published: April 2021

Planarians have long been studied for their regenerative abilities. Moving forward, tools for ectopic expression of non-native proteins will be of substantial value. Using a luminescent reporter to overcome the strong autofluorescence background of planarian tissues, we demonstrate heterologous protein expression in planarian cells and live animals. Our approach is based on the introduction of mRNA through several nanotechnological and chemical transfection methods. We improve reporter expression by altering untranslated region (UTR) sequences and codon bias, facilitating measurement of expression kinetics both in isolated cells and in whole planarians using luminescence imaging. We also examine protein expression as a function of variations in the UTRs of delivered mRNA, demonstrating a framework to investigate gene regulation at the post-transcriptional level. Together, these advances expand the toolbox for the mechanistic analysis of planarian biology and establish a strong foundation for the development and expansion of transgenic techniques in this unique model system.

Motivation

The study of planarians has contributed to advances in our understanding of regeneration, stem cell dynamics, and many other fundamental biological processes. However, the persistent challenge of expressing transgenes in planarians has led to the speculation that they may be resistant to transfection. In this work, we develop methods to express exogenous mRNAs in both isolated planarian cells and whole animals by optimizing delivery techniques, genetic constructs, and detection methods. These methods allow us to study transfection kinetics and post-transcriptional regulation of gene expression in a quantitative manner. Beyond planarian research, this work should also provide a broadly applicable strategy to develop similar tools for animals that are also challenging to modify genetically.
Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease
Authors: MacDonald Elizabeth A. , Frey Gary , Namchuk Mark N. , Harrison Stephen C. , Hinshaw Stephen M. , Windsor Ian W.
Published: April 2021

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. It is required for infection, it cleaves the viral polyprotein at multiple sites, and it is conserved among coronaviruses and distinct from human proteases. We present crystal structures of SARS-CoV-2 Mprobound to two viral substrate peptides. The structures show how Mprorecognizes substrates and how the peptide sequence can dictate catalytic efficiency by influencing the position of the scissile bond. One peptide, constituting the junction between viral non-structural proteins 8 and 9 (nsp8/9), has P1’ and P2’ residues that are unique among SARS-CoV-2 cleavage sites but conserved among nsp8/9 junctions in coronaviruses. Mprocleaves nsp8/9 inefficiently, and amino acid substitutions at P1’ or P2’ can enhance catalysis. Visualization of Mprowith intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters.
Prediction of COVID-19 cases during Tokyo’s Olympic and Paralympic Games
Authors: Tokuda Yasuharu , Kuniya Toshikazu
Published: April 2021

Tokyo’s Olympic and Paralympic Games set to begin in late July 2021 without spectators from abroad, but vaccine rollout has been slow in Japan compared to other developed countries. In this study, COVID-19 epidemic curve in Tokyo is developed based on weekly reported data from January 23, 2020 until April 16, 2021. The maximum daily number of the infected cases in Tokyo in August 2021 would be 7,991 if the current pace of vaccinations (1/1,000 per day). This daily number is greater than the highest daily cases (2,447) recorded on January 7, 2021. However, if the rollout pace could be doubled (1/500 per day), the peak daily new cases would be 4,470 in August. If it could be quadrupled (1/250 per day), the peak would be noted at 2,128 in July and the highest number in August would be 1,977. If vaccine rollout could not be enhanced, the cancellation might be an acceptable decision, since health is the most precious to our Olympians.
REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion
Authors: Prestigio Cosimo , Ferrante Daniele , Marte Antonella , Romei Alessandra , Lignani Gabriele , Onofri Franco , Valente Pierluigi , Benfenati Fabio , Baldelli P Pietro
Published: April 2021

The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation triggers a homeostatic enhancement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs. Notably, this effect was only observed at inhibitory-onto-excitatory neuron synapses, whose density increased at perisomatic sites, demonstrating a strict target-selectivity. These effects were occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and BDNF gene programs. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at preserving physiological levels of neuronal activity in front of the ever-changing environment.

Impact Statement

This work elucidates the mechanisms by which the transcriptional regulator REST/NRSF selectively upregulates GABAergic transmission onto excitatory neurons in response to hyperactivity to rescue neuronal homeostasis.
Deep time course proteomics of SARS-CoV- and SARS-CoV-2-infected human lung epithelial cells (Calu-3) reveals strong induction of interferon-stimulated gene (ISG) expression by SARS-CoV-2 in contrast to SARS-CoV
Authors: Grossegesse Marica , Bourquain Daniel , Neumann Markus , Schaade Lars , Nitsche Andreas , Doellinger Joerg
Published: April 2021

SARS-CoV and SARS-CoV-2 infections are characterized by remarkable differences, including contagiosity and case fatality rate. The underlying mechanisms are not well understood, illustrating major knowledge gaps of coronavirus biology. In this study, protein expression of SARS-CoV- and SARS-CoV-2-infected human lung epithelial cell line Calu-3 was analysed using data-independent acquisition mass spectrometry (DIA-MS). This resulted in the so far most comprehensive map of infection-related proteome-wide expression changes in human cells covering the quantification of 7478 proteins across 4 time points. Most notably, the activation of interferon type-I response was observed, which surprisingly is absent in other recent proteome studies, but is known to occur in SARS-CoV-2-infected patients. The data reveal that SARS-CoV-2 triggers interferon-stimulated gene (ISG) expression much stronger than SARS-CoV, which reflects the already described differences in interferon sensitivity. Potentially, this may be caused by the enhanced expression of viral M protein of SARS-CoV in comparison to SARS-CoV-2, which is a known inhibitor of type I interferon expression. This study expands the knowledge on the host response to SARS-CoV-2 infections on a global scale using an infection model, which seems to be well suited to analyse innate immunity.
Comparative Analysis of Emerging B.1.1.7+E484K SARS-CoV-2 isolates from Pennsylvania
Authors: Moustafa Ahmed M. , Bianco Colleen , Denu Lidiya , Ahmed Azad , Neide Brandy , Everett John , Reddy Shantan , Rabut Emilie , Deseignora Jasmine , Feldman Michael D. , Rodino Kyle G. , Bushman Frederic , Harris Rebecca M. , Mell Josh Chang , Planet Paul J.
Published: April 2021

Rapid whole genome sequencing of SARS-CoV-2 has presented the ability to detect new emerging variants of concern in near real time. Here we report the genome of a virus isolated in Pennsylvania in March 2021 that was identified as lineage B.1.1.7 (VOC-202012/01) that also harbors the E484K spike mutation, which has been shown to promote “escape” from neutralizing antibodiesin vitro. We compare this sequence to the only 5 other B.1.1.7+E484K genomes from Pennsylvania, all of which were isolated in mid March. Beginning in February 2021, only a small number (n=60) of isolates with this profile have been detected in the US, and only a total of 253 have been reported globally (first in the UK in December 2020). Comparative genomics of all currently available high coverage B.1.1.7+E484K genomes (n=235) available on GISAID suggested the existence of 7 distinct groups or clonal complexes (CC; as defined by GNUVID) bearing the E484K mutation raising the possibility of 7 independent acquisitions of the E484K spike mutation in each background. Phylogenetic analysis suggested the presence of at least 3 distinct clades of B.1.1.7+E484K circulating in the US, with the Pennsylvanian isolates belonging to two distinct clades. Increased genomic surveillance will be crucial for detection of emerging variants of concern that can escape natural and vaccine induced immunity.
Genome-wide strand asymmetry in massively parallel reporter activity favors genic strands
Authors: Roberts Brian S. , Partridge E. Christopher , Moyers Bryan A. , Agarwal Vikram , Newberry Kimberly M. , Martin Beth K. , Shendure Jay , Myers Richard M. , Cooper Gregory M.
Published: April 2021

Massively parallel reporter assays (MPRAs) are useful tools to characterize regulatory elements in human genomes. An aspect of MPRAs that is not typically the focus of analysis is their intrinsic ability to differentiate activity levels for a given sequence element when placed in both of its possible orientations relative to the reporter construct. Here, we describe pervasive strand asymmetry of MPRA signals in data sets from multiple reporter configurations in both published and newly reported data. These effects are reproducible across different cell types and in different treatments within a cell type and are observed both within and outside of annotated regulatory elements. From elements in gene bodies, MPRA strand asymmetry favors the sense strand, suggesting that function related to endogenous transcription is driving the phenomenon. Similarly, we find that within Alu mobile element insertions, strand asymmetry favors the transcribed strand of the ancestral retrotransposon. The effect is consistent across the multiplicity of Alu elements in human genomes and is more pronounced in less diverged Alu elements. We find sequence features driving MPRA strand asymmetry and show its prediction from sequence alone. We see some evidence for RNA stabilization and transcriptional activation mechanisms and hypothesize that the effect is driven by natural selection favoring efficient transcription. Our results indicate that strand asymmetry is a pervasive and reproducible feature in MPRA data. More importantly, the fact that MPRA asymmetry favors naturally transcribed strands suggests that it stems from preserved biological functions that have a substantial, global impact on gene and genome evolution.
Less‐favoured‐area payments, farmland abandonment and farm size: evidence from hilly and mountainous areas in Japan*
Authors: Takayama Taisuke , Nakatani Tomoaki , Senda Tetsuji , Fujie Takeshi
Published: April 2021

A direct payment (DP) scheme for hilly and mountfainous areas has been in place in Japan since 2000. This scheme’s objective is to fill the gap in production costs between these less favourable areas and other agricultural locations and prevent abandoned farmland from increasing. Eligible rural communities decide whether to receive DPs, and half of the DP allocation in communities with DPs is distributed for collaborative community activities, with the remaining half allocated directly to farmers. We apply a difference‐in‐differences approach to examine the effect of these payments on farmland use. Using a large farm‐level panel data set from before and after the payments were initiated, we employ a causal framework of analysis with a treatment group and two alternative control groups. We find that the payments led to a slowdown in the increase of abandoned farmland among surviving farms. Moreover, the payments have a marginal positive effect on the operated farm size of surviving farmers. The results imply that direct payment schemes in less‐favoured areas play a key role in maintaining farmland.
Resource dependence and the causes of local economic growth: An empirical investigation*
Authors: Hilmawan Rian , Clark Jeremy
Published: April 2021

Previous research has found that regional resource dependence in Indonesia has been positively associated with income growth, contrary to a ‘resource curse’. We test five potential causal mechanisms for this positive effect: spillovers to manufacturing or to agriculture, higher education provision, improved institutional quality and share of public spending on capital. We follow 390 Indonesian districts from 2006 to 2015, using four alternative resource dependence measures, and instrumenting for their potential endogeneity. We first confirm a positive overall effect of resource dependence on real per capita Gross Regional Domestic Product (GRDP), then test whether district resource dependence positively affects manufacturing, agriculture, education, public capital investment and institutional quality. We finally test whether these factors contribute to GRDP while reducing the remaining effect of resource dependence. We find that resource dependence may aid income in part by raising district institutional quality, which in turn raises GRDP. We also find little support for a ‘contingent curse’ hypothesis that resource dependence only benefits districts that already have higher institutional quality.
Is a nudge all we need to promote deliberate clinical inertia and thoughtful clinical decision making?
Authors: Foster Mieke , Egerton‐Warburton Diana , Cullen Louise , Fatovich Daniel M , Keijzers Gerben
Published: April 2021

Deliberate clinical inertia is the art of doing nothing as a positive response. Individual clinicians can promote deliberate clinical inertia through teaching, re‐framing the act of ‘doing nothing’ as ‘doing something’ and engaging in shared decision making. Behaviour change on a larger scale requires a systematic approach. Nudging is a subtle change to the decision‐making context to prompt specific choices. A nudge unit is a team of relevant professionals who engage with various multidisciplinary teams within a health service who help test and implement nudge interventions in a clinical environment. A nudge unit could be used to design environments to prompt clinicians to re‐think before ordering unnecessary tests or treatments. Nudge units could improve knowledge translation, support continuous quality improvement and help build a learning health system. They could also boost collaboration and empower staff to evaluate their workplace decision‐making frameworks.
International student mobilities in a contagion: (Im)mobilising higher education?
Authors: Sidhu Ravinder , Cheng Yi' En , Collins Francis , Ho Kong Chong , Yeoh Brenda
Published: April 2021

This article reflects on the possible effects of the COVID‐19 pandemic on international student mobilities and higher education systems. Celebrated as a ‘success’ story of a mutually beneficial globalisation, international higher education as we have known it is unravelling and reassembling. We offer an overview of the material changes and public discourses that are reframing student mobilities and higher education from three Anglophone positions involving Australia, Singapore, and New Zealand. The authors interrogate the amplified role of digital infrastructures in remaking international higher education, through border management practices and digital learning strategies. We outline changes at the urban scale that are starting to take hold from the stasis in student mobilities. We also speculate on emerging modalities of international higher education and their accompanying economies of opportunities and vulnerabilities. Our reflections take seriously calls to understand the wide‐reaching implications of an invisible, border‐crossing microbe, and interrupt the impulse to resurrect what came before the pandemic. It is in this spirit of thoughtful reflection to stop rebuilding ‘more of the same’ that we interrogate novel border rationalities and market making, which are being called on in work to govern space–time and subjects in a fragile post‐COVID world.
Morphological and scanning electron microscopic study of the gonadal arterioles in the Tibetan sheep
Authors: Guo Yajun , Yang Yanan , Wang Biao , Liu Chengze , Li Mingna , Wang Xinrong
Published: April 2021

This research aimed at revealing the structural features of Tibetan sheep's testicular and ovarian vasculature and providing theoretical basis for Tibetan sheep's physiological adaptability in plateau and low‐oxygen environments. Through scanning electron microscopy, corrosion casts of the feature of the gonad arterioles were observed and analysed. The results of this study found that centrifugal arteries, centrifugal and centripetal arterioles were distributed in a ‘dendritic’ fashion in the testis lobule, the ovarian arteries and arterioles, which had a spiral shape. Testicular Tibetan Sheep knot‐like artery had a denser spiral structure, and there were more branches in the microarteries. On the testis lobule and arteriole of caput epididymidis, the arteriole surface shows the ‘fusiform’ indentation to be more shallower. The ovarian artery had a higher degree of helix; its surface was distributed like a ‘bark‐like’ indentation; and the ring was narrower and denser. Nevertheless, the arteriole network had a high concentration and a wide number of branches, as that of the ovarian arteriole network which had more end branches, the surface of the arterioles of ovaries and testicles was scarred and denser. The studies indicate that the structural features of testicular lobule, epididymal arterioles and ovarian arterioles are more conducive to increase the oxygen supply to the gonads tissue and controlling blood flow velocity and metabolism to respond to high altitudes and low‐oxygen environments.
Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation‐dependent probe amplification and genotype–phenotype correlation in 138 Turkish patients
Authors: Güneş Nilay , Yeşil Gözde , Geyik Filiz , Kasap Büşra , Celkan Tiraje , Kebudi Rejin , Tüysüz Beyhan
Published: April 2021

Objective

To investigate the variant spectrum and genotype–phenotype correlations in a Turkish cohort with Neurofibromatosis Type‐1 (NF1).

Materials and methods

 We retrospectively investigated the clinical and molecular data of 138 NF1 patients from 129 families who had been followed‐up for a median of 3.9 (1.25–18.5) years.

Results

NF1 sequencing revealed 73 different intragenic variants, 19 of which were novel. Seven large deletions were detected by multiplex ligation‐dependent probe amplification (MLPA) analyses. The total detection rate of pathogenic NF1 variants was found to be 87.1%. Comparing age groups, cutaneous neurofibromas, freckling, and Lisch nodules were more prevalent in patients older than 12 years (p > .05). Optic glioma detected in 17.3% of the patients and was significantly more common before the age of 6 (p > .001). Other solid tumors developed in 5% of the patients. There was no genotype–phenotype correlation between patients with truncating and nontruncating variants. However, six out of seven patients with large deletions had significant developmental delay, one patient with the c.2970_2972delAAT (p.Met992del) variant had only typical pigmentary features, and another patient with the c.4267A > G (p.Lys1423Glu) variant had CALMs, freckling, neurofibromas, and Noonan‐like phenotype.

Conclusions

We described 19 novel variants and seven large deletions in NF1. Applying MLPA assay in NF1 is useful in expanding the molecular diagnosis. Although very limited genotype–phenotype correlation has been reported in NF1, the fact that specific phenotypic findings were observed in our patients with large deletions and two intragenic variants supports the studies published recently.
Visualising and understanding cGMP signals in the cardiovascular system
Authors: Feil Robert , Lehners Moritz , Stehle Daniel , Feil Susanne
Published: April 2021

cGMP is an important signalling molecule in humans. Fluorescent cGMP biosensors have emerged as powerful tools for the sensitive analysis of cGMP pathways at the single‐cell level. Here, we briefly outline cGMP's multifaceted role in (patho)physiology and pharmacotherapy. Then we summarise what new insights cGMP imaging has provided into endogenous cGMP signalling and drug action, with a focus on the cardiovascular system. Indeed, the use of cGMP biosensors has led to several conceptual advances, such as the discovery of local, intercellular and mechanosensitive cGMP signals. Importantly, single‐cell imaging can provide valuable information about the heterogeneity of cGMP signals within and between individual cells of an isolated cell population or tissue. We also discuss current challenges and future directions of cGMP imaging, such as the direct visualisation of cGMP microdomains, simultaneous monitoring of cGMP and other signalling molecules and, ultimately, cGMP imaging in tissues and animals under close‐to‐native conditions.

LINKED ARTICLES

This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc
L‐NAME, a nitric oxide synthase inhibitor, increases the protein expression of both executioner and inhibitor of apoptosis in the placental bed of mid‐to‐late pregnant rats
Authors: Ishikawa Wataru , Kazama Shugo , Suzuki Takehito , Yamana Rei , Miyazaki Yoko , Tanaka Kazuaki , Usami Makoto , Takizawa Tatsuya
Published: April 2021

The involvement of nitric oxide (NO) signaling in apoptosis was examined in the placental bed of mid‐to‐late pregnant rats. Pregnant rats were treated with l‐NAME, a nitric oxide synthase inhibitor, by subcutaneous infusion for 48 hours before the examination at day 13.5, 17.5, or 21.5. l‐NAME induced apoptosis in the placental bed to a limited extent at days 13.5 and 17.5, but not at day 21.5. When the placental bed was examined at day 17.5, the protein expression of both executioner (C‐Cas3) and inhibitor (XIAP) of apoptosis was increased by l‐NAME, but they did not co‐localized with apoptosis. It was presumed that placental bed apoptosis induced by l‐NAME is regulated through the expression of both executioner and inhibitor, possibly involving protein S‐nitrosylation.
Nickel and tattoos: Where are we?
Authors: Kluger Nicolas
Published: April 2021

Tattoos are not mentioned as a source of exposure to nickel. Traces of nickel are, however, almost inevitably found in tattoo inks as impurities and sometimes in tattooed skin. Whether nickel in tattoos has any health consequence is debated. We performed a narrative review of what is currently known about this topic. Today, nickel is frequently detected in inks, but at highly variable levels. It appears to be at higher concentrations in green, blue, and sometimes brown and violet inks. Only nickel allergy in tattooed individuals and nickel‐associated tattoo ink allergy are addressed in the literature. Reports of tattoo ink allergy related to nickel are rare and heterogenous. Authors often neglect possible implications of other metals or dyes. A positive patch test is not enough to confirm the role of nickel in a reaction observed after tattooing. We found no report of any systemic complication attributed to nickel from tattoos. The Council of Europe bans the presence of nickel at high levels in tattoo inks, which is a safety net for individuals with nickel allergy. Large epidemiologic case–control studies with systematic biopsies on normal and inflamed tattoos and patch testing would help to understand the role of nickel in tattoo ink allergies.
Detecting a copycat effect in school shootings using spatio‐temporal panel count models
Authors: Schweikert Karsten , Huth Manuel , Gius Mark
Published: April 2021

School shootings are often motivated by the perpetrators' desire for media attention and notoriety. As school shootings receive intense regional and national media coverage, a high likelihood for copycat attacks can be expected. We investigate whether a copycat effect can be detected in US state‐level school shooting data from 1990 to 2017. We do so by estimating spatio‐temporal panel count models and control for socio‐economic characteristics, as well as state and Federal gun control laws. Positive spatial and temporal dependence indicate that the risk for additional school shootings in the same and neighboring states increases after the initial attack.
How Children Process Reduced Forms: A Computational Cognitive Modeling Approach to Pronoun Processing in Discourse
Authors: Vogelzang Margreet , Guasti Maria Teresa , van Rijn Hedderik , Hendriks Petra
Published: April 2021

Reduced forms such as the pronoun he provide little information about their intended meaning compared to more elaborate descriptions such as the lead singer of Coldplay. Listeners must therefore use contextual information to recover their meaning. Across languages, there appears to be a trade‐off between the informativity of a form and the prominence of its referent. For example, Italian adults generally interpret informationally empty null pronouns as in the sentence Corre (meaning “He/She/It runs”) as referring to the most prominent referent in the discourse, and more informative overt pronouns (e.g., lui in Lui corre, “He runs”) as referring to less prominent referents. Although children acquiring Italian are known to experience difficulties interpreting pronouns, it is unclear how they acquire this division of pragmatic labor between null and overt subject pronouns, and how this relates to the development of their cognitive capacities. Here we show that cognitive development can account for the general interpretation patterns displayed by Italian‐speaking children and adults. Using experimental studies and computational simulations in a framework modeling bounded‐rational behavior, we argue that null pronoun interpretation is influenced by working memory capacity and thus appears to depend on discourse context, whereas overt pronoun interpretation is influenced by processing speed, suggesting that listeners must reason about the speaker's choices. Our results demonstrate that cognitive capacities may constrain the acquisition of linguistic forms and their meanings in various ways. The novel predictions generated by the computational simulations point out several directions for future research.
Direct Versus Indirect Causation as a Semantic Linguistic Universal: Using a Computational Model of English, Hebrew, Hindi, Japanese, and K'iche’ Mayan to Predict Grammaticality Judgments in Balinese
Authors: Aryawibawa I Nyoman , Qomariana Yana , Artawa Ketut , Ambridge Ben
Published: April 2021

The aim of this study was to test the claim that languages universally employ morphosyntactic marking to differentiate events of more‐ versus less‐direct causation, preferring to mark them with less‐ and more‐ overt marking, respectively (e.g., Somebody broke the window vs. Somebody MADE the window break; *Somebody cried the boy vs. Somebody MADE the boy cry). To this end, we investigated whether a recent computational model which learns to predict speakers’ by‐verb relative preference for the two causatives in English, Hebrew, Hindi, Japanese, and K'iche’ Mayan is able to generalize to a sixth language on which it has never been trained: Balinese. Judgments of the relative acceptability of the less‐ and more‐transparent causative forms of 60 verbs were collected from 48 native‐speaking Balinese adults. The composite crosslinguistic computational model was able to predict these judgments, not only for verbs that it had seen, but also––in a split‐half validation test––to verbs that it had never seen in any language. A “random‐semantics” model showed only a relatively small decrement in performance with seen verbs, whose behavior can be learned on a verb‐by‐verb basis, but achieved zero correlation with human judgments when generalizing to unseen verbs. Together, these findings suggest that Balinese conceptualizes directness of causation in a similar way to these unrelated languages, and therefore constitute support for the view that the distinction between more‐ versus less‐distinct causation constitutes a morphosyntactic universal.
How Reliably Do Eye Parameters Indicate Internal Versus External Attentional Focus?
Authors: Annerer‐Walcher Sonja , Ceh Simon M. , Putze Felix , Kampen Marvin , Körner Christof , Benedek Mathias
Published: April 2021

Eye behavior is increasingly used as an indicator of internal versus external focus of attention both in research and application. However, available findings are partly inconsistent, which might be attributed to the different nature of the employed types of internal and external cognition tasks. The present study, therefore, investigated how consistently different eye parameters respond to internal versus external attentional focus across three task modalities: numerical, verbal, and visuo‐spatial. Three eye parameters robustly differentiated between internal and external attentional focus across all tasks. Blinks, pupil diameter variance, and fixation disparity variance were consistently increased during internally directed attention. We also observed substantial attentional focus effects on other parameters (pupil diameter, fixation disparity, saccades, and microsaccades), but they were moderated by task type. Single‐trial analysis of our data using machine learning techniques further confirmed our results: Classifying the focus of attention by means of eye tracking works well across participants, but generalizing across tasks proves to be challenging. Based on the effects of task type on eye parameters, we discuss what eye parameters are best suited as indicators of internal versus external attentional focus in different settings.
Is Aristotelian friendship disinterested?: Aristotle on loving the other for himself and wishing goods for the other's sake
Authors: Kim Bradford Jean‐Hyuk
Published: April 2021

It has been not atypical for commentators to argue that Aristotelian friendship features disinterested concern for others, that is, concern for others that is completely independent of one's own happiness. Often, the relevant commentators point to some normative features of Aristotelian friendship, wishing goods for the other's sake and loving the other for herself, where these are assumed to be disinterested. While the disinterested interpretations may be correct overall, I argue that wishing goods for the other's sake and loving the other for herself constitute a dubious foundation for disinterested interpretations. For wishing goods for the other's sake does not involve a reason for action on the other's behalf, and the primary point of loving the other for herself is the role of the other in facilitating one's own happiness, specifically conceived of by Aristotle in terms of one's own virtuous activity.
Spatiotemporal modelling of soil moisture in an Atlantic forest through machine learning algorithms
Authors: de Oliveira Vinicius Augusto , Rodrigues André Ferreira , Morais Marco Antônio Vieira , Terra Marcela de Castro Nunes Santos , Guo Li , de Mello Carlos Rogério
Published: April 2021

Understanding the spatiotemporal behaviour of soil moisture in tropical forests is fundamental because it mediates processes such as infiltration, groundwater recharge, runoff and evapotranspiration. This study aims to model the spatiotemporal dynamics of soil moisture in an Atlantic forest remnant (AFR) through four machine learning algorithms, as these dynamics represent an important knowledge gap under tropical conditions. Random forest (RF), support vector machine, average neural network and weighted k‐nearest neighbour were studied. The abilities of the models were evaluated by means of root mean square error, mean absolute error, coefficient of determination (R2) and Nash‐Sutcliffe efficiency (NS) for two calibration approaches: (a) chronological and (b) randomized. The models were further compared with a multilinear regression (MLR). The study period spans from September 2012 to November 2019 and relies on variables representing the weather, geographical location, forest structure, soil physics and morphology. RF was the best algorithm for modelling the spatiotemporal dynamics of the soil moisture with an NS of 0.77 and R2 of 0.51 in the randomized approach. This finding highlights the ability of RF to generalize a dataset with contrasting weather conditions. Kriging maps highlighted the suitability of RF to track the spatial distribution of soil moisture in the AFR. Throughfall (TF), potential evapotranspiration (ETo), longitude (Long), diameter at breast height (DBH) and species diversity (H) were the most important variables controlling soil moisture. MLR performed poorly in modelling the spatiotemporal dynamics of soil moisture due to the highly nonlinear condition of this process.

Highlights

Modelling soil moisture in an Atlantic forest through machine learning.

Machine learning algorithms are powerful tools to address the spatiotemporal dynamics of soil moisture.

Climate, position and forest variables drive the spatiotemporal pattern of soil moisture.

Random forest is the best algorithm to simulate soil moisture dynamics.