bluuebunny/crossref_metadata_2025 huggingface dataset:
RAREsim: A simulation method for very rare genetic variants
Authors: Null Megan , Dupuis Josée , Gignoux Christopher R. , Hendricks Audrey E.
Published: April 2021

Identification of rare variant associations is crucial to fully characterize the genetic architecture of complex traits and diseases. Essential in this process is the evaluation of novel methods in simulated data that mirrors the distribution of rare variants and haplotype structure in real data. Additionally, importing real variant annotation enables in silico comparison of methods that focus on putative causal variants, such as rare variant association tests, and polygenic scoring methods. Existing simulation methods are either unable to employ real variant annotation or severely under- or over-estimate the number of singletons and doubletons reducing the ability to generalize simulation results to real studies. We present RAREsim, a flexible and accurate rare variant simulation algorithm. Using parameters and haplotypes derived from real sequencing data, RAREsim efficiently simulates the expected variant distribution and enables real variant annotations. We highlight RAREsim’s utility across various genetic regions, sample sizes, ancestries, and variant classes.
Characteristic changes in EEG spectral powers of patients with opioid-use disorder as compared with those with methamphetamine- and alcohol-use disorders
Authors: Minnerly Christopher , Shokry Ibrahim M. , To William , Callanan John J , Tao Rui
Published: April 2021

Electroencephalography (EEG) likely reflects activity of cortical neurocircuits, making it an insightful estimation for mental health in patients with substance use disorder (SUD). EEG signals are recorded as sinusoidal waves, containing spectral amplitudes across several frequency bands with high spatio-temporal resolution. Prior work on EEG signal analysis has been made mainly at individual electrodes. These signals can be evaluated from advanced aspects, including sub-regional and hemispheric analyses. Due to limitation of computational techniques, few studies in earlier work could conduct data analyses from these aspects. Therefore, EEG in patients with SUD is not fully understood. In the present retrospective study, spectral powers from a data house containing opioid (OUD), methamphetamine/stimulants (MUD), and alcohol use disorder (AUD) were extracted, and then converted into five distinct topographic data (i.e., electrode-based, cortical subregion-based, left-right hemispheric, anterior-posterior based, and total cortex-based analyses). We found that EEG spectral powers in patients with OUD were significantly different from those with MUD or AUD. Differential changes were observed from multiple perspectives, including individual electrodes, subregions, hemispheres, anterior-posterior cortices, and across the cortex as a whole. Understanding the differential changes in EEG signals may be useful for future work with machine learning and artificial intelligence (AI), not only for diagnostic but also for prognostic purposes in patients with SUD.
Training Data Distribution Significantly Impacts the Estimation of Tissue Microstructure with Machine Learning
Authors: Gyori Noemi G. , Palombo Marco , Clark Christopher A. , Zhang Hui , Alexander Daniel C.
Published: April 2021

Purpose

Supervised machine learning (ML) provides a compelling alternative to traditional model fitting for parameter mapping in quantitative MRI. The aim of this work is to demonstrate and quantify the effect of different training strategies on the accuracy and precision of parameter estimates when supervised ML is used for fitting.

Methods

We fit a two-compartment biophysical model to diffusion measurements from in-vivo human brain, as well as simulated diffusion data, using both traditional model fitting and supervised ML. For supervised ML, we train several artificial neural networks, as well as random forest regressors, on different distributions of ground truth parameters. We compare the accuracy and precision of parameter estimates obtained from the different estimation approaches using synthetic test data.

Results

When the distribution of parameter combinations in the training set matches those observed in similar data sets, we observe high precision, but inaccurate estimates for atypical parameter combinations. In contrast, when training data is sampled uniformly from the entire plausible parameter space, estimates tend to be more accurate for atypical parameter combinations but may have lower precision for typical parameter combinations.

Conclusion

This work highlights the need to consider the choice of training data when deploying supervised ML for estimating microstructural metrics, as performance depends strongly on the training-set distribution. We show that high precision obtained using ML may mask strong bias, and visual assessment of the parameter maps is not sufficient for evaluating the quality of the estimates.
Intercalated Disk Nanoscale Structure Regulates Cardiac Conduction
Authors: Moise Nicolae , Struckman Heather L. , Dagher Celine , Veeraraghavan Rengasayee , Weinberg Seth H.
Published: April 2021

The intercalated disk (ID) is a specialized subcellular region that provides electrical and mechanical connections between myocytes in the heart. The ID has a clearly defined passive role in cardiac tissue, transmitting mechanical forces and electrical currents between cells. Recent studies have shown that Na+channels, the primary current responsible for cardiac excitation, are preferentially localized at the ID, particularly within nanodomains around mechanical and gap junctions, and that perturbations of ID structure alter cardiac conduction. This suggests that the ID may play an important, active role in regulating conduction. However, the structure of the ID and intercellular cleft are not well characterized, and to date, no models have incorporated the influence of ID structure on conduction in cardiac tissue. In this study, we developed an approach to generate realistic finite element model (FEM) meshes replicating ID nanoscale structure, based on experimental measurements from transmission electron microscopy (TEM) images. We then integrated measurements of the intercellular cleft electrical conductivity, derived from the FEM meshes, into a novel cardiac tissue model formulation. FEM-based calculations predict that the distribution of cleft conductances are sensitive to regional changes in ID structure, specifically the intermembrane separation and gap junction distribution. Tissue-scale simulations demonstrated that ID structural heterogeneity leads to significant spatial variation in electrical polarization within the intercellular cleft. Importantly, we find that this heterogeneous cleft polarization regulates conduction by desynchronizing the activation of post-junctional Na+currents. Additionally, these heterogeneities lead to a weaker dependence of conduction velocity on gap junctional coupling, compared with prior modeling formulations that neglect or simplify ID structure. Further, we find that disruption of local ID nanodomains can lead to either conduction slowing or enhancing, depending on gap junctional coupling strength. Overall, our study demonstrates that ID nanoscale structure can play a significant role in regulating cardiac conduction.
Dynamics ofSalmonellainoculated during rearing of black soldier fly larvae (Hermetia illucens) on chicken feed
Authors: De Smet J. , Vandeweyer D. , Van Moll L. , Lachi D. , Van Campenhout L.
Published: April 2021

The black soldier fly is currently the most produced edible insect on industrial scale, with its larval stage being processed into animal feed as the main application. As this insect species enters the feed and food chain, good hygiene and monitoring practices are needed to avoid the entrance of foodborne pathogens via the larvae. However, insufficient data on the risk of such introductions via industrial larvae production are available. To address this gap, a range of rearing trials were conducted in which the substrate, chicken feed, was inoculated with different levels ofSalmonellaand in which total viable counts andSalmonellacounts were determined during the following days. The outgrowth ofSalmonellawas slower in those experiments with a lower initial contamination level than in experiments with a higher level. No significant reducing effect originating from the larvae on the substrateSalmonellacounts was observed, in contrast to previous studies using other substrates. Our study also revealed that airborne transmission ofSalmonellais possible under rearing conditions corresponding to those applied at industrial production sites. Based on our results, we recommend insect producers to use substrate ingredients free ofSalmonella, and not to count on the antimicrobial activities that BSFL may exert in some situations towards food pathogens. More inoculation studies using otherSalmonellaserotypes, other zoonotic bacteria, other substrates, larvae of other ages and including variations on rearing protocols are needed in order to obtain a general view on the dynamics of food pathogens in this insect species and to support comprehensive risk assessments.
A Platform for Oncogenomic Reporting and Interpretation
Authors: Reisle Caralyn , Williamson Laura , Pleasance Erin , Davies Anna , Pellegrini Brayden , Bleile Dustin W , Mungall Karen L , Chuah Eric , Jones Martin R , Ma Yussanne , Beckie Isaac , Pham David , Pletz Raphael Matiello , Muhammadzadeh Amir , Pierce Brandon M , Li Jacky , Stevenson Ross , Wong Hansen , Bailey Lance , Reisle Abbey , Douglas Matthew , Bonakdar Melika , Nelson Jessica M T , Grisdale Cameron J , Krzywinski Martin , Fisic Ana , Mitchell Teresa , Renouf Daniel J , Yip Stephen , Laskin Janessa , Marra Marco A , Jones Steven J M
Published: April 2021

Manual interpretation of variants remains rate limiting in precision oncology. The increasing scale and complexity of molecular data generated from comprehensive sequencing of cancer samples requires advanced interpretative platforms as precision oncology expands beyond individual patients to entire populations. To address this unmet need, we created the Platform for Oncogenomic Reporting and Interpretation (PORI), comprising an analytic framework created to facilitate the interpretation and reporting of somatic variants in cancer. PORI is unique in its integration of reporting and graph knowledge base tools combined with support for manual curation at the reporting stage. PORI represents one of the first open-source platform alternatives to commercial reporting solutions suitable for comprehensive genomic data sets in precision oncology. We demonstrate the utility of PORI by matching 9,961 TCGA tumours to the graph knowledge base, revealing that 88.2% have at least one potentially targetable alteration, and making available reports describing select individual samples.
UCell: robust and scalable single-cell gene signature scoring
Authors: Andreatta Massimo , Carmona Santiago J.
Published: April 2021

UCell is an R package for evaluating gene signatures in single-cell datasets. UCell signature scores, based on the Mann-Whitney U statistic, are robust to dataset size and heterogeneity, and their calculation demands less computing time and memory than other available methods, enabling the processing of large datasets in a few minutes even on machines with limited computing power. UCell can be applied to any single-cell data matrix, and includes functions to directly interact with Seurat objects. The UCell package and documentation are available on GitHub athttps://github.com/carmonalab/UCell
Sex differences and risk factors for bleeding in Alagille syndrome
Authors: Hankeova Simona , Van Hul Noemi , Laznovsky Jakub , Mangold Katrin , Hensens Naomi , Verhoef Elvira , Zikmund Tomas , Dawit Feven , Kavkova Michaela , Salplachta Jakub , Sjöqvist Marika , Johansson Bengt R. , Hassan Mohamed , Fredriksson Linda , Bryja Vitezslav , Lendahl Urban , Jheon Andrew , Alten Florian , Fahnehjelm Kristina Teär , Fischler Björn , Kaiser Jozef , Andersson Emma R.
Published: April 2021

Spontaneous lethal bleeds are major cause of death in the pediatric liver disease Alagille syndrome (ALGS), yet risk factors and screening methods have not been established. We performed a systematic review and identified significantly more female than male patients with idiopathic intracranial hemorrhage (10:1). We investigated bleeding and vasculature in patients and a mouse model for ALGS (Jag1Ndr/Ndrmice) and asked whether phenotypes identified in mice could be detected in patients non-invasively.Jag1Ndr/Ndrmice bled spontaneously, exhibiting a thin skull and vascular defects including artery-vein crossings, tortuous vessels, capillary breakdown and CADASIL-like sparse vascular smooth muscle cell coverage which was aggravated by hypertension. Retinographs from patients confirmed tortuous blood vessels and artery-vein crossings in ALGS. In conclusion,Jag1Ndr/Ndrmice could be used to develop interventions for vascular defects in ALGS, and retinography could provide a non-invasive method for vascular analysis in these pediatric patients.
Visualization of reactive astrocytes in living brain of Alzheimer’s disease patient
Authors: Nam Min-Ho , Ko Hae Young , Lee Sangwon , Park Yongmin Mason , Hyeon Seung Jae , Won Woojin , Kim Seon Yoo , Jo Han Hee , Chung Jee-In , Han Young-Eun , Lee Gwan-Ho , Ju Yeonha , Stein Thor D. , Kong Mingyu , Lee Hyunbeom , Lee Seung Eun , Oh Soo-Jin , Chun Joong-Hyun , Park Ki Duk , Ryu Hoon , Yun Mijin , Lee C. Justin
Published: April 2021

An early appearance of reactive astrocytes is a hallmark of Alzheimer’s disease (AD)1,2, providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brainin vivo. Here, we report that PET/CT imaging with11C-acetate and18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.
Visualizing cancer-originated acetate uptake through MCT1 in reactive astrocytes demarcates tumor border and extends survival in glioblastoma patients
Authors: Ko Hae Young , Chung Jee-In , Kim Dongwoo , Park Yongmin Mason , Jo Han Hee , Lee Sangwon , Kim Seon Yoo , Kim Jisu , Chun Joong-Hyun , Han Kyung-Seok , Lee Misu , Ju Yeonha , Park Sun Jun , Park Ki Duk , Nam Min-Ho , Park Youngjoo , Kim Se Hoon , Shim Jin-Kyoung , Kang Seok-Gu , Chang Jong Hee , Lee C. Justin , Yun Mijin
Published: April 2021

Glioblastoma multiforme (GBM) is a devastating brain tumor with dismal prognosis of only 15-month survival regardless of surgical resection. Here, we report an advanced neuroimaging technique combining11C-acetate PET and MRI (AcePET), visualizing the boundary beyond the MRI-defined tumor. Targeted biopsy of the regions with increased11C-acetate uptake revealed the presence of reactive astrocytes with enhanced acetate-transporter MCT1, along with cancer stem cells. Reactive astrogliosis and MCT1-dependent11C-acetate-uptake were recapitulated in U87MG-orthotopic models. Mechanistically, glycolytic tumor cells release excessive acetate causing reactive astrogliosis, leading to the release of aberrant astrocytic GABA and H2O2, which further down-regulate the neuronal glucose uptake through GLUT3. Clincally, AcePET-guided surgery allows complete tumor resection of infiltrating cancer stem cells and extends the overall survival of patients by 5.25 months compared to conventional MRI-guided surgery. We established a new concept of the metabolic interactions between GBM cells and neighboring neurons through reactive astrocytes and developed AcePET-guided surgery to fight against GBM.
Optimising biodiversity protection through artificial intelligence
Authors: Silvestro Daniele , Goria Stefano , Sterner Thomas , Antonelli Alexandre
Published: April 2021

Over a million species face extinction, carrying with them untold options for food, medicine, fibre, shelter, ecological resilience, aesthetic and cultural values. There is therefore an urgent need to design conservation policies that maximise the protection of biodiversity and its contributions to people, within the constraints of limited budgets. Here we present a novel framework for spatial conservation prioritisation that combines simulation models, reinforcement learning and ground validation to identify optimal policies. Our methodology, CAPTAIN (Conservation Area Prioritisation Through Artificial Intelligence Networks), quantifies the trade-off between the costs and benefits of area and biodiversity protection, allowing the exploration of multiple biodiversity metrics. Under a fixed budget, our model protects substantially more species from extinction than the random or naively targeted protection of areas. CAPTAIN also outperforms the most widely used software for spatial conservation prioritisation (Marxan) in 97% of cases and reduces species loss by an average of 40% under simulations, besides yielding prioritisation maps at substantially higher spatial resolution using empirical data. We find that regular biodiversity monitoring, even if simple and with a degree of inaccuracy – characteristic of citizen science surveys – substantially improves biodiversity outcomes. Given the complexity of people–nature interactions and wealth of associated data, artificial intelligence holds great promise for improving the conservation of biological and ecosystem values in a rapidly changing and resource-limited world.
Measuring the health of people in places: a scoping review of OECD member countries
Authors: Murray Emily T , Shelton Nicola , Norman Paul , Head Jenny
Published: April 2021

Background

Defining and measuring population health in places is fundamental for local and national planning and conducting within-country and cross-national health comparisons. Yet availability and comparability of place-level health data is unknown.

Methods

A scoping review was performed to identify how Organisation for Economic Co-operation and Development (OECD) countries measure overall health for sub-national geographies within each country. The search was conducted across MEDLINE, Scopus and Google Scholar, supplemented by searching all 38 OECD countries statistical agency and public health institute websites.

Results

Sixty publications were selected, plus extracted information from 37 of 38 OECD countries statistical agency and/or public health institute websites. Data sources varied by categorisation into mortality (n=7) or morbidity (n=5) health indicators: the former mostly from national statistical agencies and the latter from population-level surveys. Region was the most common geographic scale: eight indicators for 26 countries, two indicators for 24 countries and one indicator for 20 countries. Similar but slightly fewer indicators were available for urban areas (max countries per most frequent indicator = 24), followed by municipality (range of 1-14 countries per indicator). Other geographies, particularly those at smaller granularity, were infrequently available across health indicators and countries.

Conclusion

Health indicator data at sub-national geographies are generally only available for a limited number of indicators at large administrative boundaries. Relative uniformity of health indicator question format allows cross-national comparisons. However, wider availability of health indicators at smaller, and non-administrative, geographies is needed to explore the best way to measure population health in local areas.
Underwater dual-magnification imaging for automated lake plankton monitoring
Authors: Merz Ewa , Kozakiewicz Thea , Reyes Marta , Ebi Christian , Isles Peter , Baity-Jesi Marco , Roberts Paul , Jaffe Jules S. , Dennis Stuart , Hardeman Thomas , Stevens Nelson , Lorimer Tom , Pomati Francesco
Published: April 2021

We present an approach for automatedin-situmonitoring of phytoplankton and zooplankton communities based on a dual magnification dark-field imaging microscope/camera. We describe the Dual Scripps Plankton Camera (DSPC) system and associated image processing, and assess its capabilities in detecting and characterizing plankton species of different size and taxonomic categories, and in measuring their abundances in both laboratory and field applications. In the laboratory, body size and abundance estimates by the DSPC significantly and robustly scale with the same measurements derived by traditional microscopy. In the field, a DSPC installed permanently at 3 m depth in Lake Greifensee (Switzerland), delivered images of plankton individuals, colonies, and heterospecific aggregates without disrupting natural arrangements of interacting organisms, their microenvironment or their behavior at hourly timescales. The DSPC was able to track the dynamics of taxa in the size range between ∼10 μm to ∼ 1 cm, covering virtually all the components of the planktonic food web (including parasites and potentially toxic cyanobacteria). Comparing data from the field-deployed DSPC to traditional sampling and microscopy revealed a general overall agreement in estimates of plankton diversity and abundances, despite imaging limitations in detecting small phytoplankton species and rare and large zooplankton taxa (e.g. carnivorous zooplankton). The most significant disagreements between traditional methods and the DSPC resided in the measurements of community properties of zooplankton, organisms that are heterogeneously distributed spatially and temporally, and whose demography appeared to be better captured by automated imaging. Time series collected by the DSPC depicted ecological succession patterns, algal bloom dynamics and circadian fluctuations with a temporal frequency and morphological resolution that would have been impossible with traditional methods. We conclude that the DSPC approach is suitable for stable long-term deployments, and robust for both research and water quality monitoring. Access to high frequency, reproducible and real-time data of a large spectrum of the planktonic ecosystem might represent a breakthrough in both applied and fundamental plankton ecology.
Visual search for upright bigrams predicts reading fluency in children
Authors: Agrawal Aakash , Nag Sonali , Hari K.V.S. , Arun S. P.
Published: April 2021

Fluent reading is an important milestone in education, but we lack a clear understanding of why children vary so widely in attaining this milestone. Language-related factors such as rapid automatized naming (RAN) and phonological awareness have been identified as important factors that influence reading fluency. Of theoretical interest is also, however, whether aspects of visual processing influence reading fluency. To investigate this issue, we tested primary school children (n = 68) on four tasks: two reading fluency tasks (word reading and passage reading), a RAN task to measure naming speed, and a visual search task using letters and bigrams to measure visual processing. As expected, the RAN score was strongly correlated with reading fluency. In addition, visual processing of bigrams was correlated with reading fluency. Importantly, this association was specific to upright but not inverted bigrams, and to bigrams with normal but not large letter spacing. Thus, reading fluency in children is accompanied by specialized changes in upright bigram processing. We propose that bigram processing during visual search could complement existing measures of language processing to understand individual differences in reading fluency.
Interacting phenotypes and the coevolutionary process: Interspecific indirect genetic effects alter coevolutionary dynamics
Authors: De Lisle Stephen P. , Bolnick Daniel I. , Brodie Edmund D. , Moore Allen J. , McGlothlin Joel W.
Published: April 2021

Coevolution occurs when species interact to influence one another’s fitness, resulting in reciprocal evolutionary change. In many coevolving lineages, trait expression in one species is modified by the genotypes and phenotypes of the other, forming feedback loops reminiscent of models of intraspecific social evolution. Here, we adapt the theory of within-species social evolution, characterized by indirect genetic effects and social selection imposed by interacting individuals, to the case of interspecific interactions. In a trait-based model, we derive general expressions for multivariate evolutionary change in two species and the expected between-species covariance in evolutionary change when selection varies across space. We show that reciprocal interspecific indirect genetic effects can dominate the coevolutionary process and drive patterns of correlated evolution beyond what is expected from direct selection alone. In extreme cases, interspecific indirect genetic effects can lead to coevolution when selection does not covary between species or even when one species lacks genetic variance. Moreover, our model indicates that interspecific indirect genetic effects may interact in complex ways with cross-species selection to determine the course of coevolution. Importantly, our model makes empirically testable predictions for how different forms of reciprocal interactions contribute to the coevolutionary process.
Soft tissue deformations explain most of the mechanical work variations of human walking
Authors: van der Zee Tim J. , Kuo Arthur D.
Published: April 2021

Humans perform mechanical work during walking, some by leg joints actuated by muscles, and some by passive, dissipative soft tissues. Dissipative losses must be restored by active muscle work, potentially in amounts sufficient to cost substantial metabolic energy. The most dissipative, and therefore costly, walking conditions might be predictable from the pendulum-like dynamics of the legs. If pendulum behavior is systematic, it may also predict the work distribution between active joints and passive soft tissues. We therefore tested whether the overall negative work of walking, and the fraction due to soft tissue dissipation, are both predictable by a pendulum model across a wide range of conditions. The model predicts whole-body negative work from the leading leg’s impact with ground (termed the Collision), to increase with the squared product of walking speed and step length. We experimentally tested this in humans (N = 9) walking in 26 different combinations of speed (0.7 – 2.0 m·s-1) and step length (0.5 – 1.1 m), with recorded motions and ground reaction forces. Whole-body negative Collision work increased as predicted (R2= 0.73), with a consistent fraction of about 63% (R2= 0.88) due to soft tissues. Soft tissue dissipation consistently accounted for about 56% of the variation in total whole-body negative work. During typical walking, active work to restore dissipative losses could account for 31% of the net metabolic cost. Soft tissue dissipation, not included in most biomechanical studies, explains most of the variation in negative work of walking, and could account for a substantial fraction of the metabolic cost.

Summary statement

Soft tissue deformations dissipate substantial energy during human walking, as predicted by a simple walking model.
Coma-corrected rapid single-particle cryo-EM data collection on the CRYO ARM 300
Authors: Efremov Rouslan G. , Stroobants Annelore
Published: April 2021

Single-particle cryogenic electron microscopy has recently become a major method for determining the structures of proteins and protein complexes. This has markedly increased the demand for throughput of high-resolution electron microscopes, which are required to produce high-resolution images at high rates. An increase in data-collection throughput can be achieved by using large beam-image shifts combined with off-axis coma correction, enabling the acquisition of multiple images from a large area of the EM grid without moving the microscope stage. Here, the optical properties of the JEOL CRYO ARM 300 electron microscope equipped with a K3 camera were characterized under off-axis illumination conditions. It is shown that efficient coma correction can be achieved for beam-image shifts with an amplitude of at least 10 µm, enabling a routine throughput for data collection of between 6000 and 9000 images per day. Use of the benchmark for the rapid data-collection procedure (with beam-image shifts of up to 7 µm) on apoferritin resulted in a reconstruction at a resolution of 1.7 Å. This demonstrates that the rapid automated acquisition of high-resolution micrographs is possible using a CRYO ARM 300.
Crystal structures of UDP-N-acetylmuramic acid L-alanine ligase (MurC) from Mycobacterium bovis with and without UDP-N-acetylglucosamine
Authors: Seo Pil-Won , Park Suk-Youl , Hofmann Andreas , Kim Jeong-Sun
Published: April 2021

Peptidoglycan comprises repeating units of N-acetylmuramic acid, N-acetylglucosamine and short cross-linking peptides. After the conversion of UDP-N-acetylglucosamine (UNAG) to UDP-N-acetylmuramic acid (UNAM) by the MurA and MurB enzymes, an amino acid is added to UNAM by UDP-N-acetylmuramic acid L-alanine ligase (MurC). As peptidoglycan is an essential component of the bacterial cell wall, the enzymes involved in its biosynthesis represent promising targets for the development of novel antibacterial drugs. Here, the crystal structure of Mycobacterium bovis MurC (MbMurC) is reported, which exhibits a three-domain architecture for the binding of UNAM, ATP and an amino acid as substrates, with a nickel ion at the domain interface. The ATP-binding loop adopts a conformation that is not seen in other MurCs. In the UNAG-bound structure of MbMurC, the substrate mimic interacts with the UDP-binding domain of MbMurC, which does not invoke rearrangement of the three domains. Interestingly, the glycine-rich loop of the UDP-binding domain of MbMurC interacts through hydrogen bonds with the glucose moiety of the ligand, but not with the pyrophosphate moiety. These findings suggest that UNAG analogs might serve as potential candidates for neutralizing the catalytic activity of bacterial MurC.
Challenges in solving structures from radiation-damaged tomograms of protein nanocrystals assessed by simulation
Authors: Peck Ariana , Yao Qing , Brewster Aaron S. , Zwart Petrus H. , Heumann John M. , Sauter Nicholas K. , Jensen Grant J.
Published: April 2021

Structure-determination methods are needed to resolve the atomic details that underlie protein function. X-ray crystallography has provided most of our knowledge of protein structure, but is constrained by the need for large, well ordered crystals and the loss of phase information. The rapidly developing methods of serial femtosecond crystallography, micro-electron diffraction and single-particle reconstruction circumvent the first of these limitations by enabling data collection from nanocrystals or purified proteins. However, the first two methods also suffer from the phase problem, while many proteins fall below the molecular-weight threshold required for single-particle reconstruction. Cryo-electron tomography of protein nanocrystals has the potential to overcome these obstacles of mainstream structure-determination methods. Here, a data-processing scheme is presented that combines routines from X-ray crystallography and new algorithms that have been developed to solve structures from tomograms of nanocrystals. This pipeline handles image-processing challenges specific to tomographic sampling of periodic specimens and is validated using simulated crystals. The tolerance of this workflow to the effects of radiation damage is also assessed. The simulations indicate a trade-off between a wider tilt range to facilitate merging data from multiple tomograms and a smaller tilt increment to improve phase accuracy. Since phase errors, but not merging errors, can be overcome with additional data sets, these results recommend distributing the dose over a wide angular range rather than using a finer sampling interval to solve the protein structure.
Intermediates in allosteric equilibria of DnaK–ATP interactions with substrate peptides
Authors: Wang Wei , Hendrickson Wayne A.
Published: April 2021

Hsp70 molecular chaperones facilitate protein disaggregation and proper folding through iterative cycles of polypeptide binding and release that are allosterically coupled to ATP binding and hydrolysis. Hsp70s are ubiquitous and highly conserved across all of life; they bind ATP at an N-terminal nucleotide-binding domain (NBD) and client peptides in the substrate-binding domain (SBD). The NBD and SBD are connected by a highly conserved linker segment that is integrated into the NBD when ATP is bound but is flexible when the NBD is nucleotide-free or bound with ADP. Allosteric coupling is lost when the linker is flexible, and the freed SBD binds peptide clients with high affinity. It was recently discovered that Hsp70–ATP is in an equilibrium between a restraining state (R) with little affinity for peptides and a low ATPase activity, and a stimulating state (S) that binds peptides efficiently, but with rapid kinetics, and has a relatively high ATPase activity. While attempting to characterize the S state, crystal structures of DnaK–ATP were obtained that demonstrate intrinsic Hsp70 plasticity that affects binding interactions with substrate peptides. These structures provide insights into intermediate states along transition pathways in the Hsp70 chaperone cycle.
Contribution of opioid and neurotensin receptors in the anti‐inflammatory activity of PK20 hybrid compound in murine airways
Authors: Russjan Ewelina , Zając Dominika , Sulejczak Dorota , Kleczkowska Patrycja , Kaczyńska Katarzyna
Published: April 2021

PK20 is an anti‐inflammatory hybrid compound, composed of an endomorphin‐2‐like and neurotensin‐like fragments. The aim of the present study is to assess the contribution of particular pharmacophores to the activity of the hybrid tested. For this purpose, airway hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid (BALF), concentration of mouse mast cell protease, malondialdehyde and secretory phospholipase 2 activity in lung tissue, as well as production of pro‐inflammatory cytokines in BALF and lung were determined by using murine model of non‐atopic asthma. Blocking either neurotensin receptors or mu opioid receptors did not alter the potential of PK20 in reducing airway hyperresponsiveness. In studies of inflammatory cells, the beneficial effect of the entire peptide occurs to be mediated by the stimulation of neurotensin receptors. However, regarding cytokine and biochemical assays, pretreatment with both receptor antagonists resulted in a different effect on its activity depending on the parameter studied. To conclude, the activation of both the opioid and neurotensin receptors seems to be necessary to induce the full anti‐inflammatory activity of the hybrid compound.
A simple, switchable pili‐labelling method by plasmid‐based replacement of pilin
Authors: Zhang Jingchao , Li Shubin , Sun Tao , Zong Yiwu , Zhang Weiwen , Zhao Kun
Published: April 2021

Labelling of Type IV pili (TFP) can greatly improve our understanding of the pivotal roles of TFP in a variety of bacterial activities including motility, surface sensing and DNA‐uptake etc. Here we show a simple and switchable pili‐labelling method by plasmid‐based inducible replacement of PilA without genetic modification in bacterial genome employed by complicated methods. Using this method, we characterized pili morphology and twitching motility of Pseudomonas aeruginosa in details. More importantly, we demonstrate its application in studying the replenishment dynamics of pilin pool of P. aeruginosa.
Sapwood and heartwood affect differentially bacterial and fungal community structure and successional dynamics duringQuercus petraeadecomposition
Authors: Viotti Chloé , Bach Cyrille , Maillard François , Ziegler‐Devin Isabelle , Mieszkin Sophie , Buée Marc
Published: April 2021

In forests, bacteria and fungi are key players in wood degradation. Still, studies focusing on bacterial and fungal successions during the decomposition process depending on the wood types (i.e. sapwood and heartwood) remain scarce. This study aimed to understand the effect of wood type on the dynamics of microbial ecological guilds in wood decomposition. Using Illumina metabarcoding, bacterial and fungal communities were monitored every 3 months for 3 years fromQuercus petraeawood discs placed on forest soil. Wood density and microbial enzymes involved in biopolymer degradation were measured. We observed rapid changes in the bacterial and fungal communities and microbial ecological guilds associated with wood decomposition throughout the experiment. Bacterial and fungal succession dynamics were very contrasted between sapwood and heartwood. The initial microbial communities were quickly replaced by new bacterial and fungal assemblages in the sapwood. Conversely, some initial functional guilds (i.e. endophytes and yeasts) persisted all along the experiment in heartwood and finally became dominant, possibly limiting the development of saprotrophic fungi. Our data also suggested a significant role of bacteria in nitrogen cycle during wood decomposition.
Fifteen Years of a PBRFS in New Zealand: Incentives and Outcomes
Authors: Buckle Robert A. , Creedy John , Ball Ashley
Published: April 2021

This article examines the transformation of New Zealand universities following the introduction in 2003 of a performance‐based research fund system. The analysis, based on a social accounting framework, utilises longitudinal researcher data available from three full assessment rounds, in 2003, 2012 and 2018. This enables identification of the entry, exit and quality transformation of researchers and their contribution to changes in university and discipline research quality. Changes in the discipline composition of universities made a negligible contribution compared to improvements in the quality of researchers. The dynamics are closely related to the new incentives created by the system.
On the International Spillover Effects of Country‐Specific Financial Sector Bailouts and Sovereign Risk Shocks*
Authors: Greenwood‐Nimmo Matthew , Nguyen Viet Hoang , Wu Eliza
Published: April 2021

We use sign‐identified macroeconomic models to study the interaction of financial sector and sovereign credit risks in Europe. We find that country‐specific financial sector bailout shocks do not generate strong international spillovers, because they primarily transfer private sector risk onto the local sovereign. By contrast, sovereign risk shocks generate substantial spillovers onto the global financial sector and for international sovereign debt markets. We conclude that any financial sector bailout policy that undermines the creditworthiness of the affected sovereign is likely to exacerbate global credit risk. Our findings highlight the unintended global consequences of country‐specific financial sector bailout programmes.
A changing sense of place: Geography and COVID‐19
Authors: Bissell David
Published: April 2021

In this essay, I explain how geography offers important ideas to better understand what is happening to our sense of place during the COVID‐19 crisis, complementing the scientific understandings provided by epidemiologists and public health experts. I explain how geographical ideas relating to place and mobility can help us make sense of our current situation and consider what we might be feeling. These geographical ideas also provide us with important political tools to identify the new forms of inequality and hardship that are unfolding, prompting questions about how we should collectively respond to shape the future of place.
Place‐based collaborative governance: The potential influence of governments
Authors: Greenway John
Published: April 2021

Governments seeking to implement state/territory‐wide or national agendas and policies can impose (un)intended impacts and consequences on self‐managed community‐led collaborative governance initiatives by which people attempt to solve place‐based environmental and resource problems. The impacts of government actions and changes to policy, funding targets and criteria, and local government reform on emergent place‐based and self‐managed community collaborative governance initiatives can be significant in relation to longevity and ongoing achievement of beneficial environmental outcomes. Such outcomes are irrespective of whether place‐based initiatives are considered to emerge in the shadow of government or independent of central government. This article establishes that place‐based self‐managed community‐led collaborative governance initiatives are not immune to the influences and consequences of state/territorial and/or federal government decisions and actions, be those through the development of environmental regulations and policies that direct actions and/or set targets for policy outcomes; the provision of funding to be administered according to set criteria; or, at state/territory government levels, forced local government amalgamations. Discussion about these issues is positioned in relation to a successful place‐based community‐led collaborative water governance initiative known as the Clarence Floodplain Project (CFP) in northern New South Wales, Australia. The experience of the CFP suggests that state/territory and/or federal government decisions and actions may result in (un)intended negative as well as positive impacts on place‐based community‐led collaborative governance initiatives. Although the CFP was impacted by government actions, its success also highlights the importance of place‐based approaches to natural resource management and governance.
Nonparametric analysis of inter‐individual relations using an attention‐based neural network
Authors: Morita Takashi , Toyoda Aru , Aisu Seitaro , Kaneko Akihisa , Suda‐Hashimoto Naoko , Adachi Ikuma , Matsuda Ikki , Koda Hiroki
Published: April 2021

Social network analysis, which has been widely adopted in animal studies over the past decade, enables the revelation of global characteristic patterns of animal social systems from pairwise inter‐individual relations. Animal social networks are typically drawn based on the geometric proximity and/or frequency of social behaviours (e.g. grooming), but the appropriate metric for inter‐individual relationship is not clear, especially when prior knowledge on the species/data is limited.

In this study, researchers explored a nonparametric analysis of inter‐individual relations using a neural network with the attention mechanism, which plays a central role in natural language processing. The high interpretability of the attention mechanism and flexibility of the entire neural network allow for automatic detection of inter‐individual relations included in the raw data, without requiring prior knowledge/assumptions about what modes/types of relations are included in the data. For these case studies, three‐dimensional location data collected from simulated agents and real Japanese macaques were analysed.

The proposed method successfully recovered the latent relations behind the simulated data and discovered female‐oriented relations in the real data, which are in accordance with the previous generalizations about the macaque social structure.

The proposed method does not exploit any behavioural patterns that are particular to Japanese macaques, and researchers can use it for location data of other animals. The flexibility of the neural network would also allow for its application to a wide variety of data with interacting components, such as vocal communication.

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The response of citrus plants to the broad mitePolyphagotarsonemus latus(Banks) (Acari: Tarsonemidae)
Authors: Cabedo‐López Marc , Cruz‐Miralles Joaquín , Peris David , Ibáñez‐Gual M. Victoria , Flors Víctor , Jaques Josep A.
Published: April 2021

Polyphagotarsonemus latus(Banks) (Acari: Tarsonemidae) is a common polyphagous mite in tropical and subtropical areas and is considered as an important citrus pest.

To understand the response of citrus toP. latusinfestation, we have characterized the volatile profile and the molecular defence mechanisms of two citrus genotypes, namely sour orange (Citrus aurantium) and Cleopatra mandarin (Citrus reshni), toP. latusinfestation. These two species are important rootstocks for the citrus industry and display differential resistance toTetranychus urticaeKoch (Acari: Tetranychidae), with sour orange showing elevated levels of constitutive and induced resistance associated with the jasmonic acid (JA) pathway compared with Cleopatra mandarin.

P. latusinfestation activated both the JA‐ and the salicylic acid‐dependent pathways in sour orange but not in Cleopatra mandarin. However, this differential activation resulted in the production of similar volatile blends (a mixture of green leaf volatiles and aromatic compounds).

Contrary toT. urticaeinfestation, sour orange supported larger densities ofP. latusthan Cleopatra mandarin with similar injury levels.

Therefore, sour orange may be more tolerant toP. latusthan Cleopatra mandarin.
Short‐term effects of COVID‐19 on semen parameters: A multicenter study of 69 cases
Authors: Erbay Guven , Sanli Ahmet , Turel Harun , Yavuz Ufuk , Erdogan Abdullah , Karabakan Mehmet , Yaris Mehmet , Gultekin Mehmet Hamza
Published: April 2021

Objective

COVID‐19, which is known to be caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is a global health problem that can cause multiorgan damage because of its use of the angiotensin‐converting enzyme 2 (ACE2) receptor in its pathophysiology. We aimed to investigate whether SARS‐CoV‐2 had a short‐term effect on spermatogenesis, which plays an important role in male reproductive health as it has abundant ACE2 expression in testicular tissue.

Material and methods

This multicenter study included 69 patients aged 20–45 years, who admitted to our hospitals between April 2020 and October 2020 with a history of a positive test result for SARS‐CoV‐2 based on the nasopharyngeal or oropharyngeal swab samples and had recovered from the disease at least three months earlier and who had undergone a spermiogram test in the hospital database within the last year before the onset of disease. The patients were divided into two groups according to their COVID‐19 symptoms being mild or moderate, depending on whether they had received home treatment or required hospitalization for oxygen therapy. Semen samples taken before and after COVID‐19 were compared within and between the groups in terms of sperm parameters.

Results

The mean age of the patients included in the study was 30.4±4.8 years in the mild symptomatic COVID‐19 group and 31.06±4.2 years in the moderate symptomatic group. When the spermiogram samples of the patients before and after COVID‐19 were evaluated, it was found that motility and vitality significantly decreased in the mild symptomatic group, while the decrease in all semen parameters was statistically significant in the moderate symptomatic group.

Conclusion

Although the mechanism by which COVID‐19 causes testicular involvement remains uncertain, its short‐term results on spermatogenesis reveals that COVID‐19 negatively affects sperm parameters.