bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress alters the activity of Leydig cells dependently on the diurnal time
Authors: Medar Marija Lj , Andric Silvana A , Kostic Tatjana S
Published: February 2021

Background

The increasing amount of data points to the circadian timing system as an essential part of processes regulating androgen homeostasis. However, the relationship between stress response, timekeeping-, and steroidogenesis-related systems is unexplored.

Objective

The purpose of the study was to analyze the stress-response of the testosterone-producing Leydig cells depending on the stressful event’s time.

Materials and methods

The study was designed to follow the effects of 3-hour immobilization (IMO) applied at different periods during the day. The IMO performed once (1xIMO) or repeated in 10 consecutive days (10xIMO). Principal-component-analysis (PCA) followed the expression study of the clock and steroidogenic-related genes in Leydig cells.

Results

Both types of IMO in all investigated periods increased corticosterone and decreased testosterone blood level. Transcriptional analysis revealed different sensitivity to IMO events depending on the circadian time. The majority of steroidogenesis-related genes (Lhcgr, Cyp11a1, Cyp17a1, Hsd3b1/2) were down-regulated in the inactive but unchanged or even up-regulated in the active phase of the day. Both types of IMO potentiated the expression of clock elementsBmal1/BMAL1,Per1/PER1 regardless of the day’s stage and reducedReverbain the inactive phase. The PCA confirmed a major shift, for both IMO-types, in the transcription of steroidogenesis and clock genes across the inactive/active phase. Further, the diurnal pattern of the glucocorticoid receptor (Nr3c1/GR) expression in Leydig cells was increased in the inactive phase due to 10xIMO. The observed time-dependent IMO-response of the Leydig cells correlated with different GR engagements.

Discussion

Stress- and the circadian-system coordinatively shape Leydig cell’s physiology, assuming diverse GR engagement as a possible factor in mediating the diurnal effect of stress.

Conclusion

The Leydig cell’s stress-response depends on the time of the stressful situation, emphasizing the importance of circadian activity in supporting androgen homeostasis and male fertility.
The Wild Worm Codon Adapter: a web tool for automated codon adaptation of transgenes for expression in non-Caenorhabditis nematodes
Authors: Bryant Astra S. , Hallem Elissa A.
Published: February 2021

Advances in genomics techniques are expanding the range of nematode species that are amenable to transgenesis. Due to divergent codon usage biases across species, codon optimization is often a critical step for the successful expression of exogenous transgenes in nematodes. Platforms for generating DNA sequences codon optimized for the free-living model nematode Caenorhabditis elegans are broadly available. However, until now such tools did not exist for non-Caenorhabditis nematodes. We therefore developed the Wild Worm Codon Adapter, a tool for rapid transgene codon optimization for expression in non-Caenorhabditis nematodes. The app includes built-in optimization for parasitic nematodes in the Strongyloides, Nippostrongylus and Brugia genera as well as the predatory nematode Pristionchus pacificus. The app also supports custom optimization for any species using user-provided optimization rules. In addition, the app supports automated insertion of synthetic or native introns, as well as the analysis of codon bias in transgene and native sequences. Here, we describe this web-based tool and demonstrate how it may be used to analyze genome-wide codon bias in Strongyloides species.
Natural variation in fertility is correlated with species-wide levels of divergence inCaenorhabditis elegans
Authors: Zhang Gaotian , Mostad Jake D. , Andersen Erik C.
Published: February 2021

Life history traits underlie the fitness of organisms and are under strong natural selection in the face of environmental challenges. A new mutation that positively impacts a life history trait will likely increase in frequency and become fixed in a population (e.g.selective sweep). The identification of the beneficial alleles that underlie selective sweeps provides insights into the mechanisms that occurred during the evolution of species. In the global population ofCaenorhabditis elegans,we previously identified selective sweeps that have drastically reduced chromosomal-scale genetic diversity in the species. Here, we measured the fertility (viable offspring) of a collection of wildC. elegansstrains, including many recently isolated divergent strains from the Hawaiian islands and found that strains with larger swept genomic regions on multiple chromosomes have significantly higher fertility than strains that do not have evidence of the recent selective sweeps. We used genome-wide association (GWA) mapping to identify three quantitative trait loci (QTL) underlying the fertility variation. Additionally, we mapped previous fertility data of wildC. elegansstrains andC. elegansrecombinant inbred advanced intercross lines (RIAILs) that were grown in various conditions and detected eight QTL across the genome using GWA and linkage mappings. These QTL show the genetic complexity of life history traits such as fertility across this species. Moreover, the haplotype structure in each GWA QTL region revealed correlations with recent selective sweeps in theC. eleganspopulation. North American and European strains had significantly higher fertility than most strains from Hawaii, a hypothesized origin of theC. elegansspecies, suggesting that beneficial alleles that cause increased fertility could underlie the selective sweeps during the worldwide expansion ofC. elegans.
Hippocampal sharp wave-ripples and the associated sequence replay emerge from structured synaptic interactions in a network model of area CA3
Authors: Ecker András , Bagi Bence , Vértes Eszter , Steinbach-Németh Orsolya , Karlócai Mária R. , Papp Orsolya I. , Miklós István , Hájos Norbert , Freund Tamás F. , Gulyás Attila I. , Káli Szabolcs
Published: February 2021

Hippocampal place cells are activated sequentially as an animal explores its environment. These activity sequences are internally recreated (“replayed”), either in the same or reversed order, during bursts of activity (sharp wave-ripples; SWRs) that occur in sleep and awake rest. SWR-associated replay is thought to be critical for the creation and maintenance of long-term memory. In order to identify the cellular and network mechanisms of SWRs and replay, we constructed and simulated a data-driven model of area CA3 of the hippocampus. Our results show that the chain-like structure of recurrent excitatory interactions established during learning not only determines the content of replay, but is essential for the generation of the SWRs as well. We find that bidirectional replay requires the interplay of the experimentally confirmed, temporally symmetric plasticity rule, and cellular adaptation. Our model provides a unifying framework for diverse phenomena involving hippocampal plasticity, representations, and dynamics, and suggests that the structured neural codes induced by learning may have greater influence over cortical network states than previously appreciated.
Probing cortical excitability under GABAergic modulation
Authors: Lepeu Grégory , Maren Ellen Van , Slabeva Kristina , Fuchs Markus , Anso Juan , Z’Graggen Werner J. , Pollo Claudio , Schindler Kaspar A. , Adamantidis Antoine , Baud Maxime O.
Published: February 2021

Cortical excitability, the variable response to a given cortical input, is widely studied in neuroscience, from slice experiments and in silico modeling work to human clinical settings. However, a unifying definition and a translational approach to the phenomenon are currently lacking. For example, at the onset of epileptic seizures, cortical excitability may impair resilience to perturbations (external or endogenous). In this study, we testedin vivowhether changes in cortical excitability quantified as evoked response to small perturbation corresponded to changes in resilience to larger perturbations. To do so, we used both cell-type circuit specific optogenetic stimulation in mice and direct intracranial stimulation in one human subject and quantified 1) evoked cortical responses to single pulses of varying intensity, and 2) evoked cortical facilitation and suppression to paired pulses at varying intervals. In the presence of a gamma-Aminobutyric acid (GABA) agonist or antagonist, we found that 1) cortical response to single pulses and 2) cortical facilitation decreased and increased, respectively. Additionally, using trains of opto-pulses in mice in the presence of a GABA agonist, we found increased resilience to the induction of seizures. With this study, we provide evidence for a tight correlation between cortical excitability and resilience, exploring a range of cortical dynamics, from physiological excitability, to pathological discharges. Our study carried out with two different stimulation methods in two species suggests that varying cortical excitability can be tracked with simple protocols involving minute short-lived perturbative stimuli.
Improving Generalizability of Protein Sequence Models with Data Augmentations
Authors: Shen Hongyu , Price Layne C. , Bahadori Taha , Seeger Franziska
Published: February 2021

Abstract

While protein sequence data is an emerging application domain for machine learning methods, small modifications to protein sequences can result in difficult-to-predict changes to the protein’s function. Consequently, protein machine learning models typically do not use randomized data augmentation procedures analogous to those used in computer vision or natural language, e.g., cropping or synonym substitution. In this paper, we empirically explore a set of simple string manipulations, which we use to augment protein sequence data when fine-tuning semi-supervised protein models. We provide 276 different comparisons to the Tasks Assessing Protein Embeddings (TAPE) baseline models, with Transformer-based models and training datasets that vary from the baseline methods only in the data augmentations and representation learning procedure. For each TAPE validation task, we demonstrate improvements to the baseline scores when the learned protein representation is fixed between tasks. We also show that contrastive learning fine-tuning methods typically outperform masked-token prediction in these models, with increasing amounts of data augmentation generally improving performance for contrastive learning protein methods. We find the most consistent results across TAPE tasks when using domain-motivated transformations, such as amino acid replacement, as well as restricting the Transformer attention to randomly sampled sub-regions of the protein sequence. In rarer cases, we even find that information-destroying augmentations, such as randomly shuffling entire protein sequences, can improve downstream performance.
CTCF association with episomal HPV16 genomes regulates viral oncogene transcription and splicing
Authors: Groves Ian J , Tang George , Pentland Ieisha , Parish Joanna L , Coleman Nicholas
Published: February 2021

Human papillomavirus 16 (HPV16) is a high-risk alphapapillomavirus that is associated with cancers of mucosal epithelia. The virus genome exists in cells as an episome but can integrate and overexpress theE6andE7viral oncogenes. In related high-risk family members HPV18 and HPV31, host proteins including CTCF, an insulator, and SMC1A, a component of the cohesion complex, are known to interact with the viral genome and alter transcriptional activity, splicing patterns and episome amplification. However, the roles of these two proteins during HPV16 infection has not yet been fully examined. Here, we show during differentiation of the episomal HPV16-containing W12 cell line that CTCF association increases with the virus genome at the knownE2binding site, whilst additional CTCF binding now occurs at the putativeL2binding site, with SMC1A association occurring unchanged here. While expression of virus late transcripts (E4^L1, L2, L1) is stimulated, early transcript levels decrease by 48 hours, with the exception of the E6*IV spliced transcript. Conversely, in undifferentiated, monolayer W12 cells, CTCF knockdown increases the level of all early transcripts, whereas E6*IV level increases. Additionally, CTCF ablation as well as SMC1A knockdown results in decreases to HPV16 genome copy number. Taken together, this supports the model that while CTCF and SMC1A have a role in HPV16 genome maintenance, CTCF plays a greater part in regulating HPV16 oncogene splicing and expression during the natural lifecycle of the virus, and may be involved in a reduced risk of cancer development during episomal HPV16 infections.
Spatially confined sub-tumor microenvironments orchestrate pancreatic cancer pathobiology
Authors: Grünwald Barbara T , Devisme Antoine , Andrieux Geoffroy , Vyas Foram , Aliar Kazeera , McCloskey Curtis W , Macklin Andrew , Jang Gun Ho , Denroche Robert , Romero Joan Miguel , Bavi Prashant , Bronsert Peter , Notta Faiyaz , O’Kane Grainne , Wilson Julie , Knox Jennifer , Tamblyn Laura , Radulovich Nikolina , Fischer Sandra E , Boerries Melanie , Gallinger Steven , Kislinger Thomas , Khokha Rama
Published: February 2021

Pancreatic ductal adenocarcinoma (PDAC) remains resistant to most treatments and demonstrates a complex pathobiology. Here, we deconvolute regional heterogeneity in the human PDAC tumor microenvironment (TME), a long-standing obstacle, to define precise stromal contributions to PDAC progression. Large scale integration of histology-guided multiOMICs with clinical data sets and functionalin vitromodels uncovers two microenvironmental programs in PDAC that were anchored in fibroblast differentiation states. These sub-tumor microenvironments (subTMEs) co-occurred intratumorally and were spatially confined, producing patient-specific cellular and molecular heterogeneity associated with shortened patient survival. Each subTME was uniquely structured to support discrete aspects of tumor biology: reactive regions rich in activated fibroblast communities were immune-hot and promoted aggressive tumor progression while deserted regions enriched in extracellular matrix supported tumor differentiation yet were markedly chemoprotective. In conclusion, PDAC regional heterogeneity derives from biologically distinct reactive and protective TME elements with a defined, active role in PDAC progression.

Graphical Abstract & Key findings

PDAC regional heterogeneity originates in sub-tumor microenvironments (subTMEs)

SubTMEs exhibit distinct immune phenotypes and CAF differentiation states

Different subTMEs are either tumor-promoting or chemoprotective

Intratumoral subTME co-occurrence links stromal heterogeneity to patient outcome
A Multiple Regression Assessment of the Biomineral Urease Activity from Urine Drainpipes of California Rest Areas
Authors: Lim Kahui , Leverenz Harold , Wademan Cara , Barnum Samantha
Published: February 2021

Clogging and odor is strongly associated with ureolytic biomineralization in waterless and low-flow urinal drainage systems in high usage settings. These blockages continue to hinder widespread waterless and low-flow urinal adoption due to subsequent high maintenance requirements and hygiene concerns. Through field observations, hypothesis testing, and multiple regression analysis, this study attempts to characterize, for the first time, the ureolytic activity of the biomineralization found in alternative technologies located at 9 State-owned restrooms. Multiple regression analysis (n= 55, df = 4,R2= 0.665) suggests that intrasystem sampling location, annual users per rest area, and the organic/inorganic mass fraction, are statistically significant influencers of the ureolytic activity of biomineral samples (p< 0.05). Conversely,ureCgene abundance (p= 0.551), urinal type (p= 0.521) and sampling season (p= 0.956) are not significant predictors of biomineral ureolytic activity. We conclude that high concentrations of the urease alpha subunit,ureC, which can be interpreted as proxy measure of a strong, potentially ureolytic community, does not necessarily mean that the gene is being expressed. Future studies should assessureCtranscriptional activity to measure gene expression rather than gene abundance to assess the relationship between environmental conditions, their role in transcription, and urease activities. In sum, this study presents a method to characterize biomineral ureolysis and establishes baseline values for future ureolytic inhibition treatment studies that seek to improve the usability of urine collection and related source separation technologies.
Decreased neutralization of SARS-CoV-2 global variants by therapeutic anti-spike protein monoclonal antibodies
Authors: Tada Takuya , Dcosta Belinda M. , Zhou Hao , Vaill Ada , Kazmierski Wes , Landau Nathaniel R.
Published: February 2021

Monoclonal antibodies against the SARS-CoV-2 spike protein, notably, those developed by Regeneron Pharmaceuticals and Eli Lilly and Company have proven to provide protection against severe COVID-19. The emergence of SARS-CoV-2 variants with heavily mutated spike proteins raises the concern that the therapy could become less effective if any of the mutations disrupt epitopes engaged by the antibodies. In this study, we tested monoclonal antibodies REGN10933 and REGN10987 that are used in combination, for their ability to neutralize SARS-CoV-2 variants B.1.1.7, B.1.351, mink cluster 5 and COH.20G/677H. We report that REGN10987 maintains most of its neutralization activity against viruses with B.1.1.7, B.1.351 and mink cluster 5 spike proteins but that REGN10933 has lost activity against B.1.351 and mink cluster 5. The failure of REGN10933 to neutralize B.1.351 is caused by the K417N and E484K mutations in the receptor binding domain; the failure to neutralize the mink cluster 5 spike protein is caused by the Y453F mutation. The REGN10933 and REGN10987 combination was 9.1-fold less potent on B.1.351 and 16.2-fold less potent on mink cluster 5, raising concerns of reduced efficacy in the treatment of patients infected with variant viruses. The results suggest that there is a need to develop additional monoclonal antibodies that are not affected by the current spike protein mutations.
Development and validation of a miniaturized host range screening assay for bacteriophages
Authors: Ng Renee Nicole , Grey Lucinda Jean , Vaitekenas Andrew , McLean Samantha Abagail , Laucirica Daniel Rodolfo , Poh Matthew Wee-Peng , Hillas Jessica , Winslow Scott Glenn , Iszatt Joshua James , Iosifidis Thomas , Tai Anna Sze , Agudelo-Romero Patricia , Chang Barbara Jane , Stick Stephen Michael , Kicic Anthony
Published: February 2021

Antimicrobial resistance is a global health crisis, partly contributed by inappropriate use of antibiotics. The increasing emergence of multidrug resistant infections has led to the resurgent interest in bacteriophages as an alternative treatment. Current procedures assessing susceptibility and breadth of host range to bacteriophage are conducted using large-scale manual processes that are labor-intensive. The aim here was to establish and validate a scaled down methodology for high-throughput screening in order to reduce procedural footprint. Bacteriophages were isolated from wastewater samples and screened for specificity against 29 clinicalPseudomonas aeruginosaisolates and PA01 using a spot test (2 μL/ drop). Host range assessment was performed on four representativeP. aeruginosaisolates using both double agar overlay assay on petri dishes and 24-well culture plates. The breadth of host range of bacteriophages that exhibited lytic activity onP. aeruginosaisolates were corroborated between the current standard practice of whole plate phage assay and 24-well phage assay. The high correlation achieved in this study confirms miniaturization as the first step in future automation that could test phage diversity and efficacy as antimicrobials.
Rapid Characterization of AAV gene therapy vectors by Mass Photometry
Authors: Wu Di , Hwang Philsang , Li Tiansen , Piszczek Grzegorz
Published: February 2021

Recombinant adeno-associated viruses (rAAV) are extensively used as gene delivery vectors in clinical studies, and several rAAV based treatments have already been approved. Significant progress has been made in rAAV manufacturing, and large-scale vector production and purification methods have been developed. However, a better and more precise capsid characterization techniques are still needed to guarantee the purity and safety of the rAAV preparations. A recently developed single-molecule technique, mass photometry (MP), measures mass distributions of biomolecules with high resolution and sensitivity. Here we explore applications of MP for the characterization of capsid fractions. We demonstrate that MP is able to resolve and quantify not only empty and full-genome containing capsid populations, but also identify the partially packaged capsid impurities. MP data accurately measures full and empty capsid ratios, and can be used to estimate the size of the encapsidated genome. MP distributions provide information on sample heterogeneity and on the presence of aggregates. Current analytical techniques used to characterize rAAV preparations are susceptible to background signals, have limited accuracy, or are time-consuming and require a large amount of material. MP can analyze sub-picomole quantities of sample, and data can be obtained and analyzed within minutes. This method provides a simple, robust, and effective tool to monitor physical attributes of rAAV vectors.
Constructing An Adult Orofacial Premotor Atlas In Allen Mouse CCF
Authors: Takatoh Jun , Park Jae Hong , Lu Jinghao , Li Shun , Thompson P. M. , Han Bao-Xia , Zhao Shengli , Kleinfeld David , Friedman Beth , Wang Fan
Published: February 2021

Premotor circuits in the brainstem control pools of orofacial motoneurons to execute essential functions such as drinking, eating, breathing, and in rodent, whisking. Previous transsynaptic tracing studies only mapped orofacial premotor circuits in neonatal mice but the adult circuits remain unknown due to technical difficulties. Here we developed a three-step monosynaptic transsynaptic tracing strategy to identify premotor neurons controlling whisker, tongue protrusion, and jaw-closing muscles in the adult. We registered these different groups of premotor neurons onto the Allen mouse brain common coordinate framework (CCF) and consequently generated a combined 3D orofacial premotor atlas, revealing unique spatial organizations of distinct premotor circuits. We also uncovered premotor neurons simultaneously innervating multiple motor nuclei and, thus, likely coordinating different muscles involved in the same orofacial behaviors. Our method for tracing adult premotor circuits and registering to Allen CCF is generally applicable and should facilitate the investigations of motor controls of diverse behaviors.
An Exhaustive Multiple Knockout Approach to Understanding Cell Wall Hydrolase Function inBacillus subtilis
Authors: Wilson Sean A. , Tank Raveen K. J. , Hobbs Jamie K. , Foster Simon J. , Garner Ethan C.
Published: February 2021

Most bacteria are surrounded by their cell wall, containing a highly crosslinked protective envelope of peptidoglycan. To grow, bacteria must continuously remodel their wall, inserting new material and breaking old bonds. Bond cleavage is performed by cell wall hydrolases, allowing the wall to expand. Understanding the functions of individual hydrolases has been impeded by their redundancy: single knockouts usually present no phenotype. We used an exhaustive multiple-knockout approach to determine the minimal set of hydrolases required for growth in Bacillus subtilis. We identified 42 candidate hydrolases. Strikingly, we were able to remove all but two of these genes in a single strain; this “Δ40” strain shows only a mild reduction in growth rate, indicating that none of the 40 hydrolases are necessary for growth. The Δ40 strain does not detectably shed old wall, suggesting that turnover is not essential for growth. The remaining hydrolases in the Δ40 strain are LytE and CwlO, previously shown to be synthetically lethal. Either can be removed in Δ40, indicating that either hydrolase alone is sufficient for cell growth. Screening of environmental conditions and biochemistry revealed that LytE activity is inhibited by Mg2+ and that RlpA-like proteins may stimulate LytE activity. Together, these results suggest that the only essential function of cell wall hydrolases in B. subtilis is to enable cell growth by expanding the wall and that LytE or CwlO alone is sufficient for this function. These experiments introduce the Δ40 strain as a tool to study hydrolase activity and regulation in B. subtilis.

IMPORTANCE

In order to grow, bacterial cells must both create and break down their cell wall. The enzymes that are responsible for these processes are the target of some of our best antibiotics. Our understanding of the proteins that break down the wall – cell wall hydrolases – has been limited by redundancy among the large number of hydrolases many bacteria contain. To solve this problem, we identified 42 cell wall hydrolases inBacillus subtilisand created a strain lacking 40 of them. We show that cells can survive using only a single cell wall hydrolase; this means that to understand the growth ofB. subtilisin standard laboratory conditions, it is only necessary to study a very limited number of proteins, simplifying the problem substantially. We additionally show that the Δ40 strain is a research tool to characterize hydrolases, using it to identify 3 ‘helper’ hydrolases that act in certain stress conditions.
Cryo-TEM simulations of amorphous radiation-sensitive samples using multislice wave propagation
Authors: Himes Benjamin A. , Grigorieff Nikolaus
Published: February 2021

Image simulation plays a central role in the development and practice of high-resolution electron microscopy, including transmission electron microscopy of frozen-hydrated specimens (cryo-EM). Simulating images with contrast that matches the contrast observed in experimental images remains challenging, especially for amorphous samples. Current state-of-the-art simulators apply post hoc scaling to approximate empirical solvent contrast, attenuated image intensity due to specimen thickness, and amplitude contrast. This practice fails for images that require spatially variable scaling,e.g., simulations of a crowded or cellular environment. Modeling both the signal and the noise accurately is necessary to simulate images of biological specimens with contrast that is correct on an absolute scale. The “Frozen-Plasmon” method is introduced which explicitly models spatially variable inelastic scattering processes in cryo-EM specimens. This approach produces amplitude contrast that depends on the atomic composition of the specimen, reproduces the total inelastic mean free path as observed experimentally, and allows for the incorporation of radiation damage in the simulation. These improvements are quantified using the matched-filter concept to compare simulation and experiment. The Frozen-Plasmon method, in combination with a new mathematical formulation for accurately sampling the tabulated atomic scattering potentials onto a Cartesian grid, is implemented in the open-source software packagecisTEM.
Recent structural insights into the mechanism of lysozyme hydrolysis
Authors: Tanaka Ichiro , Nishinomiya Ryota , Goto Ryosuke , Shimazaki Shun , Chatake Toshiyuki
Published: February 2021

Lysozyme hydrolyzes the glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine in peptidoglycans located in the bacterial cell wall. The mechanism of the hydrolysis reaction of lysozyme was first studied more than 50 years ago; however, it has not yet been fully elucidated and various mechanisms are still being investigated. One reaction system that has commonly been proposed is that the lysozyme intermediate undergoes covalent ligand binding during hydrolysis. However, these findings resulted from experiments performed under laboratory conditions using fluorine-based ligands, which facilitate the formation of covalent bonds between the ligands and the catalytic side chain of lysozyme. More recently, high-resolution X-ray structural analysis was used to study the complex of lysozyme with an N-acetylglucosamine tetramer. As a result, the carboxyl group of Asp52 was found to form a relatively strong hydrogen-bond network and had difficulty binding covalently to C1 of the carbohydrate ring. To confirm this hydrogen-bond network, neutron test measurements were successfully performed to a resolution of better than 1.9 Å.
Processual responsiveness in dialogic facilitation
Authors: Alrø Helle , Billund Lise
Published: February 2021

Purpose

The purpose of this paper is to elaborate on the role of a group facilitator when taking a dialogical stance. A special interest is facilitator’s processual responsiveness and its potential for supporting a dialogic approach to process facilitation.

Design/methodology/approach

Theoretically, the article is based on dialogue and dialectic relationship theory. Empirically, it is based on pragmatic analysis of excerpts from audio recordings of a two-day process facilitation with an organizational group called KUDIAS.

Findings

The analysis highlights the importance of processual responsiveness of the facilitator in terms of focused attention to the process as well as to the interpersonal relations between the participants in the process. Being processually responsive, the facilitator supports the process in becoming dialogic toward all participants’ perspectives and in creating a climate characterized by curiosity, wondering, exploration and recognition. However, facilitator’s processual responsiveness also requires the ability to balance the process between support and confrontation.

Originality/value

Processual responsiveness is developed and discussed theoretically as well as empirically.
Extreme climate shifts pest dominance hierarchy through thermal evolution and transgenerational plasticity
Authors: Zhu Liang , Hoffmann Ary A. , Li Shi‐Min , Ma Chun‐Sen
Published: February 2021

Dominance hierarchy, the dominance ranking of members in a community, is determined by the relative population fitness of coexisting species. Climate change can shift dominance hierarchies depending on how species respond to changing climate, but ecological mechanisms underlying such shifts remain largely unknown. Specifically, dominance hierarchy shifts under climate change have rarely been linked to eco‐evolutionary responses to thermal extremes, which we consider in this study.

We conducted an 8‐year field survey to link extreme high‐temperature events to the shift in dominance hierarchy of two worldwide cereal aphid species (Rhopalosiphum padi and Sitobion avenae), which may respond rapidly through evolutionary or plastic responses to thermal extremes due to their short generation duration, clonal structure and high thermal sensitivity. To further understand the mechanism involved in this change in species' dominance, we characterised aphid heat tolerance and demography of the two species sourced from relatively mild (Xinxiang) and hot (Wuhan) locations in a common garden design and compared the same measures in up‐ and down‐selected lines of the two aphid species.

We found that accumulation of extreme high‐temperature events (EHTs) affected per capita growth rate of S. avenae but not R. padi, driving a shift in annual relative dominance of these two common species in wheat fields. Furthermore, evidence from common garden tests and artificial thermal selection revealed that evolutionary and plastic changes in thermal tolerance under EHTs were species‐dependent; R. padi evolved higher heat tolerance without reducing fitness while S. avenae did not evolve heat tolerance but showed detrimental transgenerational plastic changes under thermal extremes. Rhopalosiphum padi may take over the dominant position of S. avenae in a warmer future, due to a higher evolutionary potential of heat tolerance and less detrimental plasticity following selection.

Field surveys and laboratory experiments together point to a shift in species dominance related to interspecific differences in species' evolutionary rates and transgenerational plasticity of thermal traits during selection events associated with extreme climatic conditions. This study highlights that eco‐evolutionary dynamics can contribute to community responses to natural thermal extremes.

A free Plain Language Summary can be found within the Supporting Information of this article.
Same Problems, Different Solutions: Stealth Democracy and the Vote for a Populist Party
Authors: Esteban Irene , Stiers Dieter
Published: February 2021

In this study, we explore heterogeneity in the relationship between dissatisfaction with democratic representation and voting for a populist party. More specifically, we argue that numerous citizens are dissatisfied with modern political elites and processes, but that not all are attracted by populist parties' programmatic appeal. In particular, while citizens with stealth democratic attitudes are also dissatisfied with democratic representation – similar to citizens with populist ideas – voters with high levels of stealth democracy hold preferences for alternative forms of representation other than those proposed by populist parties. Hence, although stealth democrats are similar to populists on the attitudinal level, they will not be appealed to vote for a populist party. Analyses using the data of the Finnish Election Studies provide support for our hypotheses.
Mapping data‐driven individualized neurobehavioral phenotypes in heavy alcohol drinkers
Authors: DeMartini Kelly S. , Gueorguieva Ralitza , Pearlson Godfrey , Krishnan‐Sarin Suchitra , Anticevic Alan , Ji Lisa J. , Krystal John H. , O’Malley Stephanie S.
Published: February 2021

Objective

Recent studies have examined the factor structure and associated correlates of three neurofunctional domains, executive function, incentive salience, and negative emotionality in the development and maintenance of alcohol use disorders in clinical samples. The current study sought to replicate and extend prior work by testing this 3‐factor model, utilizing both exact and similar phenotypic measures, as well as novel measures, in a non–treatment‐seeking sample.

Methods

Self‐report measures of alcohol addiction, impulsivity, behavior, and exposure to early‐life stress were collected as part of baseline assessments for alcohol imaging and pharmacotherapy studies in 335 individuals. Confirmatory factor analysis (CFA) was used to examine model structure and fit. A multiple indicators, multiple causes (MIMIC) model identified predictors of latent factors identified by CFA.

Results

Results supported an intercorrelated model with three factors: executive function, incentive salience, and emotionality. All factors were associated with current AUD, and incentive salience was uniquely associated with past 30‐day drinking frequency. MIMIC results identified multiple significant predictors of these latent factors, including history of alcohol use disorder, positive family history of alcohol dependence, earlier age of first drink, and a history of childhood emotional abuse and physical neglect.

Conclusions

Our results support an intercorrelated 3‐factor model of neurofunctional domains in alcohol use models, consistent with published findings. Because childhood physical neglect was a significant predictor of all latent factors, these results also highlight the significant negative impact of childhood neglect on later addiction development.
Temporal changes in rates of active management and infant survival following live birth at 22–24 weeks' gestation in Victoria
Authors: Boland Rosemarie A. , Cheong Jeanie L. Y. , Stewart Michael J. , Doyle Lex W.
Published: February 2021

Background

Management of livebirths at 22–24 weeks' gestation in high‐income countries varies widely and has changed over time.

Aims

Our aim was to determine how rates of active management and infant survival of livebirths at 22–24 weeks varied with perinatal variables known at birth, and over time in Victoria, Australia.

Materials and methods

We conducted a population‐based cohort study of all 22–24 weeks' gestation live births, free of lethal congenital anomalies in 2009–2017. Rates of active management and survival to one year of age were reported. ‘Active management’ was defined as receiving resuscitation at birth or nursery admission for intensive care.

Results

Over the nine‐year period, there were 796 eligible live births. Overall, 438 (55%) were actively managed: 5% at 22 weeks, 45% at 23 weeks and 90% at 24 weeks' gestation, but rates of active management did not vary substantially over time. Of livebirths actively managed, 263 (60%) survived to one year: 0% at 22 weeks, 50% at 23 weeks and 66% at 24 weeks. Apart from gestational age, being born in a tertiary perinatal centre and increased size at birth were associated with survival in those actively managed, but sex and plurality were not. Survival rates of actively managed infants rose over time (adjusted odds ratio 1.09 per year; 95% CI 1.01‐1.18; P = 0.03).

Conclusions

Although active management rates did not change substantially over time in Victoria, an overall increase in infant survival was observed. With increasing gestational age, rates of active management and infant survival rapidly rose.
Tackling nasal symptoms in athletes: Moving towards personalized medicine
Authors: Hox Valerie , Beyaert Simon , Bullens Dominique , Couto Mariana , Langer Daniel , Hellings Peter‐Willem , Huart Caroline , Rombaux Philippe , Seys Sven F. , Surda Pavol , Walker Abigail , Steelant Brecht
Published: February 2021

Adequate nasal breathing is indispensable for athletes, and nasal symptoms have been shown to interfere with their subjective feeling of comfortable breathing and quality of life. Nasal symptoms are caused by either structural abnormalities or mucosal pathology. Structural pathologies are managed differently from mucosal disease, and therefore, adequate diagnosis is of utmost importance in athletes in order to choose the correct treatment option for the individual. Literature suggests that nasal symptoms are more prevalent in athletes compared to the general population and certain sports environments might even trigger the development of symptoms. Given the high demands of respiratory function in athletes, insight into triggering factors is of high importance for disease prevention. Also, it has been suggested that athletes are more neglectful to their symptoms and hence remain undertreated, meaning that special attention should be paid to education of athletes and their caregivers. This review aims at giving an overview of nasal physiology in exercise as well as the possible types of nasal pathology. Additionally, diagnostic and treatment options are discussed and we focus on unmet needs for the management and prevention of these symptoms in athletes within the concept of precision medicine.
Provincialising American Capitalism: From Universal Instance to Contingent Case
Authors: Omstedt Mikael
Published: February 2021

This article draws on theories of uneven development to deconstruct a set of universalising assumptions in the critique of American capitalism. While these theories have called for more relational understandings of capitalism, there is a tendency to naturalise the United States as an instance of universal capitalist relations. Engaging such diverse thinkers as Paul Baran and Paul Sweezy, Michel Aglietta, and Cedric Robinson, the article identifies three recurrent universals, including: (1) abstraction from the US as the most “advanced” capitalist formation; (2) assumption of American capitalism as developing in a particularly “pure” state; and (3) subsumption of the dynamics of American capitalism under universal logics. Reading these against the methodological principles of Uneven and Combined Development, the article argues for provincialising the capitalist formation that appears the most “complete”.
First experience using the Senhance surgical system in laparoscopic local gastrectomy for gastrointestinal stromal tumor
Authors: Sugita Hirofumi , Sakuramoto Shinichi , Aoyama Junya , Ito Sunao , Oya Shuichiro , Watanabe Kenji , Fujiwara Naoto , Kondo Hiroka , Miyawaki Yutaka , Hirano Yasumitsu , Sato Hiroshi , Yamaguchi Shigeki , Koyama Isamu
Published: February 2021

Various innovative robotic systems have been developed to improve surgery precision. The Senhance Surgical System (SSS) is a digital laparoscopic system offering eye tracking and haptic feedback. Several reports have described application of the SSS to general surgeries, including cholecystectomy and colectomy. However, use of the SSS for gastric tumor has not been reported. We experienced a case of laparoscopic local gastrectomy (LLG) for gastrointestinal stromal tumor (GIST) with the SSS. A 74‐year‐old man diagnosed with GIST underwent LLG with the SSS. Operation, docking, and console times were 117, 11, and 59 minutes, respectively. No perioperative complications were encountered. This study is the first to report LLG for GIST with the SSS. LLG with the SSS was safe and feasible. The SSS can use reusable forceps and contribute to reducing medical costs. The development of instruments is also progressing, and various kinds of surgery are likely to be indicated.
Measuring prescription opioid misuse and its consequences
Authors: Dart Richard C. , Iwanicki Janetta L. , Black Joshua C. , Olsen Heather A. , Severtson Stevan G.
Published: February 2021

Aims

Prescription drug misuse in the USA increased during the 1990s to 2010. The epidemic stimulated the need new analytical strategies and techniques to understand the medications involved, user characteristics and other factors needed to address the epidemic.

Methods

A strategy of mosaic surveillance has evolved. Using real world evidence, the goal is to paint a more complete profile of a drug's real world misuse using triangulation—integrating results from multiple sources, where each approach has unrelated sources of bias.

Results

Research findings have been remarkably consistent across multiple data sources. The most commonly misused opioid medications: hydrocodone = oxycodone > methadone = buprenorphine = tramadol = fentanyl (prescription form) > morphine > hydromorphone = oxymorphone > tapentadol. This rank order is similar to the number of prescriptions dispensed for each product in the USA. In the USA, prescription opioid misuse started to decrease about 2011. Typically, multiple drugs are misused together, particularly in lethal cases. Immediate release formulations are more commonly misused than extended release formulations. The introduction of tamper resistant formulations to resist crushing were followed by a decrease in misuse of those products.

Conclusions

The rapid expansion of opioid prescribing was accompanied by increasing misuse and mortality. Interventions such as prescription drug monitoring programmes, increased law enforcement and abuse deterrent formulations have been followed by decreases in misuse of most opioid analgesics.
Dysregulation of the centrosome induced by BRCA1 deficiency contributes to tissue‐specific carcinogenesis
Authors: Yoshino Yuki , Fang Zhenzhou , Qi Huicheng , Kobayashi Akihiro , Chiba Natsuko
Published: February 2021

Alterations in breast cancer gene 1 (BRCA1), a tumor suppressor gene, increase the risk of breast and ovarian cancers. BRCA1 forms a heterodimer with BRCA1‐associated RING domain protein 1 (BARD1) and functions in multiple cellular processes, including DNA repair and centrosome regulation. BRCA1 acts as a tumor suppressor by promoting homologous recombination (HR) repair, and alterations in BRCA1 cause HR deficiency, not only in breast and ovarian tissues but also in other tissues. The molecular mechanisms underlying BRCA1 alteration‐induced carcinogenesis remain unclear. Centrosomes are the major microtubule‐organizing centers and function in bipolar spindle formation. The regulation of centrosome number is critical for chromosome segregation in mitosis, which maintains genomic stability. BRCA1/BARD1 function in centrosome regulation together with Obg‐like ATPase (OLA1) and receptor for activating protein C kinase 1 (RACK1). Cancer‐derived variants of BRCA1, BARD1, OLA1, and RACK1 do not interact, and aberrant expression of these proteins results in abnormal centrosome duplication in mammary‐derived cells, and rarely in other cell types. RACK1 is involved in centriole duplication in the S phase by promoting polo‐like kinase 1 activation by Aurora A, which is critical for centrosome duplication. Centriole number is higher in cells derived from mammary tissues compared with in those derived from other tissues, suggesting that tissue‐specific centrosome characterization may shed light on the tissue specificity of BRCA1‐associated carcinogenesis. Here, we explored the role of the BRCA1‐containing complex in centrosome regulation and the effect of its deficiency on tissue‐specific carcinogenesis.
Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants
Authors: Fusco Carmela , Nardella Grazia , Petracca Antonio , Ronchi Dario , Paciello Nicola , Di Giacomo Marilena , Gambardella Stefano , Lanfranconi Silvia , Zampatti Stefania , D'Agruma Leonardo , Micale Lucia , Castori Marco
Published: February 2021

Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system which may occur sporadically or segregate within families due to heterozygous variants in KRIT1/CCM1, MGC4607/CCM2 or PDCD10/CCM3. Intronic variants are not uncommon in familial CCM, but their clinical interpretation is often hampered by insufficient data supporting in silico predictions. Here, the mRNA analysis for two intronic unpublished variants (KRIT1 c.1147‐7 T > G and PDCD10 c.395 + 2 T > G) and three previously published variants in KRIT1 but without data supporting their effects was carried out. This study demonstrated that all variants can induce a frameshift with the lack of residues located in the C‐terminal regions and involved in protein–protein complex formation, which is essential for vascular homeostasis. These results support the introduction of mRNA analysis in the diagnostic pathway of familial CCM and expand the knowledge of abnormal splicing patterning in this disorder.
Shall we exclude parapsoriasis from the medical vocabulary?
Authors: Xavier José Cândido Caldeira , Ocanha‐Xavier Juliana Polizel , Marques Mariângela Esther Alencar
Published: February 2021

Since the first description of parapsoriasis more than 100 years ago, parapsoriasis has been a questionable condition and occasionally considered a precursor of cutaneous lymphoma. The name “parapsoriasis” is related to a heterogenous group of diseases that show a distinct clinical presentation; however, the histopathological criteria are not strongly specific. Pathologists do not consider parapsoriasis as a possible histopathological diagnosis, but dermatologists use the term as clinical hypothesis. We aim to provide an historical review of parapsoriasis focusing on histopathological criteria, considering its possible relation with cutaneous skin lymphoma, based on articles from PubMed and standard dermatopathological books. Parapsoriasis does not have well‐defined histopathological criteria, so its use should be avoided. Being aware of parapsoriasis complexity, a consensus meeting can help to create a guideline regarding this topic.