bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

SummaryPancreatic 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 findingsPDAC regional heterogeneity originates in sub-tumor microenvironments (subTMEs)SubTMEs exhibit distinct immune phenotypes and CAF differentiation statesDifferent subTMEs are either tumor-promoting or chemoprotectiveIntratumoral 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

AbstractClogging 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

AbstractMonoclonal 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

AbstractAntimicrobial 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

AbstractRecombinant 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

AbstractPremotor 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

ABSTRACTMost 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.IMPORTANCEIn 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

AbstractImage 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.
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

Abstract

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.
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

AbstractObjectiveRecent 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.MethodsSelf‐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.ResultsResults 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.ConclusionsOur 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

BackgroundManagement of livebirths at 22–24 weeks' gestation in high‐income countries varies widely and has changed over time.AimsOur 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 methodsWe 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.ResultsOver 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).ConclusionsAlthough 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

AbstractAdequate 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.