bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced Nursing Practice für Patient_innen mit Kopf-Hals-Tumorerkrankungen und ihre Angehörigen
Authors: Baumgartner Eva , Giger Roland , Spichiger Elisabeth
Published: October 2022

Zusammenfassung. Hintergrund: Kopf-Hals-Tumore stellen Patient_innen und Angehörige wegen komplexer Behandlungen und Veränderungen vitaler Funktionen sowie des Aussehens vor große Herausforderungen. Sie benötigen vielseitige Unterstützung und profitieren von koordinierter, interprofessioneller Zusammenarbeit sowie Advanced Nursing Practice. Problem/Ziel: In einem Kopf-Hals-Tumorzentrum fehlte eine koordinierende Ansprechperson für Betroffene und das Betreuungsteam. Deshalb sollte ein Advanced Nursing Practice-Angebot entwickelt werden. Methoden: Es wurden ein Konzept für Advanced Nursing Practice, Methoden der Praxisentwicklung und Aktionsforschung eingesetzt. Das Projekt verlief in vier Phasen: Nach Stakeholderanalyse und Literaturrecherche wurde das Angebot konzipiert, in einer Pilotphase getestet und mittels Struktur-/Prozessdaten sowie einer zweiten Stakeholderbefragung evaluiert. Ergebnisse: Für Betroffene wurde eine evidenzbasierte, kontinuierliche, personenzentrierte Betreuung über das Behandlungskontinuum gefördert. Die Expertise von Pflegenden sowie die Zusammenarbeit mit internen und externen Fachpersonen wurde gefördert. Betroffene schätzten die Kontinuität, welche die Advanced Practice Nurse bot. Diskussion: Die methodischen Ansätze unterstützten ein zielorientiertes Vorgehen, insbesondere wurden durch partizipative Praxisentwicklung Befürchtungen von Mitarbeitenden aufgefangen. Grenzen/Transfer: Ein nachhaltiges Angebot kann noch nicht gewährleistet werden. Zu empfehlen ist das Vorgehen mit Stakeholderanalyse, interprofessionellem Fokus und frühzeitigem Planen der Evaluation.
Ring Fault Slip Reversal at Bárðarbunga Volcano, Iceland: Seismicity During Caldera Collapse and Re‐Inflation 2014–2018
Authors: Glastonbury‐Southern E. , Winder T. , White R. S. , Brandsdóttir B.
Published: October 2022

Microearthquakes reveal the kinematics of the Bárðarbunga caldera ring fault; during the 2014–2015 rifting event and gradual caldera collapse, and its subsequent, ongoing re‐inflation. Tightly constrained focal mechanisms during re‐inflation have reversed phase arrival polarities from events during the caldera collapse. Thus, the inner side of the steeply dipping northern caldera faults (averaging 81 ± 8°) has been moving upwards during the post‐eruptive period. Both precise relative relocations of the seismicity and fault plane solutions confirm that this is due to slip reversal on the same ring fault structure.
Quantifying the Uncertainty Sources of Future Climate Projections and Narrowing Uncertainties With Bias Correction Techniques
Authors: Wu Yi , Miao Chiyuan , Fan Xuewei , Gou Jiaojiao , Zhang Qi , Zheng Haiyan
Published: October 2022

Decomposing the uncertainty of global climate models is highly instructive in understanding climate change. However, it remains unclear whether sources of uncertainty have changed as the models have evolved and the extents to which uncertainty in temperature and precipitation are narrowed after bias correction (BC). We quantified uncertainty in temperature and precipitation projections over global land from three sources—model uncertainty, scenario uncertainty, and internal variability—and compared results from the models participating in the 5th and 6th phases of the Coupled Model Intercomparison Project (CMIP5 and CMIP6). In addition, we investigated the potential of four BC methods for narrowing uncertainty in temperature and precipitation over the globe and individual continents. Raw projections of temperature and precipitation have greater uncertainty and lower fractional uncertainty relative to their anomalies. The largest temperature uncertainties appear in high‐latitude and high‐altitude regions, and the largest precipitation uncertainties are in low‐latitude regions and mountainous and coastal areas. For uncertainties in CMIP6 temperatures, the contribution from model uncertainty decreases with time (from 99% to 39%), while the contribution from scenario uncertainty increases with time (from 0.01% to 61%). For precipitation projections, the contribution from model uncertainty predominates (98%), while the contributions from scenario uncertainty (1.8%) and internal variability (0.2%) are extremely low. Four BC methods have exhibited excellent ability to reduce uncertainty, and among them, BC and spatial disaggregation has the best performance. These findings can help us better understand the characteristics of the models, while also providing decision makers with more accurate information to address climate mitigation and adaptation measures.
Nanoscale Damage Production by Dynamic Tensile Rupture in α‐Quartz
Authors: Guren Marthe G. , Sveinsson Henrik A. , Malthe‐Sørenssen Anders , Renard François
Published: October 2022

The creation of new fractures during an earthquake produces rock damage and contributes to the dissipation of strain energy. During dynamic rupture propagation, tensile microfractures can form in the earthquake process zone and in the domains around a fault that host large transient tensile stress. These microfractures can produce rock fragments with a wide range of sizes. Using molecular dynamics simulations, we model tensile rupture propagation in α‐quartz under conditions of stress that occur during earthquake propagation. Our results show that for rupture speeds below 15% of the Rayleigh wave speed, fractures propagate linearly. At higher speeds, fracture propagation undergoes path instabilities with crack oscillations and microbranching leading to the formation of nanoscale roughness and fragments. This nanoscale damage can form in and around the earthquake process zone before any significant slip has occurred on the fault. The produced nanoparticles may control further energy dissipation during frictional slip.
Multi‐Level Monte Carlo Models for Flood Inundation Uncertainty Quantification
Authors: Aitken G. , Beevers L. , Christie M. A.
Published: October 2022

Flood events are the most commonly occurring natural disaster, with over 5 million properties at risk in the UK alone. Changes in the global climate are expected to increase the frequency and magnitude of flood events. Flood hazard assessments, using climate projections as input, guide policy decisions and engineering projects to reduce the impact of large return period events. Probabilistic flood modeling is required to take into account uncertainties in climate model projections. However, the dichotomous relationship between probabilistic modeling, computational cost and model resolution limits the applicability of such techniques. This paper examines improvements to traditional Monte Carlo methods using Latin hypercube sampling (LHS) and Multi‐level Monte Carlo (MLMC) to quantify the uncertainty in flood extent resulting from input hydrograph uncertainty. The results demonstrate that MLMC is a more efficient modeling strategy than current methods (i.e., traditional Monte Carlo) with high resolution outputs produced in less time than previously possible. The novel application of MLMC technique to three Scottish case studies, demonstrating a variety of river characteristics, domain sizes and computational costs, using a high resolution 5 m grid resulted in a 99.2% reduction in computational cost compared to traditional Monte Carlo methods and up to 2.3 times speedup over Latin Hypercube Sampling.
Comparing Well and Geophysical Data for Temperature Monitoring Within a Bayesian Experimental Design Framework
Authors: Thibaut Robin , Compaire Nicolas , Lesparre Nolwenn , Ramgraber Maximilian , Laloy Eric , Hermans Thomas
Published: October 2022

Temperature logs are an important tool in the geothermal industry. Temperature measurements from boreholes are used for exploration, system design, and monitoring. The number of observations, however, is not always sufficient to fully determine the temperature field or explore the entire parameter space of interest. Drilling in the best locations is still difficult and expensive. It is therefore critical to optimize the number and location of boreholes. Due to its higher spatial resolution and lower cost, four‐dimensional (4D) temperature field monitoring via time‐lapse Electrical Resistivity Tomography has been investigated as a potential alternative. We use Bayesian Evidential Learning (BEL), a Monte Carlo‐based training approach, to optimize the design of a 4D temperature field monitoring experiment. We demonstrate how BEL can take into account various data source combinations (temperature logs combined with geophysical data) in the Bayesian optimal experimental design (BOED). To determine the optimal data source combination, we use the Root Mean Squared Error of the predicted target in the low dimensional latent space where BEL is solving the prediction problem. The parameter estimates are accurate enough to use in BOED. Furthermore, the method is not limited to monitoring temperature fields and can be applied to other similar experimental design problems. The method is computationally efficient and requires little training data. For the considered optimal design problem, a training set of only 200 samples and a test set of 50 samples is sufficient.
Carbonized polymer dots enhanced stability and flexibility of quasi-2D perovskite photodetector
Authors: Tan Mingrui , Li Mingbian , Pan Wanting , Feng Xiaopeng , He Yuhong , Liu Junjun , Dong Fengxia , Wei Haotong , Yang Bai
Published: October 2022

Quasi-2D perovskites have been demonstrated to be competitive materials in the photodetection fields due to the enhanced moisture stability by large organic cations. However, as the increasing demands of modern technology, it is still challenging to combine the flexibility with the capability of weak light detection in a low-cost way. Here, amides, carboxylic acids, and anhydrides groups-rich carbonized polymer dots (CPDs) were employed to fill in the perovskite grain boundaries, which can passivate the point defects of perovskite by coordinating with the unbonded Pb atoms, and reduce the leakage current. Weak light detection capability was demonstrated by directly resolving light with an intensity of 10.1 pW cm−2. More importantly, the stretchable polymer chains on CPDs strongly interact with perovskite ions through multiple supramolecular interactions, and extend the stretchable properties to the perovskite/CPDs composites, which can maintain the integral structure stability during the deformation of perovskite crystals and restricted any crack by releasing the film strain. Our fabricated devices show extraordinary flexible stability in the bending-dependent response tests. The viscoelasticity of CPDs improves the bending stability of the flexible quasi-2D perovskite photodetectors, and device performance shows no degradation after bending 10000 times, comparable or even outperforming the dominating flexible photodetectors.
Fyn nanoclustering requires switching to an open conformation and is enhanced by FTLD-Tau biomolecular condensates
Authors: Martínez-Mármol Ramón , Small Christopher , Jiang Anmin , Palliyaguru Tishila , Wallis Tristan P. , Gormal Rachel S. , Sibarita Jean-Baptiste , Götz Jürgen , Meunier Frédéric A.
Published: October 2022

Fyn is a Src kinase that controls critical signalling cascades and has been implicated in learning and memory. Postsynaptic enrichment of Fyn underpins synaptotoxicity in dementias such as Alzheimer’s disease and frontotemporal lobar degeneration with Tau pathology (FTLD-Tau). The FLTD P301L mutant Tau is associated with a higher propensity to undergo liquid–liquid phase separation (LLPS) and form biomolecular condensates. Expression of P301L mutant Tau promotes aberrant trapping of Fyn in nanoclusters within hippocampal dendrites by an unknown mechanism. Here, we used single-particle tracking photoactivated localisation microscopy to demonstrate that the opening of Fyn into its primed conformation promotes its nanoclustering in dendrites leading to increased Fyn/ERK/S6 downstream signalling. Preventing the auto-inhibitory closed conformation of Fyn through phospho-inhibition or through perturbation of its SH3 domain increased Fyn’s nanoscale trapping, whereas inhibition of the catalytic domain had no impact. By combining pharmacological and genetic approaches, we demonstrate that P301L Tau enhanced both Fyn nanoclustering and Fyn/ERK/S6 signalling via its ability to form biomolecular condensates. Together, our findings demonstrate that Fyn alternates between a closed and an open conformation, the latter being enzymatically active and clustered. Furthermore, pathogenic immobilisation of Fyn relies on the ability of P301L Tau to form biomolecular condensates, thus highlighting the critical importance of LLPS in controlling nanoclustering and downstream intracellular signalling events.
A one-year follow-up study of treatment-compliant suicide attempt survivors: relationship of CYP2D6-CYP2C19 and polypharmacy with suicide reattempts
Authors: Peñas-Lledó Eva M. , Guillaume Sebastien , de Andrés Fernando , Cortés-Martínez Ana , Dubois Jonathan , Kahn Jean Pierre , Leboyer Marion , Olié Emilie , LLerena Adrián , Courtet Philippe
Published: October 2022

This study of a cohort of 1-year treatment-compliant survivors of a suicide attempt examined for the first time whether a highCYP2D6-CYP2C19metabolic capacity (pharmacogenes related to psychopathology, suicide, and attempt severity) and/or polypharmacy treatments predicted repeat suicide attempts, adjusting for sociodemographic and clinical factors as confounders. Of the 461 (63% women) consecutively hospitalized patients who attempted suicide and were evaluated and treated after an index attempt, 191 (67.5% women) attended their 6- and 12-month follow-up sessions. Clinicians were blinded to the activity scores (AS) of their genotypes, which were calculated as the sum of the values assigned to each allele (CYP2C19 *2,*17;CYP2D6 *3,*4,*4xN,*5,*6,*10,wtxN). No differences were found in polypharmacy prescription patterns and the variability ofCYP2D6andCYP2C19genotypes between adherents and dropouts, but the formers were older, with a higher frequency of anxiety and bipolar disorders and fewer alcohol and substance use disorders. The risk of reattempts was higher forCYP2D6ultrarapid (AS > 2) metabolizers (β = 0.561,p = 0.005) and violent suicide survivors (β = −0.219,p = 0.042) if the attempt occurred during the first 6-month period, individuals with an increased number of MINI DSM-IV Axis I mental disorders (β = 0.092,p = 0.032) during the second 6-month period and individuals with a combined highCYP2D6-CYP2C19metabolic capacity (AS > 4) (β = 0.345,p = 0.024) and an increased use of drugs other than antidepressants, anxiolytics-depressants and antipsychotics-lithium (β = 0.088,p = 0.005) in multiple repeaters during both periods. CYP2D6 and CYP2C19 rapid metabolism and polypharmacy treatment for somatic comorbidities must be considered to prevent the severe side effects of short-term multiple suicide reattempts after a previous attempt.
Positive moods are all alike? Differential affect amplification effects of ‘elated’ versus ‘calm’ mental imagery in young adults reporting hypomanic-like experiences
Authors: Vannucci Caterina , Bonsall Michael B. , Di Simplicio Martina , Cairns Aimee , Holmes Emily A. , Burnett Heyes Stephanie
Published: October 2022

Positive mood amplification is a hallmark of the bipolar disorder spectrum (BPDS). We need better understanding of cognitive mechanisms contributing to such elevated mood. Generation of vivid, emotionally compelling mental imagery is proposed to act as an ‘emotional amplifier’ in BPDS. We used a positive mental imagery generation paradigm to manipulate affect in a subclinical BPDS-relevant sample reporting high (n = 31) vs. low (n = 30) hypomanic-like experiences on the Mood Disorder Questionnaire (MDQ). Participants were randomized to an ‘elated’ or ‘calm’ mental imagery condition, rating their momentary affect four times across the experimental session. We hypothesized greater affect increase in the high (vs. low) MDQ group assigned to the elated (vs. calm) imagery generation condition. We further hypothesized that affect increase in the high MDQ group would be particularly apparent in the types of affect typically associated with (hypo)mania, i.e., suggestive of high activity levels. Mixed model and time-series analysis showed that for the high MDQ group, affect increased steeply and in a sustained manner over time in the ‘elated’ imagery condition, and more shallowly in ‘calm’. The low-MDQ group did not show this amplification effect. Analysis of affect clusters showed high-MDQ mood amplification in the ‘elated’ imagery condition was most pronounced for active affective states. This experimental model of BPDS-relevant mood amplification shows evidence that positive mental imagery drives changes in affect in the high MDQ group in a targeted manner. Findings inform cognitive mechanisms of mood amplification, and spotlight prevention strategies targeting elated imagery, while potentially retaining calm imagery to preserve adaptive positive emotionality.
How does the genomic naive public perceive whole genomic testing for health purposes? A scoping review
Authors: Sherburn Isabella A. , Finlay Keri , Best Stephanie
Published: October 2022

The benefits of genomic testing are primarily reported in rare disease, cancer diagnosis and disease management. However, as research into its application in common, more complex conditions grows, as well as the increased prevalence of carrier screening programs, the genomic naive public is more likely to be offered testing in future. To promote social acceptability and ethical application of this technology, it is essential that public perceptions of genomics are considered. Previous studies, however, have primarily focussed on the views of those with genetic conditions or those undergoing genetic testing. The aim of this scoping review is to investigate the genomic naive public’s perceptions of clinical genomics and clinical genomic testing. Embase, MEDLINE and PubMed databases were searched, with a total of 3460 articles identified. Data analysis was organised according to the nonadoption, abandonment, scale-up, spread, and sustainability (NASSS) framework. Sixteen full-text articles were included in the final analysis. Most of the studies used questionnaires to determine attitudes of the public toward clinical genomics (n = 12). Public perceptions were found to underpin technology (Domain 2), value proposition (Domain 3), the adopter system (Domain 4) and the wider context (Domain 6) of the NASSS framework, highlighting its importance when considering implementation of an innovative technology such as genomic testing. Our study shows public perceptions are diverse, and highlights the need for more studies on the views of underrepresented groups and the impact of cultural contexts on perceptions.
A synthetic transcription platform for programmable gene expression in mammalian cells
Authors: Chen William C. W. , Gaidukov Leonid , Lai Yong , Wu Ming-Ru , Cao Jicong , Gutbrod Michael J. , Choi Gigi C. G. , Utomo Rachel P. , Chen Ying-Chou , Wroblewska Liliana , Kellis Manolis , Zhang Lin , Weiss Ron , Lu Timothy K.
Published: October 2022

Precise, scalable, and sustainable control of genetic and cellular activities in mammalian cells is key to developing precision therapeutics and smart biomanufacturing. Here we create a highly tunable, modular, versatile CRISPR-based synthetic transcription system for the programmable control of gene expression and cellular phenotypes in mammalian cells. Genetic circuits consisting of well-characterized libraries of guide RNAs, binding motifs of synthetic operators, transcriptional activators, and additional genetic regulatory elements express mammalian genes in a highly predictable and tunable manner. We demonstrate the programmable control of reporter genes episomally and chromosomally, with up to 25-fold more activity than seen with the EF1α promoter, in multiple cell types. We use these circuits to program the secretion of human monoclonal antibodies and to control T-cell effector function marked by interferon-γ production. Antibody titers and interferon-γ concentrations significantly correlate with synthetic promoter strengths, providing a platform for programming gene expression and cellular function in diverse applications.
Flexibility of functional neuronal assemblies supports human memory
Authors: Umbach Gray , Tan Ryan , Jacobs Joshua , Pfeiffer Brad E. , Lega Bradley
Published: October 2022

Episodic memories, or consciously accessible memories of unique events, represent a key aspect of human cognition. Evidence from rodent models suggests that the neural representation of these complex memories requires cooperative firing of groups of neurons on short time scales, organized by gamma oscillations. These co-firing groups, termed “neuronal assemblies,” represent a fundamental neurophysiological unit supporting memory. Using microelectrode data from neurosurgical patients, we identify neuronal assemblies in the human MTL and show that they exhibit consistent organization in their firing pattern based on gamma phase information. We connect these properties to memory performance across recording sessions. Finally, we describe how human neuronal assemblies flexibly adjust over longer time scales. Our findings provide key evidence linking assemblies to human episodic memory for the first time.
Direct visualization of Rashba-split bands and spin/orbital-charge interconversion at KTaO3 interfaces
Authors: Varotto Sara , Johansson Annika , Göbel Börge , Vicente-Arche Luis M. , Mallik Srijani , Bréhin Julien , Salazar Raphaël , Bertran François , Fèvre Patrick Le , Bergeal Nicolas , Rault Julien , Mertig Ingrid , Bibes Manuel
Published: October 2022

Rashba interfaces have emerged as promising platforms for spin-charge interconversion through the direct and inverse Edelstein effects. Notably, oxide-based two-dimensional electron gases display a large and gate-tunable conversion efficiency, as determined by transport measurements. However, a direct visualization of the Rashba-split bands in oxide two-dimensional electron gases is lacking, which hampers an advanced understanding of their rich spin-orbit physics. Here, we investigate KTaO3 two-dimensional electron gases and evidence their Rashba-split bands using angle resolved photoemission spectroscopy. Fitting the bands with a tight-binding Hamiltonian, we extract the effective Rashba coefficient and bring insight into the complex multiorbital nature of the band structure. Our calculations reveal unconventional spin and orbital textures, showing compensation effects from quasi-degenerate band pairs which strongly depend on in-plane anisotropy. We compute the band-resolved spin and orbital Edelstein effects, and predict interconversion efficiencies exceeding those of other oxide two-dimensional electron gases. Finally, we suggest design rules for Rashba systems to optimize spin-charge interconversion performance.
Untangling the threads of cellulose mercerization
Authors: Sawada Daisuke , Nishiyama Yoshiharu , Shah Riddhi , Forsyth V. Trevor , Mossou Estelle , O’Neill Hugh Michael , Wada Masahisa , Langan Paul
Published: October 2022

Naturally occurring plant cellulose, our most abundant renewable resource, consists of fibers of long polymer chains that are tightly packed in parallel arrays in either of two crystal phases collectively referred to as cellulose I. During mercerization, a process that involves treatment with sodium hydroxide, cellulose goes through a conversion to another crystal form called cellulose II, within which every other chain has remarkably changed direction. We designed a neutron diffraction experiment with deuterium labelling in order to understand how this change of cellulose chain direction is possible. Here we show that during mercerization of bacterial cellulose, chains fold back on themselves in a zigzag pattern to form crystalline anti-parallel domains. This result provides a molecular level understanding of one of the most widely used industrial processes for improving cellulosic materials.
Sublinear scaling of the cellular proteome with ploidy
Authors: Yahya G. , Menges P. , Amponsah P. S. , Ngandiri D. A. , Schulz D. , Wallek A. , Kulak N. , Mann M. , Cramer P. , Savage V. , Räschle M. , Storchova Z.
Published: October 2022

Ploidy changes are frequent in nature and contribute to evolution, functional specialization and tumorigenesis. Analysis of model organisms of different ploidies revealed that increased ploidy leads to an increase in cell and nuclear volume, reduced proliferation, metabolic changes, lower fitness, and increased genomic instability, but the underlying mechanisms remain poorly understood. To investigate how gene expression changes with cellular ploidy, we analyzed isogenic series of budding yeasts from 1N to 4N. We show that mRNA and protein abundance scales allometrically with ploidy, with tetraploid cells showing only threefold increase in protein abundance compared to haploids. This ploidy-dependent sublinear scaling occurs via decreased rRNA and ribosomal protein abundance and reduced translation. We demonstrate that the activity of Tor1 is reduced with increasing ploidy, which leads to diminished rRNA gene repression via a Tor1-Sch9-Tup1 signaling pathway. mTORC1 and S6K activity are also reduced in human tetraploid cells and the concomitant increase of the Tup1 homolog Tle1 downregulates the rDNA transcription. Our results suggest that the mTORC1-Sch9/S6K-Tup1/TLE1 pathway ensures proteome remodeling in response to increased ploidy.
A medium-entropy transition metal oxide cathode for high-capacity lithium metal batteries
Authors: Pei Yi , Chen Qing , Wang Meiyu , Zhang Pengjun , Ren Qingyong , Qin Jingkai , Xiao Penghao , Song Li , Chen Yu , Yin Wen , Tong Xin , Zhen Liang , Wang Peng , Xu Cheng-Yan
Published: October 2022

The limited capacity of the positive electrode active material in non-aqueous rechargeable lithium-based batteries acts as a stumbling block for developing high-energy storage devices. Although lithium transition metal oxides are high-capacity electrochemical active materials, the structural instability at high cell voltages (e.g., >4.3 V) detrimentally affects the battery performance. Here, to circumvent this issue, we propose a Li1.46Ni0.32Mn1.2O4-x (0 < x < 4) material capable of forming a medium-entropy state spinel phase with partial cation disordering after initial delithiation. Via physicochemical measurements and theoretical calculations, we demonstrate the structural disorder in delithiated Li1.46Ni0.32Mn1.2O4-x, the direct shuttling of Li ions from octahedral sites to the spinel structure and the charge-compensation Mn3+/Mn4+ cationic redox mechanism after the initial delithiation. When tested in a coin cell configuration in combination with a Li metal anode and a LiPF6-based non-aqueous electrolyte, the Li1.46Ni0.32Mn1.2O4-x-based positive electrode enables a discharge capacity of 314.1 mA h g−1 at 100 mA g−1 with an average cell discharge voltage of about 3.2 V at 25 ± 5 °C, which results in a calculated initial specific energy of 999.3 Wh kg−1 (based on mass of positive electrode’s active material).
Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery
Authors: Yang Yeon-Suk , Kim Jung-Min , Xie Jun , Chaugule Sachin , Lin Chujiao , Ma Hong , Hsiao Edward , Hong Jaehyoung , Chun Hyonho , Shore Eileen M. , Kaplan Frederick S. , Gao Guangping , Shim Jae-Hyuck
Published: October 2022

Heterotopic ossification is the most disabling feature of fibrodysplasia ossificans progressiva, an ultra-rare genetic disorder for which there is currently no prevention or treatment. Most patients with this disease harbor a heterozygous activating mutation (c.617 G > A;p.R206H) in ACVR1. Here, we identify recombinant AAV9 as the most effective serotype for transduction of the major cells-of-origin of heterotopic ossification. We use AAV9 delivery for gene replacement by expression of codon-optimized human ACVR1, ACVR1R206H allele-specific silencing by AAV-compatible artificial miRNA and a combination of gene replacement and silencing. In mouse skeletal cells harboring a conditional knock-in allele of human mutant ACVR1 and in patient-derived induced pluripotent stem cells, AAV gene therapy ablated aberrant Activin A signaling and chondrogenic and osteogenic differentiation. In Acvr1(R206H) knock-in mice treated locally in early adulthood or systemically at birth, trauma-induced endochondral bone formation was markedly reduced, while inflammation and fibroproliferative responses remained largely intact in the injured muscle. Remarkably, spontaneous heterotopic ossification also substantially decreased in in Acvr1(R206H) knock-in mice treated systemically at birth or in early adulthood. Collectively, we develop promising gene therapeutics that can prevent disabling heterotopic ossification in mice, supporting clinical translation to patients with fibrodysplasia ossificans progressiva.
Harnessing bioengineered microbes as a versatile platform for space nutrition
Authors: Llorente Briardo , Williams Thomas C. , Goold Hugh D. , Pretorius Isak S. , Paulsen Ian T.
Published: October 2022

Human enterprises through the solar system will entail long-duration voyages and habitation creating challenges in maintaining healthy diets. We discuss consolidating multiple sensory and nutritional attributes into microorganisms to develop customizable food production systems with minimal inputs, physical footprint, and waste. We envisage that a yeast collection bioengineered for one-carbon metabolism, optimal nutrition, and diverse textures, tastes, aromas, and colors could serve as a flexible food-production platform. Beyond its potential for supporting humans in space, bioengineered microbial-based food could lead to a new paradigm for Earth’s food manufacturing that provides greater self-sufficiency and removes pressure from natural ecosystems.
CryoEM structural exploration of catalytically active enzyme pyruvate carboxylase
Authors: López-Alonso Jorge Pedro , Lázaro Melisa , Gil-Cartón David , Choi Philip H. , Dodu Alexandra , Tong Liang , Valle Mikel
Published: October 2022

Pyruvate carboxylase (PC) is a tetrameric enzyme that contains two active sites per subunit that catalyze two consecutive reactions. A mobile domain with an attached prosthetic biotin links both reactions, an initial biotin carboxylation and the subsequent carboxyl transfer to pyruvate substrate to produce oxaloacetate. Reaction sites are at long distance, and there are several co-factors that play as allosteric regulators. Here, using cryoEM we explore the structure of active PC tetramers focusing on active sites and on the conformational space of the oligomers. The results capture the mobile domain at both active sites and expose catalytic steps of both reactions at high resolution, allowing the identification of substrates and products. The analysis of catalytically active PC tetramers reveals the role of certain motions during enzyme functioning, and the structural changes in the presence of additional cofactors expose the mechanism for allosteric regulation.
Heat-inactivated modified vaccinia virus Ankara boosts Th1 cellular and humoral immunity as a vaccine adjuvant
Authors: Yang Ning , Garcia Aitor , Meyer Cindy , Tuschl Thomas , Merghoub Taha , Wolchok Jedd D. , Deng Liang
Published: October 2022

Protein or peptide-based subunit vaccines have generated excitement and renewed interest in combating human cancer or COVID-19 outbreak. One major concern for subunit vaccine application is the weak immune responses induced by protein or peptides. Developing novel and effective vaccine adjuvants are critical for the success of subunit vaccines. Here we explored the potential of heat-inactivated MVA (heat-iMVA) as a vaccine adjuvant. Heat-iMVA dramatically enhances T cell responses and antibodies responses, mainly toward Th1 immune responses when combined with protein or peptide-based immunogen. The adjuvant effect of Heat-iMVA is stronger than live MVA and is dependent on the cGAS/STING-mediated cytosolic DNA-sensing pathway. In a therapeutic vaccination model based on tumor neoantigen peptide vaccine, Heat-iMVA significantly extended the survival and delayed tumor growth. When combined with SARS-CoV-2 spike protein, Heat-iMVA induced more robust spike-specific antibody production and more potent neutralization antibodies. Our results support that Heat-iMVA can be developed as a safe and potent vaccine adjuvant for subunit vaccines against cancer or SARS-CoV-2.
A 0.6 Mpc H i structure associated with Stephan’s Quintet
Authors: Xu C. K. , Cheng C. , Appleton P. N. , Duc P.-A. , Gao Y. , Tang N.-Y. , Yun M. , Dai Y. S. , Huang J.-S. , Lisenfeld U. , Renaud F.
Published: October 2022

Stephan’s Quintet (SQ, co-moving radial distance = 85 ± 6 Mpc, taken from the NASA/IPAC Extragalactic Database (NED)1) is unique among compact groups of galaxies2–12. Observations have previously shown that interactions between multiple members, including a high-speed intruder galaxy currently colliding into the intragroup medium, have probably generated tidal debris in the form of multiple gaseous and stellar filaments6,8,13, the formation of tidal dwarfs7,14,15 and intragroup-medium starbursts16, as well as widespread intergalactic shocked gas5,10,11,17. The details and timing of the interactions and collisions remain poorly understood because of their multiple nature18,19. Here we report atomic hydrogen (H i) observations in the vicinity of SQ with a smoothed sensitivity of 1σ = 4.2 × 1016 cm−2 per channel (velocity bin-width Δv = 20 km s−1; angular resolution = 4′), which are about two orders of magnitude deeper than previous observations8,13,20,21. The data show a large H i structure (with linear scale of around 0.6 Mpc) encompassing an extended source of size approximately 0.4 Mpc associated with the debris field and a curved diffuse feature of length around 0.5 Mpc attached to the south edge of the extended source. The diffuse feature was probably produced by tidal interactions in early stages of the formation of SQ (>1 Gyr ago), although it is not clear how the low-density H i gas (NH i ≲ 1018 cm−2) can survive the ionization by the intergalactic ultraviolet background on such a long time scale. Our observations require a rethinking of properties of gas in outer parts of galaxy groups and demand complex modelling of different phases of the intragroup medium in simulations of group formation.
Color naming in Tsimane’–Spanish bilinguals indicates that differential experience with content domains affects lexical access
Authors: Malik-Moraleda Saima , Roca Manuel , Gibson Edward
Published: October 2022

A standard assumption in the bilingual language processing literature is that the ease of access of a word in a language is determined by the speaker’soverallproficiency in the language. Alternatively, it could be that proficiency varies across semantic categories of the bilingual’s two languages. Here, we investigated lexical access in color terms in Tsimane’–Spanish bilinguals. Given that color terms are generally more frequent in Spanish than Tsimane’, participants may have better lexical access for color words in Spanish despite being overall more proficient in Tsimane’. Twenty-two Tsimane’–Spanish bilinguals took part in a picture naming task where participants labeled colors and animals. Participants were equally fast and accurate at naming animals in Tsimane’ and Spanish. However, participants were faster and more accurate at naming colors in Spanish than Tsimane’ except for the three color words that are most frequent (jaibes ~ white,tsincus ~ black,jaines ~ red) in Tsimane’, for which they were equally fast in both Tsimane’ and Spanish. These results suggest that category-specific proficiency is a better predictor for lexical access than overall proficiency.
Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination
Authors: Dowling David J. , Barman Soumik , Smith Alyson J. , Borriello Francesco , Chaney Danielle , Brightman Spencer E. , Melhem Gandolina , Brook Byron , Menon Manisha , Soni Dheeraj , Schüller Simone , Siram Karthik , Nanishi Etsuro , Bazin Hélène G. , Burkhart David J. , Levy Ofer , Evans Jay T.
Published: October 2022

Infection is the most common cause of mortality early in life, yet the broad potential of immunization is not fully realized in this vulnerable population. Most vaccines are administered during infancy and childhood, but in some cases the full benefit of vaccination is not realized in-part. New adjuvants are cardinal to further optimize current immunization approaches for early life. However, only a few classes of adjuvants are presently incorporated in vaccines approved for human use. Recent advances in the discovery and delivery of Toll-like receptor (TLR) agonist adjuvants have provided a new toolbox for vaccinologists. Prominent among these candidate adjuvants are synthetic small molecule TLR7/8 agonists. The development of an effective infant Bordetella pertussis vaccine is urgently required because of the resurgence of pertussis in many countries, contemporaneous to the switch from whole cell to acellular vaccines. In this context, TLR7/8 adjuvant based vaccine formulation strategies may be a promising tool to enhance and accelerate early life immunity by acellular B. pertussis vaccines. In the present study, we optimized (a) the formulation delivery system, (b) structure, and (c) immunologic activity of novel small molecule imidazoquinoline TLR7/8 adjuvants towards human infant leukocytes, including dendritic cells. Upon immunization of neonatal mice, this TLR7/8 adjuvant overcame neonatal hyporesponsiveness to acellular pertussis vaccination by driving a T helper (Th)1/Th17 biased T cell- and IgG2c-skewed humoral response to a licensed acellular vaccine (DTaP). This potent immunization strategy may represent a new paradigm for effective immunization against pertussis and other pathogens in early life.
Multiplex quadruple bioluminescent assay system
Authors: Kamiya Genta , Kitada Nobuo , Maki Shojiro , Kim Sung Bae
Published: October 2022

Bioluminescence (BL) is unique cold body radiation of light, generated by luciferin–luciferase reactions and commonly used in various bioassays and molecular imaging. However, most of the peak emissions of BL populate the blue-yellow region and have broad spectral bandwidths and thus superimpose each other, causing optical cross-leakages in multiplex assays. This study synthesized a new series of coelenterazine (CTZ) analogues, named K-series, that selectively illuminates marine luciferases with unique, blue-shifted spectral properties. The optical property and specificity of the K-series CTZ analogues were characterized by marine luciferases, with K2 and K5 found to specifically luminesce with ALuc- and RLuc-series marine luciferases, respectively. The results confirmed that the luciferase specificity and color variation of the CTZ analogues minimize the cross-leakages of BL signals and enable high-throughput screening of specific ligands in the mixture. The specificity and color variation of the substrates were further tailored to marine luciferases (or single-chain bioluminescent probes) to create a multiplex quadruple assay system with four integrated, single-chain bioluminescent probes, with each probe designed to selectively luminesce only with its specific ligand (first authentication) and a specific CTZ analogue (second authentication). This unique multiplex quadruple bioluminescent assay system is an efficient optical platform for specific and high-throughput imaging of multiple optical markers in bioassays without optical cross-leakages.
Maternal supplementation with a casein hydrolysate and yeast beta-glucan from late gestation through lactation improves gastrointestinal health of piglets at weaning
Authors: Dowley Alison , O’Doherty John V. , Mukhopadhya Anindya , Conway Eadaoin , Vigors Stafford , Maher Shane , Ryan Marion T. , Sweeney Torres
Published: October 2022

Improving maternal nutrition during pregnancy/lactation is a promising strategy to maximise the intestinal health of piglets undergoing abrupt weaning under commercial production conditions. This experiment investigated the effects of maternal supplementation of a casein hydrolysate and yeast β-glucan (CH-YBG) from day 83 of gestation until weaning (day 28) on sow faecal microbial populations and measures of piglet gastrointestinal health parameters at weaning. Sows (n = 10 sows/group) were assigned to: (1) control diet, and (2) control diet + CH-YBG. Maternal supplementation increased the abundance of the phylum Firmicutes, including members Lactobacillus in the sows faeces, with a concomitant increase in the caecal abundance of Lactobacillus in the weaned piglets compared to the controls. Piglets weaned from the supplemented sows had increased villus height in the duodenum (P < 0.05) and increased villus height to crypt depth ratio in the jejunum, as well as a decreased expression of the proinflammatory cytokine genes (IL6/TNF/TGFB), the tight junction gene CLDN3 and the mucin gene MUC2 in the duodenum/jejunum compared to the controls (P < 0.05). In conclusion, maternal CH-YBG supplementation during pregnancy/lactation improved microbial, structural, and inflammatory measures of gastrointestinal health of piglets at weaning. This is a promising strategy to alleviate the challenges that occur with early abrupt weaning in commercial pig production.
Study on the role of SLC14A1 gene in biochemical recurrence of prostate cancer
Authors: Ye Bin , Ding Ke , Li KaiXuan , Zhu Quan
Published: October 2022

Prostate cancer (PCa) is a common malignant disease among men and biochemical recurrence (BCR) is considered to be a decisive risk factor for clinical recurrence and PCa metastasis. Clarifying the genes related to BCR and its possible pathways is vital for providing diagnosis and treatment methods to delay the progress of BCR. An analysis of data concerning PCa from previous datasets of The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) was performed. Immunohistochemical (IHC) staining were used to evaluate the expression of SLC14A1 in prostate tissues. Kaplan–Meier analysis, Pearson correlation, and single sample Gene Set Enrichment Analysis (ssGSEA) were used to identify the potential pathway and molecular mechanism of the function of SLC14A1 in BCR of PCa. The expression of SLC14A1 is significantly reduced in prostate cancer cells and tissue comparing to normal prostate epithelial cell and para-cancerous tissue. As indicated by Kaplan–Meier analysis, High expression of SLC14A1 could increase the BCR-free survival time of PCa patients. This effect might be related to the interaction with miRNAs (has-miR-508, has-mir-514a2, and has-mir-449a) and the infiltration of B cells. SLC14A1 is a novel important gene associated with BCR of PCa, and further studies of its molecular mechanism may delay the progress of BCR.
Agarose gel microcapsules enable easy-to-prepare, picolitre-scale, single-cell genomics, yielding high-coverage genome sequences
Authors: Aoki Hiroyoshi , Masahiro Yuki , Shimizu Michiru , Hongoh Yuichi , Ohkuma Moriya , Yamagata Yutaka
Published: October 2022

A novel type of agarose gel microcapsule (AGM), consisting of an alginate picolitre sol core and an agarose gel shell, was developed to obtain high-quality, single-cell, amplified genomic DNA of bacteria. The AGM is easy to prepare in a stable emulsion with oil of water-equivalent density, which prevents AGM aggregation, with only standard laboratory equipment. Single cells from a pure culture of Escherichia coli, a mock community comprising 15 strains of human gut bacteria, and a termite gut bacterial community were encapsulated within AGMs, and their genomic DNA samples were prepared with massively parallel amplifications in a tube. The genome sequencing did not need second-round amplification and showed an average genome completeness that was much higher than that obtained using a conventional amplification method on the microlitre scale, regardless of the genomic guanine–cytosine content. Our novel method using AGM will allow many researchers to perform single-cell genomics easily and effectively, and can accelerate genomic analysis of yet-uncultured microorganisms.
Generation of a bovine cell line for gene engineering using an HIV-1-based lentiviral vector
Authors: Morizako Nanami , Butlertanaka Erika P. , Tanaka Yuri L. , Shibata Honoka , Okabayashi Tamaki , Mekata Hirohisa , Saito Akatsuki
Published: October 2022

Human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors are indispensable tools for gene engineering in mammalian cells. Conversely, lentiviral vector transduction is severely inhibited in bovine cells. Previous studies demonstrated that this inhibition is caused by the anti-lentiviral host factor tripartite motif containing 5 (TRIM5), which targets incoming HIV-1 virions by interacting with the viral capsid. In this study, we investigated several methods for overcoming the limited applicability of lentiviral vectors in bovine cells. First, we demonstrated that the SPRY domain of bovine TRIM5 is the major determinant of anti-viral activity. Second, we found that mutations that allow the capsid to evade rhesus macaque TRIM5α minimally rescued HIV-1 infectivity in bovine-derived MDBK cells. Third, we found that cyclosporine A, which relieves the inhibition of HIV-1 infection in monkey cells, significantly rescued the impaired HIV-1 infectivity in MDBK cells. Lastly, we successfully generated a bovine cell line lacking intact TRIM5 using the CRISPR/Cas9 technique. This TRIM5 knockout cell line displayed significantly higher susceptibility to an HIV-1-based lentiviral vector. In conclusion, our findings provide a promising gene engineering strategy for bovine cells, thereby contributing to innovations in agriculture and improvements in animal health.
Comparison of two ultra-widefield color-fundus imaging devices for visualization of retinal periphery and microvascular lesions in patients with early diabetic retinopathy
Authors: Stino Heiko , Riessland Susanna , Sedova Aleksandra , Datlinger Felix , Sacu Stefan , Schmidt-Erfurth Ursula , Pollreisz Andreas
Published: October 2022

Comparison of two ultra-widefield (UWF) color-fundus (CF) imaging devices in diabetic patients for visualization of retinal periphery and detection of early microvascular lesions. The total gradable areas (TGA) seen on non-mydriatic CF-images of two UWF-imaging devices (Optos Daytona P200T; Zeiss Clarus 700) were compared and differences in projected area measured. Retinal periphery outside the 7 standard fields (7SF) was divided into: F3 temporal, F4 superotemporal, F5 inferotemporal, F6 superonasal, F7 inferonasal. DR stage was evaluated in the 7SF and the TGA on images of both devices and compared using Cohens κ. 67 eyes of 67 patients (52.5 ± 15.3 years) were analysed. DR stages in the 7SF were no (n = 36 Optos, n = 35 Clarus), mild (n = 16 Optos, n = 17 Clarus), and moderate DR (n = 15). Optos depicted significantly more area in F3 (median [interquartile range]; 2.41% [1.06–4.11] vs 0% [0–0], P < 0.001) and Clarus in F7 (3.29% [0–7.69] vs 0% [0–3.27], P = 0.002). In 4 eyes DR-stage was higher using Optos due to peripheral lesions not seen on the Clarus. Interrater reliability of DR-stage on both devices was almost perfect in the 7SF (κ = 0.975) and the TGA (κ = 0.855). Reliability in detecting signs of early DR is high on both devices. Clarus allowed for better visualization of the inferonasal field, Optos of the temporal field.