bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial organization of pathway enzymes via self‐assembly to improve 2′‐fucosyllactose biosynthesis in engineered Escherichia coli
Authors: Chen Roulin , Wan Li , Zhu Yingying , Liu Yuanlin , Zhang Wenli , Mu Wanmeng 
Published: November 2022

AbstractAs one of the most abundant components in human milk oligosaccharides, 2′‐fucosyllactose (2′‐FL) possesses versatile beneficial health effects. Although most studies focused on overexpressing or fine‐tuning the expression of pathway enzymes and achieved a striking increase of 2′‐FL production, directly facilitating the metabolic flux toward the key intermediate GDP‐l‐fucose seems to be ignored. Here, multienzyme complexes consisting of sequential pathway enzymes were constructed by using specific peptide interaction motifs in recombinant Escherichia coli to achieve a higher titer of 2′‐FL. Specifically, we first fine‐tuned the expression level of pathway enzymes and balanced the metabolic flux toward 2′‐FL synthesis. Then, two key enzymes (GDP‐mannose 4,6‐dehydratase and GDP‐
l‐fucose synthase) were self‐assembled into enzyme complexes in vivo via a short peptide interaction pair RIAD–RIDD (RI anchoring disruptor–RI dimer D/D domains), resulting in noticeable improvement of 2′‐FL production. Next, to further strengthen the metabolic flux toward 2′‐FL, three pathway enzymes were further aggregated into multienzyme assemblies by using another orthogonal protein interaction motif (Spycatcher–SpyTag or PDZ–PDZlig). Intracellular multienzyme assemblies remarkably enlarged the flux toward 2′‐FL biosynthesis and showed a 2.1‐fold increase of 2′‐FL production compared with a strain expressing free‐floating and unassembled enzymes. The optimally engineered strain EZJ23 accumulated 4.8 g/L 2′‐FL in shake flask fermentation and was capable of producing 25.1 g/L 2′‐FL by fed‐batch cultivation. This work provides novel approaches for further improvement and large‐scale production of 2′‐FL and demonstrates the effectiveness of spatial assembly of pathway enzymes to improve the production of valuable products in the engineered host strain.
Clinical and molecular characteristics of kinase domain duplications across diverse cancer types in the Chinese population
Authors: Lai Xiaojing , Yu Ruoying , Ou Qiuxiang , Bao Hua , Wu Xue , Shao Yang , Li Yang , Zhang Ying , Ding Qingqing 
Published: November 2022

AbstractBackgroundKinase domain duplications (KDDs) have recently been recognized as oncogenic mutations and possible association with drug resistance in cancers.MethodHere, targeted sequencing was performed with the tumor tissue and/or plasma from 65 cancer patients with KDDs.ResultIntact KDDs were identified in approximately 0.1% of the total population across multiple cancer types. EGFR KDD was first identified in colorectal cancer and breast cancer, whereas FGFR2 KDD was first identified in gastric cancer. Tumors with EGFR KDD displayed lower concurrent TP53 gene alterations (p = 0.03) and slightly higher chromosome instability (p = 0.27) compared to tumors with non‐EGFR‐KDDs. Immune pathway analysis further revealed the enrichment of the cytokine receptors pathway (93%) in the KDD carriers. Hyperprogression‐related gene mutations were identified in four cases.ConclusionCollectively, our data revealed the genomic features of KDD alterations in a multi‐cancer cohort, providing more information for the potential treatment application in the KDD carriers.
Evolution of lung adenocarcinoma from preneoplasia to invasive adenocarcinoma
Authors: Zhu Jianfei , Wang Wenchen , Xiong Yanlu , Xu Shuonan , Chen Jiankuan , Wen Miaomiao , Zhao Yabo , Lei Jie , Jiang Tao 
Published: November 2022

AbstractObjectiveMutations in driver genes contribute to the development and progression of lung adenocarcinoma (LUAD). However, in the dynamic evolutionary process from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and eventually to invasive adenocarcinoma (IAC), the role of driver genes is currently unclear. This study aimed to analyse the role of driver gene status in the progression of LUAD from preneoplasia to IAC.MethodsPatients with LUAD who underwent surgery in our centre from March 2015 to December 2019 were retrospectively analysed, and LUAD patients with tumour sizes ≤3.0 cm and pN0 were included in the final analysis. The mutation status of common driver genes, including EGFR, ALK and ROS1, was detected. According to the pathological characteristics, the patients were divided into three stages: AIS, MIA and IAC. We analysed the distribution of driver gene mutation frequencies across three stages of LUAD. In addition, we performed univariate and multivariate analyses of IAC patients to screen for relevant variables (driver genes and clinicopathological features) affecting their prognosis.ResultsUltimately, 759 patients with LUAD were enrolled, including 135, 130, and 494 cases of AIS, MIA, and IAC, respectively. EGFR mutations were identified in 359 (61.8%) patients, and with the transition from AIS to MIA, the frequency of EGFR mutations increased from 33.3% to 50.8%, p = 0.004, whereas the frequency of EGFR mutations was comparable for MIA and IAC (50.8% vs. 50.2%, p = 0.922). Moreover, ALK and ROS1 gene fusions were identified in 17 cases (2.2%) and 2 cases (3.0‰) respectively. For AIS, neither ALK gene nor ROS1 gene fusions were observed. When the tumour progressed to MIA, the ALK fusion frequency was 2.3% (3/130), which was basically consistent with the ALK fusion frequency of 2.8% in IAC, p = 0.143. For IAC, fusions of ROS1 fell into this category. In addition, we found that 40 patients (5.3%) developed metastasis/recurrence, and 14 patients (1.8%) died of cancer‐specific related diseases. Notably, for AIS, there were no recurrences and no deaths, and for MIA, only 1 patient died with LUAD. Finally, survival analysis was performed in patients with stage IA invasive adenocarcinoma, and EGFR‐mutant patients showed better DFS than EGFR‐wild‐type patients (p = 0.036). Conversely, patients with ALK fusions showed worse DFS than those with ALK wild‐type (p = 0.004), and the same results were found in OS analysis.ConclusionsThe accumulation of EGFR driver gene mutation frequencies mediates the progression of LUAD from AIS to MIA. When the tumour progresses to stage IA invasive adenocarcinoma, multivariate analysis based on driver gene status can be used as a pivotal prognostic factor.
Automatic hierarchical model builder
Authors: Marchi Lorenzo , Krylov Ivan , Roginski Robert T. , Wise Barry , Di Donato Francesca , Nieto‐Ortega Sonia , Pereira José Francielson Q. , Bro Rasmus 
Published: November 2022

AbstractWhen building classification models of complex systems with many classes, the traditional chemometric approaches such as discriminant analysis or soft independent modeling of class analogy often fail. Some people resort to advanced deep neural network, but this is only an option if there is access to very many samples. Another alternative often used is to build hierarchical models where subclasses are sort of peeled off one or a few at a time. Such approaches often outperform classical classification as well as deep neural network on small multi‐class problems. The downside though is that it is very cumbersome to build such hierarchies of models. It requires substantial work of a skilled person. In this paper, we develop a fully automated approach for building hierarchical models and test the performance on a number of classification problems.
Hydrogen Bonding in Platinum Indolylphosphine Polyfluorido and Fluorido Complexes
Authors: Sander Stefan , Cosgrove Elizabeth J. , Müller Robert , Kaupp Martin , Braun Thomas 
Published: November 2022

AbstractThe reaction of the Pt complexescis‐[Pt(CH3)(Ar){Ph2P(Ind)}2] (Ind=2‐(3‐methyl)indolyl, Ar=4‐tBuC6H4(1 a),4‐CH3C6H4(1 b), Ph (1 c), 4‐FC6H4(1 d), 4‐ClC6H4(1 e), 4‐CF3C6H4(1 f)) with HF afforded the polyfluorido complexestrans‐[Pt(F(HF)2)(Ar){Ph2P(Ind)}2]2 a–f, which can be converted into the fluoride derivativestrans‐[Pt(F)(Ar){Ph2P(Ind)}2] (3 a–f) by treatment with CsF. The compounds2 a–fand3 a–fwere characterised thoroughly by multinuclear NMR spectroscopy. The data reveal hydrogen bonding of the fluorido ligand with HF molecules and the indolylphosphine ligand. Polyfluorido complexes2 a–fshow larger |1J(F,Pt)|, but lower1J(H,F) coupling constants when compared to the fluorido complexes3 a–f. Decreasing1J(P,Pt) coupling constants in2 a–fand3 a–fsuggest acisinfluence of the aryl ligands in the following order: 4‐tBuC6H4(a) ≈4‐CH3C6H4(b)<Ph (c)≪4‐FC6H4(d)<4‐ClC6H4(e)<4‐CF3C6H4(f). In addition, the largercisinfluence of aryl ligands bearing electron‐withdrawing groups in theparaposition correlates with decreasing magnitudes of |1J(F,Pt)| coupling constants. The interpretation of the experimental data was supported by quantum‐chemical DFT calculations.
Revealing Phosphorus Nitrides up to the Megabar Regime: Synthesis of α′‐P3N5, δ‐P3N5 and PN2
Authors: Laniel Dominique , Trybel Florian , Néri Adrien , Yin Yuqing , Aslandukov Andrey , Fedotenko Timofey , Khandarkhaeva Saiana , Tasnádi Ferenc , Chariton Stella , Giacobbe Carlotta , Lawrence‐Bright Eleanor , Hanfland Michael , Prakapenka Vitali , Schnick Wolfgang , Abrikosov Igor A. , Dubrovinsky Leonid , Dubrovinskaia Natalia 
Published: November 2022

AbstractInvited for the cover of this issue are Dominique Laniel (University of Edinburgh), Florian Trybel (University of Linköping), and their colleagues. The image depicts a bridge built of the newly discovered δ‐P3N5 solid with the structure featuring PN6 units, a previously missing connection between the carbon group elements nitrides and chalcogens nitrides. Read the full text of the article at 10.1002/chem.202201998.
Process‐aware data‐driven modelling and model predictive control of bioreactor for the production of monoclonal antibodies
Authors: Sarna Samardeep , Patel Nikesh , Corbett Brandon , McCready Chris , Mhaskar Prashant 
Published: November 2022

AbstractThis manuscript addresses the problem of controlling a bioreactor to maximize the production of a desired product while respecting the constraints imposed by the nature of the bio‐process. The approach is demonstrated by first building a data‐driven model and then formulating a model predictive controller (MPC) with the results illustrated by implementing a detailed monoclonal antibody production model (the test bed) created by Sartorius Inc. In particular, a recently developed data‐driven modelling approach using an adaptation of subspace identification techniques is utilized that enables the incorporation of known physical relationships in the data‐driven model development (constrained subspace model identification), making the data‐driven model process aware. The resultant controller implementation demonstrates a significant improvement in production compared to the existing proportional integral (PI) controller strategy used in the monoclonal antibody production. Simulation results also demonstrate the superiority of the process‐aware or constrained subspace MPC compared to traditional subspace MPC. Finally, the robustness of the controller design is illustrated via the implementation of a model developed using data from a test bed with a different set of parameters, thus showing the ability of the controller design to maintain good performance in the event of changes such as a different cell line or feed characteristics.
Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development – (III) A Randomized Trial with Interferon Beta‐1a Products
Authors: Florian Jeffry , Gershuny Victoria , Sun Qin , Schrieber Sarah J. , Matta Murali K. , Hazel Anthony , Sheikhy Morasa , Weaver James L. , Hyland Paula L. , Hsiao Cheng‐Hui , Vegesna Giri , DePalma Ryan , Shah Aanchal , Prentice Kristin , Sanabria Carlos , Wang Yow‐Ming , Strauss David G. 
Published: November 2022

The US Food and Drug Administration (FDA) has taken steps to bring efficiency to the development of biosimilars, including establishing guidance for the use of pharmacokinetic and pharmacodynamic (PD) similarity study data without a comparative clinical study with efficacy end point(s). To better understand the potential role for PD biomarkers in biosimilar development and inform best practices for biomarker selection and analysis, we conducted a randomized, double‐blinded, placebo‐controlled, single‐dose, parallel‐arm clinical study in healthy participants. Eighty‐four healthy participants (n = 12 per dose arm) received either placebo or one of three doses of either interferon β‐1a (7.5–30 μg) or pegylated interferon β‐1a (31.25–125 μg) to evaluate the maximum change from baseline and the baseline‐adjusted area under the effect curve for the biomarkers neopterin in serum and myxovirus resistance protein 1 in blood. Both PD biomarkers increased following product administration with clear separation from baseline (neopterin: 3.4‐fold and 3.9‐fold increase for interferon β‐1a and pegylated interferon β‐1a, respectively; myxovirus resistance protein 1: 19.0‐fold and 47.2‐fold increase for interferon β‐1a and pegylated interferon β‐1a, respectively). The dose–response curves support that therapeutic doses were adequately sensitive to detect differences in both PD biomarkers for consideration in a PD similarity study design. Because baseline levels of both biomarkers are low compared with on‐treatment values, there was little difference in using PD measures adjusted to baseline compared with the results without baseline adjustment. This study illustrates potential methodologies for evaluating PD biomarkers and an approach to address information gaps when limited information is publicly available for one or more PD biomarkers.
Behaviour‐based pain scales: Validity and interrater reliability of BPS‐NI and PAINAD‐G on general wards
Authors: Wandrey Jan D. , Behnel Niklas , Weidner Elisa , Dummin Ulrike , von Dincklage Falk , Tafelski Sascha 
Published: November 2022

AbstractBackgroundMeasuring pain intensity in patients unable to communicate is a challenge on general wards. Observation‐based pain scoring tools have been used for patients with dementia or in critically ill intensive care unit (ICU) patients. However, there is no established or validated assessment tool for non‐ICU patients without dementia related cognitive deficiencies who cannot communicate. The “Behavioural Pain Scale Non‐Intubated” (BPS‐NI) and the “Pain Assessment In Advanced Dementia‐German” (PAINAD‐G) are potential tools to fill this gap.MethodsThis study was performed with verbal non‐ICU patients on general wards at Charité Berlin. Two assessors independently rated pain intensity using the BPS‐NI and the PAINAD‐G along with patients' self‐ratings on the Numeric Rating Scale (NRS). The interrater‐reliability of BPS‐NI and PAINAD‐G was calculated and ROC‐analyses were performed to identify cut‐off values for medium and intense pain for each score. Effectiveness was calculated using percentage agreement. In total, 126 patients were included into analysis.ResultsThe BPS‐NI showed substantial congruence in interrater‐reliability (Cohens‐Kappa 0.71), whereas the PAINAD‐G showed moderate congruence (Kappa 0.48). Based on ROC‐analyses, for medium pain levels a cut‐off 4 (BPS‐NI) or 2 (PAINAD‐G) and for severe pain levels cut‐off 5 (BPS‐NI) and 3 (PAINAD‐G) would result in good accordance with self‐reported NRS for pain.ConclusionThe BPS‐NI shows a good validity in measuring pain intensity in patients on general wards and may possibly be used for patients unable to communicate. Using defined cut‐off values for BPS‐NI and PAINAD‐G, clinically relevant pain intensities in patients can reliably be detected.SignificanceMeasuring the pain intensity in patients unable to communicate is a common challenge on general wards. This study assessed reliability and applicability BPS‐NI and the PAINAD‐G in a general ward setting. Furthermore, it provides cut‐off values in order to estimate pain intensity and support analgesic response.
Experimental study on combustion characteristics of a fischer‐tropsch diesel/methanol reactivity controlled compression ignition mode engine
Authors: Bai Zechuan , Wang Zhong , Li Ruina , Liu Shuai 
Published: November 2022

AbstractF‐T diesel is an alternative fuel with a high cetane number (CN) for internal combustion engines. Methanol has a low CN and contains oxygen. F‐T diesel and methanol are potential fuels for the reactivity controlled compression ignition (RCCI) engines. In a single‐cylinder 186FA compression‐ignition engine with a combination of methanol inlet pipe injection and F‐T diesel in‐cylinder injection, the combustion characteristics of the F‐T diesel/methanol RCCI mode engine are investigated. The results show that as methanol premixed ratio (MPR) increases, the ignition delay (ID) is prolonged at low load conditions, the maximum in‐cylinder pressure (Pmax) and indicated thermal efficiency (ITE) a decreased. When the MPR increases from 0% to 60%, the ID is extended by 1.7°CA, the Pmax decreases by 8.1%, and the ITE decreases by 1.1%. At high load conditions, MPR rises from 0% to 60%, combustion duration (CD) is shortened by 2.4°CA, Pmax is increased by 8.3%, and the ITE is increased by 1.7%. The fuel injection advance angle (IAA) of F‐T diesel significantly influences the combustion process of the RCCI engine. As the IAA increases, the ID is shortened at high loads, and the Pmax and the ITE are increased. When the MPR is 60% and the IAA is 14°CA, the ITE of the engine is increased by 2.04%, and the equivalent indicated fuel consumption rate(be) is reduced by 5.68% compared with the engine fueled with F‐T diesel under high loads.
Hybrid simulation of a partial‐strength steel–concrete composite moment‐resisting frame endowed with hysteretic replaceable beam splices
Authors: Andreotti Roberto , Giuliani Giulia , Tondini Nicola , Bursi Oreste S. 
Published: November 2022

AbstractThis paper deals with the seismic response assessment of a steel–concrete moment‐resisting frame (MRF) equipped with special dissipative replaceable components (DRCs): the dissipative replaceable beam splices (DRBeS), which combine large energy dissipation with ease of replacement. The evaluation of the full potential of DRBeS requires a system‐level investigation, that is, a six‐story MRF, whereby the hysteretic effects of beam splices partial‐strength joints are considered on the global response of the structural system. Therefore, an OpenSees finite element (FE) frame model, based on previous experimental campaigns with cyclic displacements on partial‐strength joints, and a Matlab model validated on OpenSees, were used for a more complex experimental activity via hybrid simulation (HS). The aim of the simulations was twofold: (i) to increase knowledge of the non‐linear behaviour of steel‐concrete composite partial‐strength MRFs; and (ii) to study the effectiveness of the DRBeS components for increasing the recovery of functionality after a major seismic event. Therefore, to appreciate the performance of the partial‐strength MRF at damage limitation (DL), significant damage (SD) and near collapse (NC) within the performance‐based earthquake engineering (PBEE) approach, HSs were carried out. In such instances, the ground floor was physically tested at full scale in the laboratory and the remainder of the structure was numerically simulated. Relevant results showed that the DRBeS were capable of dissipating a significant amount of hysteretic energy and of protecting the non‐dissipative parts of partial‐strength joints and the overall structure with an ease of replacement.
Arroyo formation impacts on an early dryland agricultural community in Northeastern Utah, USA
Authors: Finley Judson Byrd , Robinson Erick , Justin DeRose R. 
Published: November 2022

AbstractIndigenous Fremont farmers in Cub Creek, a part of northeastern Utah's Dinosaur National Monument, occupied the northern ecological margin of maize cultivation in western North America from A.D. 300 to 1300. Agriculture in Cub Creek was a response to multidecadal precipitation variability, but when precipitation stabilized between A.D. 750 and 1050, agricultural conditions improved and populations expanded to form villages along the floodplains of local dryland streams. Did the very same conditions (i.e., decreased precipitation variability) that allowed the growth of agricultural societies make them simultaneously vulnerable to arroyo formation, a key geomorphic risk to floodplain agriculturalists? Preliminary results from Cub Creek show that rapid sedimentation punctuated by episodic arroyo formation characterized the last 2000 years. We use stratigraphic and chronological evidence formalized in a Bayesian age model to develop a set of working hypotheses that a 2.5 m‐deep discontinuous arroyo formed before either A.D. 1020 or A.D. 1275. The earlier age corresponds with occupation of the Cub Creek village, while the later age corresponds with the end of Fremont agriculture in Cub Creek, and demonstrates regional synchronicity with arroyo formation across the Colorado Plateau. A second arroyo formed before A.D. 1490, indicating rapid alluvial cycling in Cub Creek. We conclude that floodplain instability and arroyo formation combined with the return of the dominant multidecadal precipitation variability regime beginning at A.D. 1050 was a key constraint on the growth potential of local populations. These findings have potential implications for the development of early Indigenous dryland agricultural systems throughout the interior of western North America.
Quorum Sensing Facilitates Interpopulation Signaling by Vibrio fischeri within the Light Organ of Euprymna scolopes
Authors: Yount Taylor A. , Murtha Andrew N. , Cecere Andrew G. , Miyashiro Tim I. 
Published: November 2022

AbstractQuorum sensing is an intercellular signaling mechanism that enables bacterial cells to coordinate population‐level behaviors. How quorum sensing functions in natural habitats remains poorly understood. Vibrio fischeri is a bacterial symbiont of the Hawaiian bobtail squid Euprymna scolopes and depends on LuxI/LuxR quorum sensing to produce the symbiotic trait of bioluminescence. A previous study demonstrated that animals emit light when co‐colonized by a Δlux mutant, which lacks several genes within the lux operon that are necessary for bioluminescence production, and a LuxI− mutant, which cannot synthesize the quorum signaling molecule N‐3‐oxohexanoyl‐homoserine lactone. Here, we build upon that observation and show that populations of LuxI− feature elevated promoter activity for the lux operon. We find that population structures comprising of Δlux and LuxI− are attenuated within the squid, but a wild‐type strain enables the LuxI− strain type to be maintained in vivo. These experimental results support a model of interpopulation signaling, which provides basic insight into how quorum sensing functions within the natural habitats found within a host.
Income inequality and monetary policy in the euro area
Authors: Creel Jérôme , El Herradi Mehdi 
Published: November 2022

AbstractThis paper examines the distributional implications of ECB monetary policy on income inequality on a panel of 10 Euro area countries between 2000 and 2015. In contrast with the literature, we investigate different transmission channels and introduce several specifications (different monetary policy instruments, different indicators of income inequality, different data sources, parsimonious and larger models, shocks on monetary policy per se, on long‐term rates and on inflation rates) in a panel VAR setting to highlight the robustness of results. Results suggest that: (i) the distributional effects of ECB's monetary policy have been modest and (ii) mainly driven in times of conventional monetary policy measures, especially in countries with a high level of income inequality, while, overall, (iii) standard and non‐standard monetary policies do not significantly differ in terms of impact and (iv) baseline results persist when redistributive public policies are introduced. We further document that our results are more likely to be channelled via income composition effects.