bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistor: an algorithm for predicting resistance mutations using Pareto optimization over multistate protein design and mutational signatures
Authors: Guerin Nathan , Feichtner Andreas , Stefan Eduard , Kaserer Teresa , Donald Bruce R. 
Published: January 2022

AbstractResistance to pharmacological treatments is a major public health challenge. Here we report Resistor—a novel structure- and sequence-based algorithm for drug design providing prospective prediction of resistance mutations. Resistor computes the Pareto frontier of four resistance-causing criteria: the change in binding affinity (ΔKa) of the (1) drug and (2) endogenous ligand upon a protein’s mutation; (3) the probability a mutation will occur based on empirically derived mutational signatures; and (4) the cardinality of mutations comprising a hotspot. To validate Resistor, we applied it to kinase inhibitors targeting EGFR and BRAF in lung adenocarcinoma and melanoma. Resistor correctly identified eight clinically significant EGFR resistance mutations, including the “gatekeeper” T790M mutation to erlotinib and gefitinib and five known resistance mutations to osimertinib. Furthermore, Resistor predictions are consistent with sensitivity data on BRAF inhibitors from both retrospective and prospective experiments using the KinCon biosensor technology. Resistor is available in the open-source protein design software OSPREY.
Event-related potential correlates of learning to produce novel foreign phonemes
Authors: Railo Henry , Varjonen Anni , Lehtonen Minna , Sikka Pilleriin 
Published: January 2022

AbstractLearning to pronounce a foreign phoneme requires an individual to acquire a motor program that enables the reproduction of the new acoustic target sound. This process is largely based on the use of auditory feedback to detect pronunciation errors to adjust vocalization. While early auditory evoked neural activity underlies automatic detection and adaptation to vocalization errors, little is known about the neural correlates of acquiring novel speech targets. To investigate the neural processes that mediate the learning of foreign phoneme pronunciation, we recorded event-related potentials (ERP) when participants (N=19) pronounced native or foreign phonemes. Behavioral results indicated that the participants’ pronunciation of the foreign phoneme improved during the experiment. Early auditory responses (N1 and P2 waves, approx. 85–290 ms after the sound onset) revealed no differences between foreign and native phonemes. In contrast, the amplitude of the fronto-centrally distributed late slow wave (LSW, 320–440 ms) was modulated by the pronunciation of the foreign phonemes, and the effect changed during the experiment, paralleling the improvement in pronunciation. These results suggest that the LSW may reflect higher-order monitoring processes that signal successful pronunciation and help learn novel phonemes.
The accuracy of protein structures in solution determined by AlphaFold and NMR
Authors: Fowler Nicholas J. , Williamson Mike P. 
Published: January 2022

AbstractIn the recent CASP (Critical Assessment of Structure Prediction) competition, AlphaFold2 performed outstandingly. Its worst predictions were for NMR structures, which has two alternative explanations: either the NMR structures were poor, implying that AlphaFold may be more accurate than NMR; or there is a genuine difference between crystal and solution structures. Here, we use the program ANSURR, which measures the accuracy of solution structures, and show that one of the NMR structures was indeed poor. We then compare AlphaFold predictions to NMR structures, and show that AlphaFold tends to be more accurate than NMR ensembles, in particular correctly more rigid in loops. There are however some cases where the NMR ensembles are more accurate. These tend to be dynamic structures where AlphaFold had low confidence. We suggest that AlphaFold could be used as the model for NMR structure refinements, and that AlphaFold structures validated by ANSURR require no further refinement.
Proton-pumping rhodopsins in marine diatoms
Authors: Yoshizawa Susumu , Azuma Tomonori , Kojima Keiichi , Inomura Keisuke , Hasegawa Masumi , Nishimura Yosuke , Kikuchi Masuzu , Armin Gabrielle , Miyashita Hideaki , Ifuku Kentaro , Yamano Takashi , Marchetti Adrian , Fukuzawa Hideya , Sudo Yuki , Kamikawa Ryoma 
Published: January 2022

AbstractDiatoms are a major phytoplankton group responsible for about 20% of Earth’s primary production. They carry out photosynthesis inside the plastid, an organelle obtained through eukaryote-eukaryote endosymbiosis. Recently, microbial rhodopsin, a photoreceptor distinct from chlorophyll-based photosystems, has been identified in certain diatoms. However, the physiological function of diatom rhodopsin is not well understood. Here we show that the diatom rhodopsin acts as a light-driven proton pump and localizes to the outermost membrane of the four membrane-bound complex plastids. Heterologous expression techniques were used to investigate the protein function and subcellular localization of diatom rhodopsin. Using model simulations, we further evaluated the physiological role of the acidic pool in the plastid produced by proton-transporting rhodopsin. Our results propose that the rhodopsin-derived acidic pool may be involved in a photosynthetic CO2-concentrating mechanism and assist CO2 fixation in diatom cells.
Massively parallel genomic perturbations with multi-target CRISPR reveal new insights on Cas9 activity and DNA damage responses at endogenous sites
Authors: Zou Roger S. , Marin-Gonzalez Alberto , Liu Yang , Liu Hans B. , Shen Leo , Dveirin Rachel , Luo Jay X. J. , Kalhor Reza , Ha Taekjip 
Published: January 2022

ABSTRACTWe present an approach that combines a Cas9 that simultaneously targets hundreds of epigenetically diverse endogenous genomic sites with high-throughput sequencing technologies to measure Cas9 dynamics and cellular responses at scale. This massive multiplexing of CRISPR is enabled by means of novel multi-target gRNAs (mgRNAs), degenerate gRNAs that direct Cas9 to a pre-determined number of well-mapped sites. mgRNAs uncovered generalizable insights into Cas9 binding and cleavage, discovering rapid post-cleavage Cas9 departure and repair factor loading at PAM-proximal genomic DNA. Moreover, by bypassing confounding effects from gRNA sequence, mgRNAs unveiled that Cas9 binding is enhanced at chromatin-accessible regions, and Cas9 cleavage is more efficient near transcribed regions. Combined with light-mediated activation and deactivation of Cas9 activity, mgRNAs further enabled high-throughput study of the cellular response to double strand breaks with high temporal resolution, discovering the presence, extent (under 2 kb), and kinetics (~ 0.5 hr) of reversible DNA damage-induced chromatin decompaction. Altogether, this work establishes mgRNAs as a generalizable platform for multiplexing CRISPR and advances our understanding of intracellular Cas9 activity and the DNA damage response at endogenous loci.
RNF213 loss of function reshapes vascular transcriptome and spliceosome leading to disrupted angiogenesis and aggravated vascular inflammatory responses
Authors: Zhang Liyin , Rashad Sherif , Zhou Yuan , Niizuma Kuniyasu , Tominaga Teiji 
Published: January 2022

AbstractRationaleMoyamoya disease (MMD) is a rare cerebrovascular occlusive disease that affects Asian population more often. The pathogenesis of MMD is related to mutation in RNF213 gene. However, why, and how RNF213 mutation leads to MMD is still not fully understood.ObjectiveAnalyze the impact of RNF213 loss of function on vascular cells and the observed changes correlate with MMD.Methods and resultsRNF213 KD was conducted in HUVEC and vascular smooth muscle cells (vSMCs). First, HUVEC cells showed alteration of angiogenesis, migration under LPS stimulation, Leukocyte endothelial transmigration, and endothelial-to-vSMCs communication.Transcriptome analysis revealed downregulation of genes regulating cell division and mitosis. Interestingly, Alternative splicing (AS) analysis revealed hundreds of AS events to occur after RNF213 KD in various types of AS. The alternatively spliced genes showed minimal overlap with transcriptome profiling. Pathway analysis revealed many processes and pathways to be regulated by AS events observed. Transcriptome profiling was also performed after LPS treatment and revealed the basis for increased sensitivity to LPS observed in our analysis. AS changes were also observed after LPS treatment in RNF213 KD HUVEC. Different types of AS showed different patterns of convergence or divergence in terms of the regulated pathways after LPS treatment. Finally, transcriptome and AS analysis was performed in vSMCs and showed various processes that impact vSMCs function and phenotype in RNF213 loss of function.ConclusionOur data provide a wealth of information on RNF213 gene function in vascular tissues and shed important light on different processes that contribute to MMD pathogenesis. Our results signify an immune-driven and hemodynamically linked process of MMD initiation and progression.
Environmental and taxonomic drivers of bacterial extracellular vesicle production in marine ecosystems
Authors: Biller Steven J. , Coe Allison , Arellano Aldo A. , Dooley Keven , Gong Jacqueline S. , Yeager Emily A. , Becker Jamie W. , Chisholm Sallie W. 
Published: January 2022

AbstractExtracellular vesicles are small (∼50-250 nm diameter) membrane-bound structures released by cells into their surrounding environment. Vesicles are abundant in the global oceans and likely play a number of ecological roles in these microbially dominated ecosystems, yet we know nothing about what influences their production and distributions. Here we examine how vesicle production varies among different strains of cultivated marine microbes and explore the degree to which this is influenced by some key environmental variables. We show that vesicle production rates – the number of vesicles produced per cell per generation – vary across an order of magnitude in cultures of marine Proteobacteria, Cyanobacteria, and Bacteroidetes. Vesicle production rates further differ among strains of the cyanobacteriumProchlorococcus, and vary across temperature and light gradients. These data suggest that both community composition and local environmental conditions modulate the production and standing stock of vesicles in the oceans. Examining samples from the oligotrophic North Pacific Gyre, we show depth-dependent changes in the abundance of vesicle-like particles in the upper water column in a manner broadly consistent with culture observations: highest vesicle abundances are found near the surface, where light irradiances and temperatures are greatest, and then decrease with depth. This work represents the beginnings of a quantitative framework for describing extracellular vesicle dynamics in the oceans – essential as we begin to incorporate vesicles into our ecological and biogeochemical understanding of marine ecosystems.ImportanceBacteria secrete extracellular vesicles containing a wide variety of cellular compounds, including lipids, proteins, nucleic acids, and small molecules, into their surrounding environment. These structures are found in diverse microbial habitats, including the oceans, where their distributions vary throughout the water column. Differences in vesicle abundances likely affect their functional impacts within microbial ecosystems, but the factors influencing vesicle distributions in the environment remain poorly understood. Using quantitative analysis of marine microbial cultures, we show that bacterial vesicle production in the oceans is shaped by a combination of biotic and abiotic factors. Our data indicate that different marine taxa release vesicles at rates varying across an order of magnitude, and that vesicle production can change dynamically as a function of environmental conditions. Taken together with direct measurements of vesicle concentrations in the oceans, these culture-based measurements further provide a window into estimating vesicle loss rates. These findings represent a step forward in our understanding of marine vesicle distributions and provide a basis for quantitatively exploring vesicle dynamics in natural ecosystems.
Psychological flexibility and the moderating role of the therapeutic working alliance in Acceptance and Commitment Therapy in Daily Life (ACT-DL) in an early psychosis sample
Authors: van Aubel Evelyne , Vaessen Thomas , van Winkel Ruud , Lafit Ginette , Beijer-Klippel Annelie , Viechtbauer Wolfgang , Batink Tim , van der Gaag Mark , van Amelsvoort Therese , Marcelis Machteld , Schirmbeck Frederike , de Haan Lieuwe , Reininghaus Ulrich , Myin-Germeys Inez 
Published: January 2022

AbstractBackgroundWe investigated treatment effects of Acceptance and Commitment Therapy in Daily Life (ACT-DL) on psychological flexibility (PF) and the moderating role of the therapeutic working alliance on these effects in patients with early psychosis.MethodsACT-DL is an ecological momentary intervention (EMI) combining face-to-face ACT with a smartphone app. In the multi-center INTERACT randomized controlled trial, n=148 early psychosis individuals were randomized to either treatment as usual (TAU as the control condition, n=77) or to ACT-DL in addition to TAU (ACT-DL + TAU as the experimental condition, n=71). We assessed global PF and the therapeutic alliance with self-report questionnaires. In addition, we used the experience sampling methodology (ESM) to assess PF with a momentary (in-the-moment and since-the-previous-beep openness) and an evening (daily PF) questionnaire. Assessments took place at baseline, post-intervention (POST), six (FU6), and twelve months (FU12) follow-up.ResultsGlobal (B=19.49 to 33.14; all P-values<.001) and daily PF (B=0.68; P-value<.001) improved equally in both conditions at each time point. Individuals in the ACT-DL condition improved more than those in TAU on momentary openness (in-the-moment openness at POST (B=0.32; P-value=0.007) and since-the-previous-beep openness at POST (B=0.33; P<.001) and FU6 (B=0.23; P-value=0.025). Client-perceived working alliance moderated in-the-moment openness such that larger improvements in openness at POST (B=0.05; P-value<.001) were found in ACT-DL in individuals with higher working alliance scores.ConclusionOur results provide partial support for the capability of ACT-DL to improve daily life measures of openness, and emphasize the importance of the therapeutic relationship in supporting processes of change.
Seeing sounds: Neural mechanisms underlying auditory contributions to visual detection
Authors: Pérez-Bellido Alexis , Spaak Eelke , de Lange Floris P. 
Published: January 2022

AbstractSounds enhance the detection of visual stimuli while concurrently biasing an observer’s decisions. To investigate the neural mechanisms that underlie such multisensory interactions, we decoded time-resolved signal detection theory (SDT) sensitivity and criterion parameters from neural activity using magnetoencalography, while participants performed a visual detection task. Using temporal generalization analysis, we found that sounds improve visual detection by enhancing the maintenance of the most informative perceptual samples over time. In parallel, criterion decoding analyses revealed that sounds evoke patterns of activity that resembled the patterns evoked by an actual visual stimulus. These two complementary mechanisms of audiovisual interaction differed in terms of their automaticity: Whereas the sound-induced enhancement in visual information maintenance depended on participants being actively engaged in a detection task, sounds evoked visual activity patterns in the visual cortex in a bottom-up fashion, challenging the classical assumption that sound- induced reductions in criterion correspond to decision-level biases.
SARS-CoV-2 Omicron efficiently infects human airway, but not alveolar epithelium
Authors: Lamers Mart M. , Mykytyn Anna Z. , Breugem Tim I. , Groen Nathalie , Knoops Kèvin , Schipper Debby , van Acker Romy , van den Doel Petra B. , Bestebroer Theo , Koopman Charlotte D. , Reusken Chantal , Muraro Mauro J. , GeurtsvanKessel Corine H. , van Royen Martin E. , Peters Peter J. , Zhang Jingshu , Haagmans Bart L. 
Published: January 2022

AbstractIn late 2021, the highly mutated SARS-CoV-2 Omicron variant emerged, raising concerns about its potential extensive immune evasion, increased transmissibility and pathogenicity. Here, we used organoids of the human airways and alveoli to investigate Omicron’s fitness and replicative potential in comparison with earlier SARS-CoV-2 variants. We report that Omicron replicates more rapidly in the airways and has an increased fitness compared to the early 614G variant and Delta. In contrast, Omicron did not replicate productively in human alveolar type 2 cells. Mechanistically, we show that Omicron does not efficiently use TMPRSS2 for entry or spread through cell-cell fusion. Altogether, our data show that Omicron has an altered tropism and protease usage, potentially explaining its higher transmissibility and decreased pathogenicity.
Examining the behavioural intention of inpatients in Indian government hospitals
Authors: Singh Deepti , Dixit Kavaldeep 
Published: January 2022

PurposeThe purpose of this research is to examine the impact of perceived service quality (PSQ) on the behavioural intention (BI) of patients in Indian government hospitals. The underlying mechanism of trust and patient satisfaction (SAT) is examined as multiple mediating effect.Design/methodology/approachData from 510 respondents were collected using structured questionnaires. Six government hospitals, namely, S.M.S. Hospital, J.L.N. Hospital, New Medical College Hospital, Maharana Bhupal Medical Hospital, Mathuradas Hospital and P.B.N. Hospital, were selected from the cities of Jaipur, Ajmer, Kota, Udaipur, Jodhpur and Bikaner, respectively. The data were collected from adult patients (>18 years old) who spent at least two nights in a government hospital between 1 October, 2020 and 30 December, 2020. PSQ formed as a reflective-formative model was analysed using the repeated indicator approach. Structural equation modelling (SEM) using SMART-PLS software was used to test the hypothesised model(s) derived deductively from literature.FindingsThe findings support the following conclusions: (1) the positive relationship between PSQ and BI is significant; (2) SAT mediates the PSQ and BI relationship; (3) trust mediates the PSQ and BI relationship; (4) the mediation effect of SAT is stronger than that of trust.Practical implicationsThe results indicate that, in order to enhance the positive BI of patients towards government hospitals, it is necessary for the hospitals to work on strategies to enhance the service quality provided to patients. The outcome of this study will enable state government hospitals to get a better understanding of the different dimensions of service quality and will help in observing the factors that contribute to patients' satisfaction and trust in building long-term relationships by encouraging a positive BI.Originality/valueThere is a dearth of research in India that evaluates the relationships between the constructs PSQ, trust, BI and SAT in the context of healthcare service. This empirical study is an attempt to fill this gap by focussing on the government hospitals in India.
A CPG-based gait planning and motion performance analysis for quadruped robot
Authors: Wei ShunXiang , Wu Haibo , Liu Liang , Zhang YiXiao , Chen Jiang , Li Quanfeng 
Published: January 2022

Purpose
To achieve stable gait planning and enhance the motion performance of quadruped robot, this paper aims to propose a motion control strategy based on central pattern generator (CPG) and back-propagation neural network (BPNN).

Design/methodology/approach
First, the Kuramoto phase oscillator is used to construct the CPG network model, and a piecewise continuous phase difference matrix is designed to optimize the duty cycle of walk gait, so as to realize the gait planning and smooth switching. Second, the mapper between CPG output and joint drive is established based on BP neural network, so that the quadruped robot based on CPG control has better foot trajectory to enhance the motion performance. Finally, to obtain better mapping effect, an evaluation function is resigned to evaluate the proximity between the actual foot trajectory and the ideal foot trajectory. Genetic algorithm and particle swarm optimization are used to optimize the initial weights and thresholds of BPNN to obtain more accurate foot trajectory.

Findings
The method provides a solution for the smooth gait switching and foot trajectory of the robot. The quintic polynomial trajectory is selected to testify the validity and practicability of the method through simulation and prototype experiment.

Originality/value
The paper solved the incorrect duty cycle under the walk gait of CPG network constructed by Kuramoto phase oscillator, and made the robot have a better foot trajectory by mapper to enhance its motion performance.
From crime prevention to norm compliance: anti-money laundering (AML) policy adoption in Singapore from 1989–2021
Authors: Menon Rishik Elias 
Published: January 2022

Purpose
Policy mobility scholarship concerning anti-money laundering (AML) has typically favoured the study of power structures and interests to the neglect of the constructivist perspective and the local cultural–symbolic driving forces of policy adoption. This study aims to redress this, by analysing the shifting ideational drivers of AML policy in Singapore over the past 31 years through a thematic analysis of Singapore’s parliamentary debates (Hansard).

Design/methodology/approach
Through a thematic analysis of Singapore's Hansard over the past 31 years, this study seeks to present a social constructivist perspective of AML policy adoption in Singapore.

Findings
The thematic analysis reveals how the internal driving forces of AML policy in Singapore have shifted, from the idea of “crime prevention” in the early 1990s, to the symbolic value of “international norm compliance” by the 2010s.

Research limitations/implications
This constructivist perspective of AML policy adoption is particularly useful in complementing the existing materialist theories of AML policy diffusion and allows us to better appreciate the historical nuances of AML policy transfer across the globe.

Practical implications
This research will provide a useful comparative case study for other policy mobility scholars interested in presenting a constructivist account of AML policy adoption in different jurisdictions.

Originality/value
There is no literature in the field of policy mobility, explaining the diffusion/transfer of AML policy from a social constructivist perspective.