bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical utility of PDX cohorts to reveal biomarkers of intrinsic resistance and clonal architecture changes underlying acquired resistance to cetuximab in HNSCC
Authors: Yao Yanli , Wang Yujue , Chen Lan , Tian Zhen , Yang Guizhu , Wang Rui , Wang Chong , Wu Qi , Wu Yaping , Gao Jiamin , Kang Xindan , Duan Shengzhong , Zhang Zhiyuan , Sun Shuyang 
Published: March 2022

AbstractCetuximab is a widely used drug for treating head and neck squamous cell carcinomas (HNSCCs); however, it provides restricted clinical benefits, and its response duration is limited by drug resistance. Here, we conducted randomized “Phase II-like clinical trials” of 49 HNSCC PDX models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab (e.g., amplification of ANKH, up-regulation of PARP3). After validating these intrinsic resistance biomarkers in another HNSCC PDX cohort (61 PDX models), we generated acquired cetuximab resistance PDX models and analyzed them to uncover resistance mechanisms. Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant PDXs, including the emergence of subclones with strongly activated RAS/MAPK. Extending these insights, we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo. Beyond revealing intrinsic resistance biomarkers, our PDX-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.
Inhibition of the ISR abrogates mGluR5-dependent long-term depression and spatial memory deficits in a rat model of Alzheimer’s disease
Authors: Hu Zhengtao , Yu Pengpeng , Zhang Yangyang , Yang Yin , Zhu Manyi , Qin Shuangying , Xu Ji-Tian , Duan Dongxiao , Wu Yong , Wang Deguo , Rowan Michael J. , Hu Neng-Wei 
Published: March 2022

AbstractSoluble amyloid-β-protein (Aβ) oligomers, a major hallmark of AD, trigger the integrated stress response (ISR) via multiple pathologies including neuronal hyperactivation, microvascular hypoxia, and neuroinflammation. Increasing eIF2α phosphorylation, the core event of ISR, facilitates metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), and suppressing its phosphorylation has the opposite effect. Having found the facilitation of mGluR5-LTD by Aβ in live rats, we wondered if suppressing eIF2α phosphorylation cascade would protect against the synaptic plasticity and cognitive disrupting effects of Aβ. We demonstrate here that the facilitation of mGluR5-LTD in a delayed rat model by single i.c.v. injection of synthetic Aβ1–42. Systemic administration of the small-molecule inhibitor of the ISR called ISRIB (trans-isomer) prevents Aβ-facilitated LTD and abrogates spatial learning and memory deficits in the hippocampus in exogenous synthetic Aβ-injected rats. Moreover, ex vivo evidence indicates that ISRIB normalizes protein synthesis in the hippocampus. Targeting the ISR by suppressing the eIF2α phosphorylation cascade with the eIF2B activator ISRIB may provide protective effects against the synaptic and cognitive disruptive effects of Aβ which likely mediate the early stage of sporadic AD.
Receiving results of uncertain clinical relevance from population genetic screening: systematic review & meta-synthesis of qualitative research
Authors: Johnson Faye , Ulph Fiona , MacLeod Rhona , Southern Kevin W. 
Published: March 2022

AbstractGenetic screening can be hugely beneficial, yet its expansion poses clinical and ethical challenges due to results of uncertain clinical relevance (such as ‘cystic fibrosis screen positive, inconclusive diagnosis’/CFSPID). This review systematically identifies, appraises, and synthesises the qualitative research on experiences of receiving results of uncertain clinical relevance from population genetic screening. Eight databases were systematically searched for original qualitative research using the SPIDER framework, and checked against inclusion criteria by the research team and an independent researcher. Nine papers were included (from USA, Canada, UK, New Zealand). PRISMA, ENTREQ, and EMERGE guidance were used to report. Quality was appraised using criteria for qualitative research. All papers focused on parental responses to uncertain results from newborn screening. Data were synthesised using meta-ethnography and first- and second-order constructs. Findings suggest that results of uncertain clinical relevance are often experienced in the same way as a ‘full-blown’ diagnosis. This has significant emotional and behavioural impact, for example adoption of lifestyle-altering disease-focused behaviours. Analysis suggests this may be due to the results not fitting a common medical model, leading recipients to interpret the significance of the result maladaptively. Findings suggest scope for professionals to negotiate and reframe uncertain screening results. Clearer initial communication is needed to reassure recipients there is no immediate severe health risk from these types of results. Public understanding of an appropriate medical model, that accounts for uncertain genetic screening results in a non-threatening way, may be key to maximising the benefits of genomic medicine and minimising potential psychological harm.
On the genetic architecture of rapidly adapting and convergent life history traits in guppies
Authors: Whiting James R. , Paris Josephine R. , Parsons Paul J. , Matthews Sophie , Reynoso Yuridia , Hughes Kimberly A. , Reznick David , Fraser Bonnie A. 
Published: March 2022

AbstractThe genetic basis of traits shapes and constrains how adaptation proceeds in nature; rapid adaptation can proceed using stores of polygenic standing genetic variation or hard selective sweeps, and increasing polygenicity fuels genetic redundancy, reducing gene re-use (genetic convergence). Guppy life history traits evolve rapidly and convergently among natural high- and low-predation environments in northern Trinidad. This system has been studied extensively at the phenotypic level, but little is known about the underlying genetic architecture. Here, we use four independent F2 QTL crosses to examine the genetic basis of seven (five female, two male) guppy life history phenotypes and discuss how these genetic architectures may facilitate or constrain rapid adaptation and convergence. We use RAD-sequencing data (16,539 SNPs) from 370 male and 267 female F2 individuals. We perform linkage mapping, estimates of genome-wide and per-chromosome heritability (multi-locus associations), and QTL mapping (single-locus associations). Our results are consistent with architectures of many loci of small-effect for male age and size at maturity and female interbrood period. Male trait associations are clustered on specific chromosomes, but female interbrood period exhibits a weak genome-wide signal suggesting a potentially highly polygenic component. Offspring weight and female size at maturity are also associated with a single significant QTL each. These results suggest rapid, repeatable phenotypic evolution of guppies may be facilitated by polygenic trait architectures, but subsequent genetic redundancy may limit gene re-use across populations, in agreement with an absence of strong signatures of genetic convergence from recent analyses of wild guppies.
Controlling blood pressure soon after intracerebral hemorrhage: The SAMURAI-ICH Study and its successors
Authors: Toyoda Kazunori , Koga Masatoshi ,   as the SAMURAI Investigators
Published: March 2022

AbstractThe impact of acute therapy for intracerebral hemorrhage (ICH) lags far behind that for acute ischemic stroke. Intensive blood pressure lowering is a promising therapeutic strategy for acute ICH, especially for East Asian patients whose etiological mechanism is more commonly hypertension than that of patients in the Western population. A multicenter, prospective, observational study named the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-IntraCerebral Hemorrhage (SAMURAI-ICH) study, involving 211 patients from ten Japanese stroke centers, was performed to elucidate the safety and feasibility of blood pressure lowering to 160 mmHg or less in acute ICH patients using intravenous nicardipine. When we started the study, intravenous nicardipine was not officially approved for hyperacute ICH patients in Japan. The SAMURAI-ICH study was also a pilot study to judge the feasibility of participation by many Japanese investigators in an international, randomized, controlled trial named the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)−2 trial. The SAMURAI-ICH study, ATACH-2 trial, and their combined individual participant data meta-analysis produced several new interesting findings on how to control blood pressure levels in acute ICH patients. Some of the findings are introduced in the present review article.
Ancient genomes from the Himalayas illuminate the genetic history of Tibetans and their Tibeto-Burman speaking neighbors
Authors: Liu Chi-Chun , Witonsky David , Gosling Anna , Lee Ju Hyeon , Ringbauer Harald , Hagan Richard , Patel Nisha , Stahl Raphaela , Novembre John , Aldenderfer Mark , Warinner Christina , Di Rienzo Anna , Jeong Choongwon 
Published: March 2022

AbstractPresent-day Tibetans have adapted both genetically and culturally to the high altitude environment of the Tibetan Plateau, but fundamental questions about their origins remain unanswered. Recent archaeological and genetic research suggests the presence of an early population on the Plateau within the past 40 thousand years, followed by the arrival of subsequent groups within the past 10 thousand years. Here, we obtain new genome-wide data for 33 ancient individuals from high elevation sites on the southern fringe of the Tibetan Plateau in Nepal, who we show are most closely related to present-day Tibetans. They derive most of their ancestry from groups related to Late Neolithic populations at the northeastern edge of the Tibetan Plateau but also harbor a minor genetic component from a distinct and deep Paleolithic Eurasian ancestry. In contrast to their Tibetan neighbors, present-day non-Tibetan Tibeto-Burman speakers living at mid-elevations along the southern and eastern margins of the Plateau form a genetic cline that reflects a distinct genetic history. Finally, a comparison between ancient and present-day highlanders confirms ongoing positive selection of high altitude adaptive alleles.
A SNP of betaine aldehyde dehydrogenase (BADH) enhances an aroma (2-acetyl-1-pyrroline) in sponge gourd (Luffa cylindrica) and ridge gourd (Luffa acutangula)
Authors: Saensuk Chatree , Ruangnam Saowalak , Pitaloka Mutiara K. , Dumhai Reajina , Mahatheeranont Sugunya , de Hoop Simon Jan , Balatero Conrado , Riangwong Kanamon , Ruanjaichon Vinitchan , Toojinda Theerayut , Vanavichit Apichart , Wanchana Samart , Arikit Siwaret 
Published: March 2022

AbstractLuffa is a genus of tropical and subtropical vines belonging to the Cucurbitaceae family. Sponge gourd (Luffa cylindrica) and ridge gourd (Luffa acutangula) are two important species of the genus Luffa and are good sources of human nutrition and herbal medicines. As a vegetable, aromatic luffa is more preferred by consumers than nonaromatic luffa. While the aroma trait is present in the sponge gourd, the trait is not present in the ridge gourd. In this study, we identified Luffa cylindrica’s betaine aldehyde dehydrogenase (LcBADH) as a gene associated with aroma in the sponge gourd based on a de novo assembly of public transcriptome data. A single nucleotide polymorphism (SNP: A > G) was identified in exon 5 of LcBADH, causing an amino acid change from tyrosine to cysteine at position 163, which is important for the formation of the substrate binding pocket of the BADH enzyme. Based on the identified SNP, a TaqMan marker, named AroLuff, was developed and validated in 370 F2 progenies of the sponge gourd. The marker genotypes were perfectly associated with the aroma phenotypes, and the segregation ratios supported Mendelian’s simple recessive inheritance. In addition, we demonstrated the use of the AroLuff marker in the introgression of LcBADH from the aromatic sponge gourd to the ridge gourd to improve aroma through interspecific hybridization. The marker proved to be useful in improving the aroma characteristics of both Luffa species.
Potential seismic precursors and surficial dynamics of a deadly Himalayan disaster: an early warning approach
Authors: Tiwari Anil , Sain Kalachand , Kumar Amit , Tiwari Jyoti , Paul Ajay , Kumar Naresh , Haldar Chinmay , Kumar Sushil , Pandey Chhavi P 
Published: March 2022

AbstractOn 7 February 2021, Chamoli district (Uttarakhand, India) was devastated by a deadly rock-ice avalanche that led to a large causality of more than 200 people and a huge economic loss. We found noteworthy sequence of precursory signals of main failure/detachment preceded by a dynamic nucleation phase. The rock-ice avalanche appears to have been initiated by seismic precursors which were continuously active for 2:30 h prior to main detachment. The seismic amplitude, frequency characteristics and signal-to-noise ratio variation of detected tremors indicate static to dynamic changes in nucleation phase located at the source of detached wedge. The characteristics of seismic data distinguished debris flow and hitting obstacles from other seismic sources and allowed the estimations of debris flow speed. We analyzed and verified the seismic signals with field evidences to estimate the associated impacts and velocity of dynamic flow. The proximal high-quality seismic data allowed us to reconstruct the complete chronological sequence and evaluate impacts since the initiation of nucleation phase to its advancement. Furthermore, we suggest that real-time seismic monitoring with existing network and future deployment of integrated dense network can be used for forecasting of flow events and hazard mitigation in the downstream.
Trust in scientific information mediates associations between conservatism and coronavirus responses in the U.S., but few other nations
Authors: McLamore Quinnehtukqut , Syropoulos Stylianos , Leidner Bernhard , Hirschberger Gilad , Young Kevin , Zein Rizqy Amelia , Baumert Anna , Bilewicz Michal , Bilgen Arda , van Bezouw Maarten J. , Chatard Armand , Chekroun Peggy , Chinchilla Juana , Choi Hoon-Seok , Euh Hyun , Gomez Angel , Kardos Peter , Khoo Ying Hooi , Li Mengyao , Légal Jean-Baptiste , Loughnan Steve , Mari Silvia , Tan-Mansukhani Roseann , Muldoon Orla , Noor Masi , Paladino Maria Paola , Petrović Nebojša , Selvanathan Hema Preya , Uluğ Özden Melis , Wohl Michael J. , Yeung Wai Lan Victoria , Burrows B. 
Published: March 2022

AbstractU.S.-based research suggests conservatism is linked with less concern about contracting coronavirus and less preventative behaviors to avoid infection. Here, we investigate whether these tendencies are partly attributable to distrust in scientific information, and evaluate whether they generalize outside the U.S., using public data and recruited representative samples across three studies (Ntotal = 34,710). In Studies 1 and 2, we examine these relationships in the U.S., yielding converging evidence for a sequential indirect effect of conservatism on compliance through scientific (dis)trust and infection concern. In Study 3, we compare these relationships across 19 distinct countries. Although the relationships between trust in scientific information about the coronavirus, concern about coronavirus infection, and compliance are consistent cross-nationally, the relationships between conservatism and trust in scientific information are not. These relationships are strongest in North America. Consequently, the indirect effects observed in Studies 1–2 only replicate in North America (the U.S. and Canada) and in Indonesia. Study 3 also found parallel direct and indirect effects on support for lockdown restrictions. These associations suggest not only that relationships between conservatism and compliance are not universal, but localized to particular countries where conservatism is more strongly related to trust in scientific information about the coronavirus pandemic.
Collection of 2429 constrained headshots of 277 volunteers for deep learning
Authors: Aoto Saki , Hangai Mayumi , Ueno-Yokohata Hitomi , Ueda Aki , Igarashi Maki , Ito Yoshikazu , Tsukamoto Motoko , Jinno Tomoko , Sakamoto Mika , Okazaki Yuka , Hasegawa Fuyuki , Ogata-Kawata Hiroko , Namura Saki , Kojima Kazuaki , Kikuya Masao , Matsubara Keiko , Taniguchi Kosuke , Okamura Kohji 
Published: March 2022

AbstractDeep learning has rapidly been filtrating many aspects of human lives. In particular, image recognition by convolutional neural networks has inspired numerous studies in this area. Hardware and software technologies as well as large quantities of data have contributed to the drastic development of the field. However, the application of deep learning is often hindered by the need for big data and the laborious manual annotation thereof. To experience deep learning using the data compiled by us, we collected 2429 constrained headshot images of 277 volunteers. The collection of face photographs is challenging in terms of protecting personal information; we therefore established an online procedure in which both the informed consent and image data could be obtained. We did not collect personal information, but issued agreement numbers to deal with withdrawal requests. Gender and smile labels were manually and subjectively annotated only from the appearances, and final labels were determined by majority among our team members. Rotated, trimmed, resolution-reduced, decolorized, and matrix-formed data were allowed to be publicly released. Moreover, simplified feature vectors for data sciences were released. We performed gender and smile recognition by building convolutional neural networks based on the Inception V3 model with pre-trained ImageNet data to demonstrate the usefulness of our dataset.
Machine learning potential for interacting dislocations in the presence of free surfaces
Authors: Lanzoni Daniele , Rovaris Fabrizio , Montalenti Francesco 
Published: March 2022

AbstractComputing the total energy of a system of N interacting dislocations in the presence of arbitrary free surfaces is a difficult task, requiring Finite Element (FE) numerical calculations. Worst, high accuracy requires very fine meshes in the proximity of each dislocation core. Here we show that FE calculations can be conveniently replaced by a Machine Learning (ML) approach. After formulating the elastic problem in terms of one and two-body terms only, we use Sobolev training to obtain consistent information on both energy and forces, fitted using a feed-forward neural network (NN) architecture. As an example, we apply the proposed methodology to corrugated, heteroepitaxial semiconductor films, searching for the minimum-energy dislocation distributions by using Monte Carlo. Importantly, the presence of an interaction cutoff allows for the application of the method to systems of different sizes without the need to repeat training. Millions of energy evaluations are performed, a task which would have been impossible by brute-force FE calculations. Finally, we show how forces can be exploited in running 2D ML-based dislocation dynamics simulations.
Solvent Front Position Extraction and some conventional sample preparation techniques for the determination of coccidiostats in poultry feed by LC–MS/MS
Authors: Rybicki Maciej Jan , Becue Ilse , Daeseleire Els , Klimek-Turek Anna , Dzido Tadeusz Henryk 
Published: March 2022

AbstractSolvent Front Position Extraction is a novel technique developed for effective sample preparation of biological samples containing coccidiostats prior to LC–MS/MS. In this study the technique was used for isolation and determination of seven coccidiostats, from both main groups being: ionophores and chemical coccidiostats. Its effectiveness was evaluated by comparing with other sample preparation procedures, used in European routine laboratories. Results obtained by Solvent Front Position Extraction were very satisfactory (linearity R2 ≥ 0.971, recovery 90.1–111.1%, RSDr: 8.7–16.6%, RSDR: 9.0–17.7%) and fulfilled requirements described in Commission Regulation (EU) 2021/808 of 22 March 2021, which showed great potential of the technique in sample preparation of coccidiostats in poultry feed.
Free-breathing gradient recalled echo-based CMR in a swine heart failure model
Authors: Morris Craig C. , Ref Jacob , Acharya Satya , Johnson Kevin J. , Squire Scott , Acharya Tuschar , Dennis Tyler , Daugherty Sherry , McArthur Alice , Chinyere Ikeotunye Royal , Koevary Jen Watson , Hare Joshua M. , Lancaster Jordan J. , Goldman Steven , Avery Ryan 
Published: March 2022

AbstractIn swine models, there are well-established protocols for creating a closed-chest myocardial infarction (MI) as well as protocols for characterization of cardiac function with cardiac magnetic resonance (CMR). This methods manuscript outlines a novel technique in CMR data acquisition utilizing smart-signal gradient recalled echo (GRE)-based array sequences in a free-breathing swine heart failure model allowing for both high spatial and temporal resolution imaging. Nine male Yucatan mini swine weighing 48.7 ± 1.6 kg at 58.2 ± 3.1 weeks old underwent the outlined imaging protocol before and 1-month after undergoing closed chest left anterior descending coronary artery (LAD) occlusion/reperfusion. The left ventricular ejection fraction (LVEF) at baseline was 59.3 ± 2.4% and decreased to 48.1 ± 3.7% 1-month post MI (P = 0.029). The average end-diastolic volume (EDV) at baseline was 55.2 ± 1.7 ml and increased to 74.2 ± 4.2 ml at 1-month post MI (P = 0.001). The resulting images from this novel technique and post-imaging analysis are presented and discussed. In a Yucatan swine model of heart failure via closed chest left anterior descending coronary artery (LAD) occlusion/reperfusion, we found that CMR with GRE-based array sequences produced clinical-grade images with high spatial and temporal resolution in the free-breathing setting.