bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous Quantitation of Anlotinib and Osimertinib by Isotope-Labeled UHPLC–MS/MS in Human Plasma: Application in NSCLC Patients
Authors: Liu Yao , Lin Zhong , Luo Wenji , Pei Xiaofeng , She Ziyue , Sha Zhou , Guan Yanping , Ming Dandan , Liang Jiabi 
Published: April 2023

Abstract
Anlotinib and osimertinib are a class of tyrosine kinase inhibitors for the treatment of malignant tumor. The combination of anlotinib and osimertinib is currently used for treating non-small cell lung cancer (NSCLC) patients. This study aimed to develop a simple and rapid isotope-labeled UHPLC–MS/MS method for the simultaneous determination of anlotinib and osimertinib in human plasma. The analytes were extracted by protein precipitation with acetonitrile and were then separated on a Shim-pack GIST C18 column. The detection was performed on Shimadzu 8050 triple quadruple mass spectrometer in the positive electrospray ionization mode with multiple reaction monitoring. The precursor-to-product ion transitions were m/z 408.10→ 339.75, 500.25→ 72.20 and 413.50 → 344.50 for anlotinib, osimertinib and D5-anlotinib, respectively. Validation is based on US Food and Drug Administration guidelines. The linearity ranges were 0.5–100 ng/mL for anlotinib and were 1–500 ng/mL for osimertinib with the correlation coefficients (r 2) ≥ 0.99. Accuracy and precision, matrix effect, extraction recovery and stability of anlotinib and osimertinib were acceptable after validation. The UHPLC–MS/MS method was successfully validated and was applied to monitor the concentration of anlotinib and osimertinib in NSCLC patients.
Non-invasive assessment of ovarian activity in free-ranging eastern black rhinoceros (Diceros bicornis michaeli) in Kenya
Authors: Kamau Maureen W , Brown Janine L , Boisseau Nicole , Gaymer Jamie , Hassell James , Martins Dino J , Murray Suzan 
Published: April 2023

AbstractEastern black rhinos (Diceros bicornis michaeli) are a critically endangered species living in diverse habitats across Africa. In Kenya, once threatened with extinction due to massive poaching pressures, increased protection has resulted in losses being less than 1% annually today. Still, some populations have failed to achieve desired population growth targets. At Ol Jogi Wildlife Conservancy, some individuals are experiencing sub-optimal reproduction based on historical calving records and long inter-calving intervals (&gt;3 years). Hormones drive the reproductive process, so non-invasive assessments of endocrine patterns can be useful indicators of individual reproductive health. In this study, we analysed longitudinal fecal progestagen metabolite (fPM) concentrations in all breeding female eastern black rhinos at Ol Jogi (n = 17) and compared the prevalence of irregular estrous cycles (longer or shorter than 20–40 days) and anestrous periods (interluteal period more than twice the length of a normal follicular phase, i.e. &gt; 10 days) between optimal (inter-calving interval &lt; 3 years) and sub-optimal (&gt;3 years) reproducing individuals. Ten rhinos were pregnant during at least part of the study period. A total of 12 complete cycles were observed in seven females with an average length of 36 ± 3 days and equal numbers of regular and irregular cycles. Single anestrous periods averaging 67 ± 13 days were observed in five females. Surprisingly, a majority of cycles in optimal reproducing individuals were categorized as irregular based on fPM profiles. Overall, results suggest that irregular ovarian activity and isolated bouts of anestrus do not have negative impacts on reproductive performance in this subpopulation at Ol Jogi. A high priority is to continue using noninvasive hormone monitoring to evaluate how ecological or other variables influence reproductive success in this and other eastern black rhino subpopulations in Kenya.
Rapid identification of healthy Tegillarca granosa using laser-induced breakdown spectroscopy and fusion model
Authors: Chen Xiaojing , Chen Yanan , Chen Xi , Yuan Leiming , Jiang Chengxi , Huang Guangzao , Shi Wen 
Published: April 2023

Abstract

Objectives
This study presents a method combining a one-class classifier and laser-induced breakdown spectrometry (LIBS) to quickly identify healthy Tegillarca granosa (T. granosa).

Materials and Methods
The sum of ranking differences (SRD) was used to fuse multiple anomaly detection metrics to build the one-class classifier, which was only trained with healthy T. granosa. The one-class classifier can identify healthy T. granosa to exclude non-healthy T. granosa. The proposed method calculated multiple anomaly detection metrics and standardized them to obtain a fusion matrix. Based on the fusion matrix, the samples were ranked by SRD and those ranked lowest and below the threshold were considered to be unhealthy.

Results
Multiple anomaly detection metrics were fused by the SRD algorithm and tested on each band, and the final fusion model achieved an accuracy rate of 98.46%, a sensitivity of 100%, and a specificity of 80%. The remaining three single classification models obtained the following results: the SVDD model achieved an accuracy rate of 87.69%, a sensitivity of 90%, and a specificity of 60%; the OCSVM model achieved an accuracy rate of 80%, a sensitivity of 76.67%, and a specificity of 60%; and the DD-SIMCA model achieved an accuracy rate of 95.38%, a sensitivity of 98.33%, and a specificity of 60%.

Conclusions
The experimental results showed that the proposed method achieved better results than the traditional one-class classification methods with a single metric. Therefore, the fusion method effectively improves the performance of traditional one-class classifiers when using LIBS to quickly identify healthy substances (healthy T. granosa).
An updated de novo transcriptome for green ash (Fraxinus pennsylvanica)
Authors: Brungardt Jordan J , Bock Clive H 
Published: April 2023

Abstract
De novo transcriptome assembly of next-generation sequencing information has become a powerful tool for the study of non-model species. Transcriptomes generated by this method can have high variability due to endless combinations of user-defined variables and programs available for assembly. Many methods have been developed for evaluating the quality of these assemblies. Here, raw sequencing information for Green ash (Fraxinus pennsylvanica Marshall) that was previously published has been re-evaluated. An updated assembly has been developed by including additional sequencing information not used for the currently accepted transcriptome in combination with more stringent trimming parameters. Input reads were assembled with Trinity and Abyss assembly programs. The resulting Trinity assembly has a 7.3-fold increase in genomic breadth of coverage, a 2.4-fold increase in predicted complete open reading frames, an increased L50 value, and increased Benchmarking Universal Single-Copy Ortholog completeness compared to the earlier published transcriptome. This updated transcriptome can be leveraged to help fight the rapid decline of green ash due to pathogens.
Extension of the DNAJB2a isoform in a dominant neuromyopathy family
Authors: Sarparanta Jaakko , Jonson Per Harald , Reimann Jens , Vihola Anna , Luque Helena , Penttilä Sini , Johari Mridul , Savarese Marco , Hackman Peter , Kornblum Cornelia , Udd Bjarne 
Published: April 2023

Abstract
Recessive mutations in the DNAJB2 gene, encoding the J-domain co-chaperones DNAJB2a and DNAJB2b, have previously been reported as the genetic cause of progressive peripheral neuropathies, rarely involving pyramidal signs, parkinsonism and myopathy. We describe here a family with the first dominantly acting DNAJB2 mutation resulting in a late-onset neuromyopathy phenotype. The c.832 T &gt; G p.(*278Glyext*83) mutation abolishes the stop codon of the DNAJB2a isoform resulting in a C-terminal extension of the protein, with no direct effect predicted on the DNAJB2b isoform of the protein. Analysis of the muscle biopsy showed reduction of both protein isoforms. In functional studies, the mutant protein mislocalized to the endoplasmic reticulum due to a transmembrane helix in the C-terminal extension. The mutant protein underwent rapid proteasomal degradation and also increased the turnover of co-expressed wild-type DNAJB2a, potentially explaining the reduced protein amount in the patient muscle tissue. In line with this dominant negative effect, both wild-type and mutant DNAJB2a were shown to form polydisperse oligomers.
Skim resequencing finely maps the downy mildew resistance loci RPF2 and RPF3 in spinach cultivars whale and Lazio
Authors: Bhattarai Gehendra , Shi Ainong , Mou Beiquan , Correll James C 
Published: April 2023

Abstract
Commercial production of spinach (Spinacia oleracea L.) is centered in California and Arizona in the US, where downy mildew caused by Peronospora effusa is the most destructive disease. Nineteen typical races of P. effusa have been reported to infect spinach, with 16 identified after 1990. The regular appearance of new pathogen races breaks the resistance gene introgressed in spinach. We attempted to map and delineate the RPF2 locus at a finer resolution, identify linked single nucleotide polymorphism (SNP) markers, and report candidate downy mildew resistance (R) genes. Progeny populations segregating for RPF2 locus derived from resistant differential cultivar Lazio were infected using race 5 of P. effusa and were used to study for genetic transmission and mapping analysis in this study. Association analysis performed with low coverage whole genome resequencing-generated SNP markers mapped the RPF2 locus between 0.47 to 1.46 Mb of chromosome 3 with peak SNP (Chr3_1, 221, 009) showing a LOD value of 61.6 in the GLM model in TASSEL, which was within 1.08 Kb from Spo12821, a gene that encodes CC-NBS-LRR plant disease resistance protein. In addition, a combined analysis of progeny panels of Lazio and Whale segregating for RPF2 and RPF3 loci delineated the resistance section in chromosome 3 between 1.18–1.23 and 1.75–1.76 Mb. This study provides valuable information on the RPF2 resistance region in the spinach cultivar Lazio compared to RPF3 loci in the cultivar Whale. The RPF2 and RPF3 specific SNP markers, plus the resistant genes reported here, could add value to breeding efforts to develop downy mildew resistant cultivars in the future.
Raising awareness of antimicrobial resistance: development of an ‘antibiotic footprint calculator’
Authors: Prapharsavat Ravikanya , Kittikongnapang Rattanasiri , Smithkittipol Chokdee , Udomrat Warute , Numsawat Sukanya , Hernandez-Koutoucheva Anastasia , Naemiratch Bhensri , Chomkatekaew Chalita , Amaratunga Chanaki , Bleho John , Mathee Kalai , Schneiders Mira Leonie , Khirikoekkong Napat , Kanthawang Nipaphan , Sumpradit Nithima , Suveeranont Rapee , Asarath Supa-at , Poomchaichote Tassawan , Schilling William , Chan Xin Hui S , Osterrieder Anne , Cheah Phaik Yeong , Limmathurotsakul Direk 
Published: April 2023

Abstract
Non-academic partners can be vital in successful public engagement activities on antimicrobial resistance. With collaboration between academic and non-academic partners, we developed and launched an open-access web-based application, the ‘antibiotic footprint calculator’, in both Thai and English. The application focused on a good user experience, addressing antibiotic overuse and its impact, and encouraging immediate action. The application was unveiled in joint public engagement activities. From 1 Nov 2021 to 31 July 2022 (9 month period), 2554 players estimated their personal antibiotic footprint by using the application.
Natural language processing-driven state machines to extract social factors from unstructured clinical documentation
Authors: Allen Katie S , Hood Dan R , Cummins Jonathan , Kasturi Suranga , Mendonca Eneida A , Vest Joshua R 
Published: April 2023

Lay Summary
Social factors, such as an individual’s housing, food, employment, and income situations, affect their overall health and well-being. As a result, data on patients’ social factors aid in clinical decision making, planning by hospital administrators and policy-makers, and enrich research studies with data representative of more factors influencing the life of an individual. Data on social factors can be collected at the time of a healthcare visit through screening questionnaires or are often documented in the clinical text as part of the social narrative. This study examines the use of natural language processing—a machine method to identify certain text within a larger document—to identify housing instability, financial insecurity, and unemployment from within the clinical notes. Using a relatively unsophisticated methodology, this study demonstrates strong performance in identifying these social factors, which will enable stakeholders to utilize these details in support of improved clinical care.
The Genetic Architecture of Adaptation to Leaf and Root Bacterial Microbiota inArabidopsis thaliana
Authors: Roux Fabrice , Frachon Léa , Bartoli Claudia 
Published: April 2023

AbstractUnderstanding the role of the host genome in modulating microbiota variation is a need to shed light on the holobiont theory and overcome the current limits on the description of host-microbiota interactions at the genomic and molecular levels. However, the host genetic architecture structuring microbiota is only partly described in plants. In addition, most association genetic studies on microbiota are often carried out outside the native habitats where the host evolves and the identification of signatures of local adaptation on the candidate genes has been overlooked. To fill these gaps and dissect the genetic architecture driving adaptive plant-microbiota interactions, we adopted a genome-environment association (GEA) analysis on 141 whole-genome sequenced natural populations of Arabidopsis thaliana characterized in situ for their leaf and root bacterial communities in fall and spring, and a large range of nonmicrobial ecological factors (i.e., climate, soil, and plant communities). A much higher fraction of among-population microbiota variance was explained by the host genetics than by nonmicrobial ecological factors. Importantly, the relative importance of host genetics and nonmicrobial ecological factors in explaining the presence of particular operational taxonomic units (OTUs) differs between bacterial families and genera. In addition, the polygenic architecture of adaptation to bacterial communities was highly flexible between plant compartments and seasons. Relatedly, signatures of local adaptation were stronger on quantitative trait loci (QTLs) of the root microbiota in spring. Finally, plant immunity appears as a major source of adaptive genetic variation structuring bacterial assemblages in A. thaliana.
LncRNAEPRregulates intestinal mucus production and protects against inflammation and tumorigenesis
Authors: Briata Paola , Mastracci Luca , Zapparoli Ettore , Caputo Luca , Ferracci Elisa , Silvestri Alessandra , Garuti Anna , Hamadou Meriem Hadjer , Inga Alberto , Marcaccini Elisa , Grillo Federica , Bucci Gabriele , Puri Pier Lorenzo , Beznoussenko Galina , Mironov Alexander , Chiacchiera Fulvio , Gherzi Roberto 
Published: April 2023

AbstractThe long non-coding RNA EPR is expressed in epithelial tissues, binds to chromatin and controls distinct biological activities in mouse mammary gland cells. Because of its high expression in the intestine, in this study we have generated a colon-specific conditional targeted deletion (EPR cKO) to evaluate EPR in vivo functions in mice. EPR cKO mice display epithelium hyperproliferation, impaired mucus production and secretion, as well as inflammatory infiltration in the proximal portion of the large intestine. RNA sequencing analysis reveals a rearrangement of the colon crypt transcriptome with strong reduction of goblet cell-specific factors including those involved in the synthesis, assembly, transport and control of mucus proteins. Further, colon mucosa integrity and permeability are impaired in EPR cKO mice, and this results in higher susceptibility to dextran sodium sulfate (DSS)-induced colitis and tumor formation. Human EPR is down-regulated in human cancer cell lines as well as in human cancers, and overexpression of EPR in a colon cancer cell line results in enhanced expression of pro-apoptotic genes. Mechanistically, we show that EPR directly interacts with select genes involved in mucus metabolism whose expression is reduced in EPR cKO mice and that EPR deletion causes tridimensional chromatin organization changes.
Catalytic mechanism and pH dependence of a methyltransferase ribozyme (MTR1) from computational enzymology
Authors: McCarthy Erika , Ekesan Şölen , Giese Timothy J , Wilson Timothy J , Deng Jie , Huang Lin , Lilley David M J , York Darrin M 
Published: April 2023

Abstract
A methyltransferase ribozyme (MTR1) was selected in vitro to catalyze alkyl transfer from exogenous O6-methylguanine (O6mG) to a target adenine N1, and recently, high-resolution crystal structures have become available. We use a combination of classical molecular dynamics, ab initio quantum mechanical/molecular mechanical (QM/MM) and alchemical free energy (AFE) simulations to elucidate the atomic-level solution mechanism of MTR1. Simulations identify an active reactant state involving protonation of C10 that hydrogen bonds with O6mG:N1. The deduced mechanism involves a stepwise mechanism with two transition states corresponding to proton transfer from C10:N3 to O6mG:N1 and rate-controlling methyl transfer (19.4  kcal·mol−1 barrier). AFE simulations predict the pKa for C10 to be 6.3, close to the experimental apparent pKa of 6.2, further implicating it as a critical general acid. The intrinsic rate derived from QM/MM simulations, together with pKa calculations, enables us to predict an activity–pH profile that agrees well with experiment. The insights gained provide further support for a putative RNA world and establish new design principles for RNA-based biochemical tools.
Impact of stereopure chimeric backbone chemistries on the potency and durability of gene silencing by RNA interference
Authors: Liu Wei , Iwamoto Naoki , Marappan Subramanian , Luu Khoa , Tripathi Snehlata , Purcell-Estabrook Erin , Shelke Juili Dilip , Shah Himali , Lamattina Anthony , Pan Qianli , Schrand Brett , Favaloro Frank , Bedekar Mugdha , Chatterjee Arindom , Desai Jigar , Kawamoto Tomomi , Lu Genliang , Metterville Jake , Samaraweera Milinda , Prakasha Priyanka Shiva , Yang Hailin , Yin Yuan , Yu Hui , Giangrande Paloma H , Byrne Michael , Kandasamy Pachamuthu , Vargeese Chandra 
Published: April 2023

Abstract
Herein, we report the systematic investigation of stereopure phosphorothioate (PS) and phosphoryl guanidine (PN) linkages on siRNA-mediated silencing. The incorporation of appropriately positioned and configured stereopure PS and PN linkages to N-acetylgalactosamine (GalNAc)-conjugated siRNAs based on multiple targets (Ttr and HSD17B13) increased potency and durability of mRNA silencing in mouse hepatocytes in vivo compared with reference molecules based on clinically proven formats. The observation that the same modification pattern had beneficial effects on unrelated transcripts suggests that it may be generalizable. The effect of stereopure PN modification on silencing is modulated by 2′-ribose modifications in the vicinity, particularly on the nucleoside 3′ to the linkage. These benefits corresponded with both an increase in thermal instability at the 5′-end of the antisense strand and improved Argonaute 2 (Ago2) loading. Application of one of our most effective designs to generate a GalNAc-siRNA targeting human HSD17B13 led to ∼80% silencing that persisted for at least 14 weeks after administration of a single 3 mg/kg subcutaneous dose in transgenic mice. The judicious use of stereopure PN linkages improved the silencing profile of GalNAc-siRNAs without disrupting endogenous RNA interference pathways and without elevating serum biomarkers for liver dysfunction, suggesting they may be suitable for therapeutic application.
Requirements for mammalian promoters to decode transcription factor dynamics
Authors: Antwi Enoch B , Marrakchi Yassine , Çiçek Özgün , Brox Thomas , Di Ventura Barbara 
Published: April 2023

Abstract
In response to different stimuli many transcription factors (TFs) display different activation dynamics that trigger the expression of specific sets of target genes, suggesting that promoters have a way to decode dynamics. Here, we use optogenetics to directly manipulate the nuclear localization of a synthetic TF in mammalian cells without affecting other processes. We generate pulsatile or sustained TF dynamics and employ live cell microscopy and mathematical modelling to analyse the behaviour of a library of reporter constructs. We find decoding of TF dynamics occurs only when the coupling between TF binding and transcription pre-initiation complex formation is inefficient and that the ability of a promoter to decode TF dynamics gets amplified by inefficient translation initiation. Using the knowledge acquired, we build a synthetic circuit that allows obtaining two gene expression programs depending solely on TF dynamics. Finally, we show that some of the promoter features identified in our study can be used to distinguish natural promoters that have previously been experimentally characterized as responsive to either sustained or pulsatile p53 and NF-κB signals. These results help elucidate how gene expression is regulated in mammalian cells and open up the possibility to build complex synthetic circuits steered by TF dynamics.
A Belgian Population-Based Study Reveals Subgroups of Right-sided Colorectal Cancer with a Better Prognosis Compared to Left-sided Cancer
Authors: Janssens Katleen , Fransen Erik , Van Camp Guy , Prenen Hans , Op de Beeck Ken , Van Damme Nancy , Peeters Marc 
Published: April 2023

Abstract

Background
Patients with left-sided colorectal cancer (L-CRC) are known to have a significantly better prognosis than those with right-sided CRC (R-CRC). It has been hypothesized that RAS, BRAF mutations, or deficient mismatch repair status (MMR) might be responsible for the prognostic effect of primary tumor location (PTL). This study aims to evaluate the prognostic effect of PTL in the Belgian population and to determine the role of biomarkers (MMR, BRAF, and RAS status) in this effect.

Patients and Methods
We performed a retrospective analysis of Belgian Cancer Registry data. First, we studied the prognostic effect of PTL on 5-year relative survival of 91,946 patients diagnosed with CRC (all stages) from 2004-2015. Second, we investigated the interaction between biomarkers and the prognostic effect of PTL in 1818 patients diagnosed with stage IV CRC in 2014-2015.

Results
L-CRC was associated with a significantly better 5-year relative survival compared to R-CRC in all stages and ages combined (68.4%, 95% CI, 67.7-69.1% vs 65.6%, 95% CI, 64.7-66.4%). Also, when stratified by age, sex, and stage, the prognosis of L-CRC was better compared to R-CRC in most subgroups. Only in stage II and certain subgroups of elderly patients, the opposite was observed. Furthermore, our data showed that none of the biomarkers had a significant interaction with the effect of PTL on survival.

Conclusion
This population-based study confirms that L-CRC is associated with significantly better relative survival compared to R-CRC, in all stages and ages combined. Furthermore, in stage IV L-CRC is associated with a longer survival than R-CRC, regardless of MMR, RAS, and BRAF status.