bluuebunny/crossref_metadata_2025_split huggingface dataset:
REDUCED FOLATE CARRIER 1 IS PRESENT IN RETINAL MICROVESSELS AND CRUCIAL FOR THE INNER BLOOD RETINAL BARRIER INTEGRITY
Authors: Gurler Gokce , Belder Nevin , Beker Mustafa Caglar , Sever-Bahcekapili Melike , Uruk Gokhan , Kilic Ertugrul , Yemisci Muge 
Published: October 2022

ABSTRACTBackgroundReduced folate carrier 1 (RFC1; SLC19a1) is the main responsible transporter for the B9 family of vitamins named folates, which are essential for normal tissue growth and development. While folate deficiency resulted in retinal vasculopathy, the expression and the role of RFC1 in blood-retinal barrier (BRB) are not well known.MethodsWe used whole mount retinas and trypsin digested microvessel samples of adult mice. To knockdown RFC1, we delivered RFC1-targeted short interfering RNA (RFC1-siRNA) intravitreally; while, to upregulate RFC1 we delivered lentiviral vector overexpressing RFC1. Retinal ischemia was induced 1-hour by applying FeCl3to central retinal artery. We used RT-qPCR and Western blotting to determine RFC1. Endothelium (CD31), pericytes (PDGFR-beta, CD13, NG2), tight-junctions (Occludin, Claudin-5 and ZO-1), main basal membrane protein (Collagen-4), endogenous IgG and RFC1 were determined immunohistochemically.ResultsOur analyses on whole mount retinas and trypsin digested microvessel samples of adult mice revealed the presence of RFC1 in the inner BRB and colocalization with endothelial cells and pericytes. Knocking down RFC1 expression via siRNA delivery resulted in the disintegration of tight junction proteins and collagen-4 in twenty-four hours, which was accompanied by significant endogenous IgG extravasation. This indicated the impairment of BRB integrity after an abrupt RFC1 decrease. Furthermore, lentiviral vector-mediated RFC1 overexpression resulted in increased tight junction proteins and collagen-4, confirming the structural role of RFC1 in the inner BRB. Acute retinal ischemia decreased collagen-4 and occludin levels and led to an increase in RFC1. Besides, the pre-ischemic overexpression of RFC1 partially rescued collagen-4 and occludin levels which would be decreased after ischemia.ConclusionIn conclusion, our study clarifies the presence of RFC1 protein in the inner BRB, which has recently been defined as hypoxia–immune-related gene in other tissues and offers a novel perspective of retinal RFC1. Hence, other than being a folate carrier, RFC1 is an acute regulator of the inner BRB in healthy and ischemic retinas.
Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project
Authors: Semaan Alexander , Bernard Vincent , Wong Justin , Makino Yuki , Swartzlander Daniel B. , Rajapakshe Kimal I. , Lee Jaewon J. , Officer Adam , Schmidt Christian Max , Wu Howard H. , Scaife Courtney L. , Affolter Kajsa E. , Nachmanson Daniela , Firpo Matthew A. , Yip-Schneider Michele , Lowy Andrew M. , Harismendy Olivier , Sen Subrata , Maitra Anirban , Jakubek Yasminka A. , Guerrero Paola A. 
Published: October 2022

AbstractIntraductal papillary mucinous neoplasms (IPMNs) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low grade (LG) to high grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multi-region sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy number alterations (CNAs) and transcriptomics changes, that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histological dysplasia obtained from 24 patients (total of 74 independent histological lesions), followed by whole exome and whole transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification, in particular, being associated with HG progression and with cases that harbored cooccurring PDAC. Furthermore, the combined assessment of single nucleotide variants (SNVs) and CNAs identified both linear and branched evolutionary trajectories, underscoring the heterogeneity in the progression of LG lesions to HG and PDAC. At the transcriptome level, upregulation of MYC-regulated targets and downregulation of transcripts associated with the MHC class I antigen presentation machinery was a common feature of progression to HG. Taken together, this work emphasizes the role of 1q copy number amplification as a putative biomarker of high-risk IPMNs, underscores the importance of immune evasion even in non-invasive precursor lesions, and supports a previously underappreciated role of CNA-driven branching evolution as an avenue for IPMN progression. Our study provides important molecular context for risk stratification and cancer interception opportunities in IPMNs.SignificanceIntegrated molecular analysis of genomic and transcriptomic alterations in the multistep progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors of pancreatic cancer, identifies features associated with progression of low-risk lesions to high-risk lesions and cancer, which might enable patient stratification and cancer interception strategies.
A metabolomic view on local climate adaptation: Latitudinal divergence of heat and drought responses in a coastal plant
Authors: Schrieber Karin , Gluesing Svea , Peters Lisa , Eichert Beke , Althoff Merle , Schwarz Karin , Erfmeier Alexandra , Demetrowitsch Tobias 
Published: October 2022

AbstractStudying natural variation in multi-stress resistance is central for predicting and managing the population dynamics of wild plant species under rapid global change. Yet, it remains a challenging goal in this field to integrate knowledge on the complex biochemical underpinnings for the targeted ‘non-model’ species. Here, we studied latitudinal divergence in combined drought and heat stress resistance in European populations of the dune plantCakile maritima, by combining comprehensive plant phenotyping with metabolic profiling via FT-ICR-MS and UPLC-TQ-MS/MS.We observed pronounced constitutive divergence in growth phenology, leaf functional traits and defence chemistry (glucosinolates, alkaloids) among population origins. Most importantly, the magnitude of growth reduction under stress was partly weaker in southern plants and associated with divergence in plastic growth responses (root expansion, leaf abscission) and the stress-induced modulation of primary and specialized metabolites with known central functions not only in plant abiotic but also biotic stress resistance.Our study supports that divergent selection has shaped the constitutive and stress-induced expression of numerous morphological and biochemical functional traits to mediate higher abiotic stress resistance in southernCakilepopulations, and highlights that metabolomics is a powerful tool to explore the mechanistic underpinnings of local stress adaptation in ‘non-model’ species.HighlightPlant defence chemistry and its modulation by abiotic stress exhibits latitudinal clines across natural populations of a coastal plant.
Multi-view confounder detection for biomedical studies
Authors: Wallner Markus , Kersten Nicolas , Pfeifer Nico 
Published: October 2022

ABSTRACTIn many biomedical studies an important first step is checking for confounding factors. For association studies, confounding can for example be caused by ethnic differences in the case and control groups. In many other settings there might be confounding factors like batch effects or founder effects that also need to be detected and controlled for1. Detecting confounding for data from one data source is well established (e.g., genomics data). Since more and more studies are now based on data from multiple data modalities (e.g., multi-omics), we evaluated whether multi-view confounder detection can benefit from state-of-the-art methods for multi-view data integration. Especially for clustering of multi-omics data, it has been shown that these methods can perform better than methods that treat the data modalities separately2. Our results show that multi-view confounder analysis is possible and that building on multi-view data integration methods is better than treating the different data modalities separately.
Synthetic EMG Based on Adversarial Style Transfer can Effectively Attack Biometric-based Personal Identification Models
Authors: Kang Peiqi , Jiang Shuo , Shull Peter B. 
Published: October 2022

AbstractBiometric-based personal identification models are generally considered to be accurate and secure because biological signals are too complex and person-specific to be fabricated, and EMG signals, in particular, have been used as biological identification tokens due to their high dimension and non-linearity. We investigate the possibility of effectively attacking EMG-based identification models with biological adversarial input via a novel EMG signal individual style transformer based on a generative adversarial network. EMG hand gesture data from eighteen subjects and three well-recognized deep EMG classifiers were used to demonstrate the effectiveness of the proposed attack methods. The proposed methods achieved an average of 99.41% success rate on confusing identification models and an average of 91.51% success rate on manipulating identification models. These results demonstrate that EMG classifiers based on deep neural networks can be vulnerable to synthetic data attacks. The proof-of-concept results reveal that synthetic EMG biological signals must be considered in biological identification system design across a vast array of relevant biometric systems to ensure personal identification security for individuals and institutions.
A nearly 30-years living collection from the Royal Botanic Garden Edinburgh is a new species: a case study ofBetula mcallisteriisp. nov. (sect.Acuminatae, Betulaceae) and its little hybridization withBetula luminifera
Authors: Zhang Huayu , Ding Junyi , Wang Nian 
Published: October 2022

SummarySpecies description meets challenges arising from various species concepts. Integrating different sources of information and multiple lines of evidence are important for species recognition and discovery.Here we use morphology, restriction site-associated DNA sequencing and flow cytometry to study the species status of the unidentifiedBetulasamples collected in this study and to assess the extent of hybridization between the unidentifiedBetulasamples andB. luminiferain natural populations.Molecular analyses show the unidentifiedBetulasamples as a distinct lineage and reveal very little genetic admixture between the unidentified samples andB. luminifera. Unexpectedly, the unidentified samples formed a well-supported monophyletic clade with the living collection ofB. luminifera19933472 in the Royal Botanic Garden Edinburgh which was introduced from Southwest China. Flow cytometry shows that the unidentified samples andB. luminifera19933472 are diploid.Our data indicates thatB. luminifera19933472 and the unidentifiedBetulasamples should be recognized as a new species, namelyB. mcallisterii. The very little introgression betweenB. mcallisteriiandB. luminiferaindicates a strong reproductive barrier. Our research shows the importance of gathering information from wild populations and the value of an integrative approach in species discovery.Societal Impact StatementA comprehensive survey of plant species from natural populations can aid greatly in taxonomy and species delimitation. Here, we discovered a new birch species from the wild and unexpectedly found that this species has been introduced to the Royal Botanic Garden Edinburgh for nearly 30 years. We found very little introgression between the new species and its closely-related species. Our study highlighted the importance in integrating sources of information from natural populations and botanic gardens for species discovery.
ATGL is differentially required for adipocyte FABP4 secretionin vivoandex vivo
Authors: Prentice Kacey J. , Lee Alexandra , Cedillo Paulina , Inouye Karen E. , Ertunc Meric Erikci , Lee Grace Yankun , Hotamışlıgil Gökhan S. 
Published: October 2022

AbstractFatty acid binding protein 4 (FABP4) is linked with the pathogenesis of metabolic diseases, including diabetes and cardiovascular disease in both mice and humans. It has also been demonstrated that the levels of hormonal FABP4 are strongly associated with obesity, and secretion is stimulated under conditions of fasting and lipolysis bothin vivoandin vitro. Here, we utilized adipocyte-specific deficiency of adipose triglyceride lipase (ATGL) in a mouse model (ATGLAdpKO) to evaluate the regulation of FABP4 secretion by lipolytic signals in the absence of actual lipolysisin vivo. Previously, lipolysis-induced FABP4 secretion was found to be significantly reduced upon pharmacological inhibition of ATGL, and from adipose tissue explants from ATGLAdpKOmice. Unexpectedly, upon activation beta-adrenergic receptors, ATGLAdpKOmice exhibited significantly higher levels of circulating FABP4 as compared to ATGLfl/flcontrolsin vivo, with no corresponding increase in non-esterified free fatty acids or glycerol, confirming the lack of lipolysis. We also generated an additional model with adipocyte-specific deletion of FABP4 in the background of ATGLAdpKOmice (ATGL/FABP4AdpKOor DKO) to evaluate the cellular source of circulating FABP4. In these animals, there was no evidence of lipolysis-induced FABP4 secretion, indicating that the elevated FABP4 hormone levels in the ATGLAdpKOmice were indeed from the adipocytes. ATGLAdpKOmice did not exhibit an increase in insulin secretion upon stimulation of lipolysis, but had a normal insulin response to glucose injection along with increased FABP4 secretion, suggesting the elevated FABP4 secretion is not due to lack of insulin. Inhibition of sympathetic signaling during lipolysis using hexamethonium significantly reduced FABP4 secretion in ATGLAdpKOmice compared to controls. Therefore, activity of a key enzymatic step of lipolysis mediated by ATGL,per se, is not required for stimulatedin vivoFABP4 secretion from adipocytes, which can be induced through sympathetic signaling.
Sequence aligners can guarantee accuracy in almostO(mlogn) time: a rigorous average-case analysis of the seed-chain-extend heuristic
Authors: Shaw Jim , Yu Yun William 
Published: October 2022

AbstractSeed-chain-extend with k-mer seeds is a powerful heuristic technique for sequence alignment employed by modern sequence aligners. While effective in practice for both runtime and accuracy, theoretical guarantees on the resulting alignment do not exist for seed-chain-extend. In this work, we give the first rigorous bounds for the efficacy of seed-chain-extend with k-mersin expectation.Assume we are given a random nucleotide sequence of length ~nthat is indexed (or seeded) and a mutated substring of length ~m≤nwith mutation rateθ< 0.206. We prove that we can find ak=Θ(logn) for the k-mer size such that the expected runtime of seed-chain-extend under optimal linear gap cost chaining and quadratic time gap extension isO(mnf(θ)logn) wheref(θ) < 2.43 ·θholds as a loose bound. The alignment also turns out to be good; we prove that more thanfraction of the homologous bases arerecoverableunder an optimal chain. We also show that our bounds work when k-mers aresketched, i.e. only a subset of all k-mers is selected, and that sketching reduces chaining time without increasing alignment time or decreasing accuracy too much, justifying the effectiveness of sketching as a practical speedup in sequence alignment. We verify our results in simulation and on real noisy long-read data and show that our theoretical runtimes can predict real runtimes accurately. We conjecture that our bounds can be improved further, and in particular,f(θ) can be further reduced.
Determinants and Mechanisms of the Low Fusogenicity and Endosomal Entry of Omicron Subvariants
Authors: Qu Panke , Evans John P. , Kurhade Chaitanya , Zeng Cong , Zheng Yi-Min , Xu Kai , Shi Pei-Yong , Xie Xuping , Liu Shan-Lu 
Published: October 2022

SummaryThe rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation, as shown by increased molecular interactions in structural modeling as well as reduced S1 shedding. Importantly, the H655Y mutation also determines the low fusogenicity and high dependence on the endosomal entry pathway of other Omicron subvariants, including BA.2, BA.2.12.1, BA.4/5 and BA.2.75. These results uncover mechanisms governing Omicron subvariant entry and provide insights into altered Omicron tissue tropism and pathogenesis.
Carbon nanofibers fabrication, surface modifications, and application as the innovative substrate for electrical stimulation of neural cell differentiation
Authors: Nekounam Houra , Samadian Hadi , Golmohammadi Hossein , Asghari Fatemeh , Shokrgozar Mohammad Ali , Ahadian Samad , Majidi Reza Faridi 
Published: October 2022

AbstractEngineered nanostructures are innovative and precisely designed, synthesized, and tailored with outstanding physicochemical properties that can be applied as the game-changer in neural tissue engineering. The present study aimed to develop an innovative approach based on electrical stimulation through a conductive scaffold to differentiate neural cells from human adipose mesenchymal stem cells without the use of a specific environment for neural differentiation. Electrospun carbon nanofibers (CNFs) were obtained using heat treatment of polyacrylonitrile nanofibers and treated by nitric acid, ethylenediamine, and oxygen Plasma. SEM imaging revealed that the treated nanofibers have s diameter in the range of 120-200 nm and the treatment did not significantly change the CNFs diameter. The FTIR results showed that the treatments were able to introduce COOH, OH, and NH2 functional groups on the CNFS surface. The XRD and Raman analysis showed that the plasma treatment induced the lowest structural changes in the CNFs microstructure. The biocompatibility assessments showed that the pristine and treated CNFs were non-toxic induced proliferative effect on human adipose-derived mesenchymal stem cells. The electrical stimulation (1.5 mA current with a frequency of 500 Hz and CMOS waveform for 7 days 10 min each day) induced the expression of neural genes and proteins by the cells cultured on the treated CNFs. The Plasma-treated CNFs mediated the highest differentiation outcome. These results indicate that electrospun CNFs can be applied as the innovative interface applicable for neural tissue regeneration under electrical stimulation.Research highlightsCNFs were fabricated from PAN nanofibersDifferent amounts of ZnONPs were incorporated into or sprayed on CNFincreasing in ZnONP amount decreased conductivity, surface wettability was improved by ∼19–33%.Also, FTIR, XRD, and Raman analyses proved that the presence of ZnONP improved structure formation with lower defect densitySchematic 1.The applied electrical stimulation setup
Risk assessment of cancer patients based on HLA-I alleles, neobinders and expression of cytokines
Authors: Dhall Anjali , Patiyal Sumeet , Kaur Harpreet , Raghava Gajendra P. S. 
Published: October 2022

AbstractAdvancements in cancer immunotherapy have shown significant outcomes in treating various types of cancers. In order to design effective immunotherapy, it is important to understand immune response of a patient based on its genomic profile. We compute prognostic biomarkers from 8346 cancer patients for twenty types of cancer. These prognostic biomarkers has been computed based on i) presence of 352 human leucocyte antigen class-I (HLA-I), ii) 660959 tumor-specific HLA1 neobinders and iii) expression profile of 153 cytokines. It was observed that survival risk of cancer patients depends on presence of certain type of HLA-I alleles; for example LIHC cancer patients with HLA-A*03:01 are on lower risk. Our analysis indicate that neobinders of HLA-I alleles have high correlation with overall survival of certain type of cancer patients. For example HLA-B*07:02 binders have 0.49 correlation with survival of LUSC and −0.77 with KICH cancer patients. It is clear from above analysis that HLA and their binders have major role in survival of cancer patients suffering from different types of cancer. In addition, we compute prognostic biomarkers for 20 types of cancer based on each type of cytokine expression. Higher expression of few cytokines is survival favourable like IL-2 for BLCA cancer patients whereas IL-5R survival unfavourable for KICH cancer patients. In order to facilitate scientific community we developed a web-based platform CancerHLA1 that maintain raw and analyzed data (https://webs.iiitd.edu.in/raghava/cancerhla1/).
Comparative Mutagenesis of SARS-CoV-2 Nonstructural Proteins (NSPs) Across Variants: The Case for RdRp as a Therapeutic Target
Authors: Lanclos Nathan 
Published: October 2022

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenicity has been studied extensively from the perspective of structural (S, E, M, N) proteins for purposes in vaccine development. The virus’ nonstructural protein (nsp) components are less characterized, and demonstrate significant potential in efforts to develop novel therapeutic agents. NSP 7, 8, and 12, formed from the cleavage of pp1a and pp1ab polyproteins, comprise the viral replicase (RdRp) complex1, the site for the mechanism of action of Remdesivir2. Presented herein is a phylogenetic analysis for the evolution of SARS-CoV-2 replicase components between variant and related coronaviruses with the aim to delineate its current and long-term efficacy as a drug target.
EVMP: Enhancing machine learning models for synthetic promoter strength prediction by Extended Vision Mutant Priority framework
Authors: Yang Weiqin , Li Dexin , Huang Ranran 
Published: October 2022

AbstractMotivationIn metabolic engineering and synthetic biology applications, promoters with appropriate strengths are critical. However, it is time-consuming and laborious to annotate promoter strength by experiments. Nowadays many machine learning (ML) methods are applied to synthetic promoter strength prediction, but existing models are limited by the excessive proximity between synthetic promoters.ResultsIn order to enhance ML models to better predict the synthetic promoter strength, we propose EVMP(Extended Vision Mutant Priority), a universal framework which utilize mutation information more effectively. In EVMP, synthetic promoters are equivalently transformed into base promoter and correspondingk-mer mutations, which are input into BaseEncoder and VarEncoder respectively. In Trc synthetic promoter library, EVMP was applied to multiple ML models and the model effect was enhanced to varying extents, up to 61.30%, while the SOTA(state-of-the-art) record was improved by 15.25%. EVMP also provides optional data augmentation based on multiple base promoters, which further improved the model performance by 17.95% compared with non-EVMP SOTA record. In further study, extended vision is shown to be essential for EVMP. We also found that EVMP can alleviate the over-smoothing phenomenon, which may contributes to its effectiveness. Our work suggests that EVMP can highlight the mutation information of synthetic promoters and significantly improve the prediction accuracy of strength.Availability and implementationThe source code is publicly available on github:https://github.com/Tiny-Snow/EVMP.Contacthuangrr@sdu.edu.cnSupplementary informationAppendix is available atbioRxivonline.