bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancer Reprogramming in Melanoma Immune Checkpoint Therapy Resistance
Authors: Maitituoheti Mayinuer , Shi Alvin , Tang Ming , Ho Li-Lun , Terranova Christopher , Galani Kyriaki , Keung Emily Z. , Creasy Caitlin A. , Wu Manrong , Chen Jiajia , Chen Nana , Singh Anand K. , Chaudhri Apoorvi , Anvar Nazanin E. , Tarantino Giuseppe , Yang Jiekun , Sarkar Sharmistha , Jiang Shan , Malke Jared , Haydu Lauren , Burton Elizabeth , Davies Michael A. , Gershenwald Jeffrey E. , Hwu Patrick , Lazar Alexander , Cheah Jaime H. , Soule Christian K. , Levine Stuart S. , Bernatchez Chantale , Saladi Srinivas V. , Liu David , Wargo Jennifer , Boland Genevieve M. , Kellis Manolis , Rai Kunal 
Published: September 2022

ABSTRACTImmune checkpoint blockade (ICB) therapy has improved long-term survival for patients with advanced melanoma. However, there is critical need to identify potential biomarkers of response and actionable strategies to improve response rates. Through generation and analysis of 148 chromatin modification maps for 36 melanoma samples from patients treated with anti-PD- 1, we identified significant enrichment of active enhancer states in non-responders at baseline. Analysis of an independent cohort of 20 samples identified a set of 437 enhancers that predicted response to anti-PD-1 therapy (Area Under the Curve of 0.8417). The activated non-responder enhancers marked a group of key regulators of several pathways in melanoma cells (including c- MET, TGFβ, EMT and AKT) that are known to mediate resistance to ICB therapy and several checkpoint receptors in T cells. Epigenetic editing experiments implicated involvement of c-MET enhancers in the modulation of immune response. Finally, inhibition of enhancers and repression of these pathways using bromodomain inhibitors along with anti-PD-1 therapy significantly decreased melanoma tumor burden and increased T-cell infiltration. Together, these findings identify a potential enhancer-based biomarker of resistance to anti-PD-1 and suggest enhancer blockade in combination with ICB as a potential strategy to improve responses.
Drug-Drug Interaction Extraction from Biomedical Text using Relation BioBERT with BLSTM
Authors: KafiKang Maryam , Hendawi Abdeltawab 
Published: September 2022

AbstractDrug-drug interactions (DDIs) happen when two or more drugs interact. DDIs may change the effect of drugs in the body which can induce adverse effects and severe diseases for patients. As a result, detecting the interaction between drugs is essential. In the last years, many new DDIs have been found and added to the medical datasets with the rise in the number of discovered drugs. On the other hand, since a lot of this information is still in Biomedical articles and sources, there is a need for a method to extract DDIs information. However, despite the development of many techniques, attaining good prediction accuracy is the main issue. This paper proposes a deep learning approach that: 1) uses the power of Relation BioBERT (R-BioBERT) to detect and classify the DDIs and 2) employs the Bidirectional Long-Short Term Memory (BLSTM) to further increase the prediction quality. Not only does this paper study whether the two drugs have an interaction or not, but it also studies specific types of interactions between drugs. The paper also provides that using BLSTM can significantly increase the F-scores compared to the baseline model on the famous SemEval 2013, TAC 2018, and TAC 2019 DDI Extraction datasets.
A two-compartment system for subfreezing temperatures preservation of large volumes of organic matter in an isochoric system
Authors: Năstase Gabriel , Botea Florin , Beșchea George-Andrei , Câmpean Ștefan-Ioan , Barcu Alexandru , Popescu Irinel , Rubinsky Boris , Șerban Alexandru 
Published: September 2022

ABSTRACTThis is a technology paper on the design of and test results from an 11-liter isochoric (constant volume) chamber, for the preservation of large, organs in a supercooled state. Details of the design are given, as well as a proof that the chamber is isochoric. Five repeats show that in this large chamber, ice nucleation of steam distilled water occurs at – 2 °C within less than 12 hours, in all the repeats. An examination of the experimental results suggests that the ice nucleation starts on the inner walls of the isochoric chamber. A new two compartment isochoric chamber was designed to reduces the probability of ice nucleation on the walls of the chamber. In the two-compartment system, the biological matter and the preservation fluid are introduced in a sealed low-density polyethylene bag, and placed in the center of the isochoric chamber, in such a way that the bag does not touch the walls. The space between the inner walls of the isochoric chamber and the outer walls of the bag are filled with a fluid with a composition that does not freeze at the storage temperature. Three repeat experiments with steam distilled water and with in vitro pig liver show that with this technique, the system remained supercooled, without any ice nucleation for the duration of the experiments. Experiments were voluntary terminated at 48 hours of supercooling. This new technology may hold promise for long term preservation of large biological organs in a supercooled state, without the use of any chemical additives.
Lifespan differences in visual short-term memory load-modulated functional connectivity
Authors: Lugtmeijer Selma , Geerligs Linda , Tsvetanov Kamen A. , Mitchell Daniel J. , Cam-CAN  , Campbell Karen L. 
Published: September 2022

AbstractWorking memory is critical to higher-order executive processes and declines throughout the adult lifespan. However, our understanding of the neural mechanisms underlying this decline is limited. Recent work suggests that functional connectivity between frontal control and posterior visual regions may be critical, but examinations of age differences therein have been limited to a small set of brain regions and extreme group designs (i.e., comparing young and older adults). In this study, we build on previous research by using a lifespan cohort and a whole-brain approach to investigate working memory load-modulated functional connectivity in relation to age and performance. The article reports on analysis of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data. Participants from a population-based lifespan cohort (N=111, age 23-86) performed a visual short-term memory task during functional magnetic resonance imaging. Visual short-term memory was measured with a delayed recall task for visual motion with three different loads. Whole-brain load-modulated connectivity was estimated using psychophysiological interactions in a hundred regions of interest, sorted into seven networks (Schaefer et al., 2018, Yeo et al., 2011). Results showed that load-modulated functional connectivity was strongest within the dorsal attention network followed by the visual network during encoding and maintenance. With increasing age, load-modulated functional connectivity strength decreased throughout the cortex. Within the dorsal attention network, increased load-modulated connectivity strength was related to better task performance in an age-invariant way. Our results demonstrate the widespread negative impact of age on the modulation of functional connectivity by working memory load. Older adults might already be close to ceiling in terms of their resources at the lowest load and therefore less able to further increase connectivity with increasing task demands.HighlightsWe examine visual short-term memory load-related functional connectivityAnd how age and performance affect modulation of connectivity by memory loadModulation of connectivity is strongest in dorsal attention and visual networksLoad-modulated connectivity strength decreases with increasing ageLoad-modulated connectivity in the dorsal attention network relates to performance
Gain-of-function dynamin-2 mutations linked to centronuclear myopathy impair Ca2+-induced exocytosis in human myoblasts
Authors: Bayonés Lucas , Guerra-Fernández María José , Hinostroza Fernando , Báez-Matus Ximena , Vásquez-Navarrete Jacqueline , Gallo Luciana I. , Parra Sergio , Martínez Agustín D. , González-Jamett Arlek , Marengo Fernando D. , Cárdenas Ana M. 
Published: September 2022

AbstractGain-of-function mutations of dynamin-2, a mechano-GTPase that remodels membrane and actin filaments, cause centronuclear myopathy (CNM), a congenital disease that mainly affects skeletal muscle tissue. Among these mutations, the variants p.A618T and p.S619L lead to gain of function and cause a severe neonatal phenotype. By using total internal reflection fluorescence microscopy (TIRFM) in immortalized human myoblasts expressing the pH-sensitive fluorescent protein (pHluorin) fused to the insulin-responsive aminopeptidase IRAP as reporter of the GLUT4 vesicle-trafficking, we measured single pHluorin signals to investigate how p.A618T and p.S619L mutations influence exocytosis. We show here that both dynamin-2 mutations significantly reduced the number and durations of pHluorin signals induced by 10 μM ionomycin, indicating that in addition to impair exocytosis, they also affect the fusion pore dynamics. These mutations also disrupt the formation of actin filaments, a process that reportedly favors exocytosis. This altered exocytosis might importantly disturb the plasmalemma expression of functional proteins such as the glucose transporter GLUT4 in skeletal muscle cells, impacting the physiology of the skeletal muscle tissue and contributing to the CNM disease.
Associations of Minor Histocompatibility Antigens with Clinical Outcomes Following Allogeneic Hematopoietic Cell Transplantation
Authors: Jadi Othmane , Tang Hancong , Olsen Kelly , Vensko Steven , Zhu Qianqian , Wang Yiwen , Haiman Christopher A , Pooler Loreall , Sheng Xin , Brock Guy , Webb Amy , Pasquini Marcelo C. , McCarthy Philip L , Spellman Stephen R. , Hahn Theresa , Vincent Benjamin , Armistead Paul , Sucheston-Campbell Lara E. 
Published: September 2022

ABSTRACTThe role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia (GvL) and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes using multi-variate survival models corrected for multiple testing. Cox proportional hazard results showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (HR=1.39, 95%CI 1.01, 1.77, P=0.046). Competing risk analyses identified the class I mHAs DLRCKYISL (gene GSTP), WEHGPTSLL (CRISPLD2) and STSPTTNVL (SERPINF2) were associated with increased GVHD death (HR=2.84, 95%CI 1.52, 5.31, P=0.01), decreased leukemia-free survival (LFS) (HR=1.94,95%CI 1.27, 2.95, P=0.044), and increased disease-related mortality (DRM) (HR=2.32, 95%CI 1.5, 3.6, P=0.008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR=3.05, 95%CI 1.75, 5.31, P=0.02). WEHGPTSLL and STSPTTNVL were present in conjunction within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to risk of mortality in an additive manner. Our study reports the first large scale investigation of the associations of predicted class I and class II mHA peptides with clinical outcomes following alloHCT.Graphical Abstract
Membrane Retrieval after Immediately Releasable Pool (IRP) Exocytosis is produced by Dynamin-Dependent and Dynamin-Independent Mechanisms
Authors: Bayonés Lucas , Montenegro Mauricio , Moya-Díaz José , Alfonso-Bueno Samuel , Gallo Luciana I. , Marengo Fernando D. 
Published: September 2022

AbstractThe importance of the immediately releasable pool (IRP) of vesicles was proposed to reside in the maintenance of chromaffin cell secretion during the firing of action potentials at basal physiological frequencies. To accomplish this duty, IRP should be replenished as a function of time. We have previously reported that an action potential-like stimulus (APls) triggers the release of ∽50% IRP, followed by a fast dynamin-dependent endocytosis and an associated rapid replenishment process. In this work we investigated the endocytosis and IRP replenishment produced after the exocytosis of variable IRP fractions in mice primary chromaffin cell cultures. Exocytosis and endocytosis were estimated by membrane capacitance measurements obtained in patch-clamped cells. In addition to the dynamin-dependent fast endocytosis activated after the application of APls or 5 ms squared depolarizations, we found that depolarizations lasting 25-50 ms, which release >80% of IRP, are related with a fast dynamin-independent, Ca2+- and protein kinase C (PKC)-dependent endocytosis (time constant < 1 s). PKC inhibitors, such as staurosporine, bisindolylmaleimide XI and prolonged treatments with high concentrations of phorbol esters, reduced and decelerated this endocytosis. Additionally, we found that the inhibition of PKC also abolished a slow component of replenishment (time constant ∽8 s) observed after total IRP exocytosis. Therefore, our results suggest that PKC contributes to the coordination of membrane retrieval and vesicle replenishment mechanisms that occur after the complete exocytosis of IRP.
Artificial Intelligence based Liver Portal Tract Region Identification and Quantification with Transplant Biopsy Whole-Slide Images
Authors: Yu Hanyi , Sharifai Nima , Jiang Kun , Wang Fusheng , Teodoro George , Farris Alton B. , Kong Jun 
Published: September 2022

AbstractLiver fibrosis staging is clinically important for liver disease progression prediction. As the portal tract fibrotic quantity and size in a liver biopsy correlate with the fibrosis stage, an accurate analysis of portal tract regions is clinically critical. Manual annotations of portal tract regions, however, are time-consuming and subject to large inter- and intra-observer variability. To address such a challenge, we develop a Multiple Up-sampling and Spatial Attention guided UNet model (MUSA-UNet) to segment liver portal tract regions in whole-slide images of liver tissue slides. To enhance the segmentation performance, we propose to use depth-wise separable convolution, the spatial attention mechanism, the residual connection, and multiple up-sampling paths in the developed model. This study includes 53 histopathology whole slide images from patients who received liver transplantation. In total, 6,012 patches derived from 30 images are used for our deep learning model training and validation. The remaining 23 whole slide images are utilized for the model testing. The average liver portal tract segmentation performance of the developed MUSA-UNet is 0.94 (Precision), 0.85 (Recall), 0.89 (F1 Score), 0.89 (Accuracy), 0.80 (Jaccard Index), and 0.91 (Fowlkes–Mallows Index), respectively. The clinical Scheuer fibrosis stage presents a strong correlation with the resulting average portal tract fibrotic area (R=0.681, p<0.001) and portal tract percentage (R=0.335, p=0.02) computed from the MUSA-UNet segmentation results. In conclusion, our developed deep learning model MUSA-UNet can accurately segment portal tract regions from whole-slide images of liver tissue biopsies, presenting its promising potential to assist liver disease diagnosis in a computational manner.
Biologic that disrupts PDE11A4 homodimerization in hippocampus CA1 reverses age-related proteinopathies in PDE11A4 and cognitive decline of social memories
Authors: Pilarzyk Katy , Capell Will , Rips-Goodwin Audrey , Porcher Latarsha , Kelly Michy P. 
Published: September 2022

ABSTRACTAge-related proteinopathies in phosphodiesterase 11A (PDE11A), an enzyme that degrades 3’,5’-cAMP/cGMP and is enriched in the ventral hippocampal formation (VHIPP), drive age-related cognitive decline (ARCD) of social memories. In the VHIPP, age-related increases in PDE11A4 occur specifically within the membrane compartment and ectopically accumulate in filamentous structures termed ghost axons. Previousin vitrostudies show that disrupting PDE11 homodimerization by expressing an isolated PDE11A-GAFB domain, which acts as a “negative sink” for monomers, selectively degrades membrane-associated PDE11A4 and prevents the punctate accumulation of PDE11A4. Therefore, we determined if disrupting PDE11A4 homodimerizationin vivovia the expression of an isolated PDE11A4-GAFB domain would be sufficient to reverse 1) age-related accumulations of PDE11A4 in VHIPP ghost axons and 2) ARCD of social memories. Indeed,in vivolentiviral expression of the isolated PDE11A4-GAFB domain in hippocampal CA1 reversed the age-related accumulation of PDE11A4 in ghost axons, reversed ACRD of social transmission of food preference memory (STFP), and improved remote long-term memory for social odor recognition (SOR) without affecting memory for non-social odor recognition.In vitrostudies suggest that disrupting homodimerization of PDE11A4 does not directly alter the catalytic activity of the enzyme but may reverse age-related decreases in cGMP by dispersing the accumulation of the enzyme independently of other intramolecular mechanisms previously established to disperse PDE11A4 (e.g., phosphorylation of PDE11A4 at serine 162). Altogether, these data suggest that a biologic designed to disrupt PDE11A4 homodimerization may serve to ameliorate age-related deficits in hippocampal cyclic nucleotide signaling and subsequent ARCD of remote social memory.
In Totoimaging of early Enteric Nervous System Development reveals that gut colonization is tied to proliferation downstream of Ret
Authors: Baker Phillip A. , Ibarra-García-Padilla Rodrigo , Venkatesh Akshaya , Singleton Eileen W. , Uribe Rosa. A. 
Published: September 2022

AbstractThe enteric nervous system (ENS) is a vast intrinsic network of neurons and glia within the gastrointestinal tract and is largely derived from enteric neural crest cells (ENCCs) that emigrate into the gut during vertebrate embryonic development. Study of ENCC migration dynamics and their genetic regulators provides great insights into fundamentals of collective cell migration and nervous system formation, and are a pertinent subject for study due to their relevance to the human congenital disease, Hirschsprung disease (HSCR). For the first time, we performedin totogut imaging and single-cell generation tracing of ENCC migration in WT and a novelretheterozygous background zebrafish (retwmr1/+) to gain insight into ENCC dynamicsin vivo. We observed thatretwmr1/+zebrafish produced fewer ENCCs while localized along the gut, which failed to reach the hindgut, resulting in HSCR-like phenotypes. Specifically, we observed a proliferation dependent migration mechanism, where cell divisions were associated with inter-cell distances and migration speed. Lastly, we detected a premature neuronal differentiation gene expression signature inretwmr1/+ENCCs, collectively suggesting that Ret signaling may function to regulate maintenance of a stem-state in ENCCs.
openNAU: An open-source platform for normalizing, analyzing, and visualizing untargeted metabolomics data
Authors: Sun Qingrong , Xu Qingqing , Wang Majie , Wang Yongcheng , Zhang Dandan , Lai Maode 
Published: September 2022

AbstractMotivationAs an important part of metabolomics analysis, untargeted metabolomics has become a powerful tool in the study of tumor mechanisms and the discovery of metabolic markers with high-throughput spectrometric data which also brings great challenges to data analysis from the extraction of raw data to the identification of differential metabolites. To date, a large number of analytical tools and processes have been developed and constructed to serve untargeted metabolomics research. The different selection of analytical tools and parameter settings lead to varied results of untargeted metabolomics data. Our goal is to establish an easily operated platform and obtain a repeatable analysis result.ResultsWe used the R language basic environment to construct the preprocessing system of the original data and the LAMP (Linux + Apache + MySQL + PHP) architecture to build a cloud mass spectrum data analysis system. An open-source analysis software for untargeted metabolomics data (openNAU) was constructed. It includes the extraction of raw mass data and quality control for the identification of differential metabolic ion peaks. A reference metabolomics database based on public databases was also constructed. Finally, a complete analysis system platform for untargeted metabolomics was established. This platform provides a complete template interface for the addition and updating of the analysis process, so we can finish complex analyses of untargeted metabolomics with simple human-computer interactions.Availability and ImplementationThe source code can be downloaded from https://github.com/zjuRong/openNAU.Contactsunqingrong@zju.edu.cn
OPUS-Fold3: a gradient-based protein all-atom folding and docking framework on TensorFlow
Authors: Xu Gang , Luo Zhenwei , Zhou Ruhong , Wang Qinghua , Ma Jianpeng 
Published: September 2022

AbstractFor refining and designing protein structures, it is essential to have an efficient protein folding and docking framework that generates a protein 3D structure based on given constraints. In this study, we introduce OPUS-Fold3 as a gradient-based, all-atom protein folding and docking framework, which accurately generates 3D protein structures in compliance with specified constraints, such as a potential function as long as it can be expressed as a function of positions of heavy atoms. Our tests show that, for example, OPUS-Fold3 achieves performance comparable to pyRosetta in backbone folding, and significantly better in side-chain modeling. Developed using Python and TensorFlow 2.4, OPUS-Fold3 is user-friendly for any source-code level modifications and can be seamlessly combined with other deep learning models, thus facilitating collaboration between the biology and AI communities. The source code of OPUS-Fold3 can be downloaded fromhttp://github.com/OPUS-MaLab/opus_fold3. It is freely available for academic usage.