bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilizing Q-Learning to Generate 3D Vascular Networks for Bioprinting Bone
Authors: Sedigh Ashkan , Tulipan Jacob E. , Rivlin Michael R. , Tomlinson Ryan E. 
Published: October 2020

ABSTRACTBioprinting is an emerging tissue engineering method used to generate cell-laden scaffolds with high spatial resolution. Bioprinted vascularized bone grafts are a potential application of this technology that would meet a critical clinical need, since current approaches to volumetric bone repair have significant limitations. However, generation of vascular networks suitable for bioprinting is challenging. Here, we propose a novel Q-learning approach to quickly generate 3D vascular networks within patient-specific bone geometry that are optimized for bioprinting. First, the inlet and outlet locations are specified and the scenario is modeled using a grid world for initial agent training. Next, the path planned in the grid world environment is converted to a Bezier curve, which is then used to generate the final 3D vascularized bone model. The vessels generated using this procedure have minimal tortuosity, which increases the likelihood of successful bioprinting. Furthermore, the ability to specify inlet and outlet position is necessary for both surgical feasibility as well as generation of more complex vascular networks. In total, this study demonstrates the reliability of our reinforcement learning method for automated generation of 3D vascular networks within patient-specific geometry that can be used for bioprinting vascularized bone grafts.
Protein diffusion on membrane domes, tubes and pearling structures
Authors: Molina R. Rojas , Liese S. , Carlson A. 
Published: October 2020

AbstractDiffusion is a fundamental mechanism for protein distribution in cell membranes. These membranes often exhibit complex shapes, which range from shallow domes to elongated tubular or pearl-like structures. Shape complexity of the membrane influences the diffusive spreading of proteins and molecules. Despite the importance membrane geometry plays in these diffusive processes, it is challenging to establish the dependence between diffusion and membrane morphology. We solve the diffusion equation numerically on various curved shapes representative for experimentally observed membrane shapes. Our results show that membrane necks become diffusion barriers. We determine the diffusive half time,i.e., the time that is required to reduce the amount of proteins in the budded region by one half and find a quadratic relation between the diffusive half time and the averaged mean curvature of the membrane shape. Our findings thus help to estimate the characteristic diffusive time scale based on the simple measure for membrane morphology.Significance statementDiffusion is an integral process for distributing proteins throughout biological membranes. These membranes can have complex shapes and structures, often featuring elongated shapes such as tubes and like a necklace of pearls. The diffusion process on these shapes is significantly different from the well studied planar substrate. We use numerical simulations to understand how the characteristic diffusion time is a function of membrane shape, where we find the diffusion of proteins on strongly curved shapes is significantly slower than on planar membranes. Our results provide a simple relationship to estimate the characteristic diffusion time of proteins on membranes based on its mean and Gaussian curvature.
Cyanobacterial NOS expression improves nitrogen use efficiency, nitrogen-deficiency tolerance and yield in Arabidopsis
Authors: Fiorella Del Castello , Noelia Foresi , Andrés Nejamkin , Christian Lindermayr , Franz Buegger , Lorenzo Lamattina , Natalia Correa-Aragunde 
Published: October 2020

ABSTRACTDeveloping strategies to improve nitrogen (N) use efficiency (NUE) in plants is a challenge to reduce environmental problems linked to over-fertilization. The nitric oxide synthase (NOS) enzyme from the cyanobacteriaSynechococcusPCC 7335 (SyNOS) has been recently identified and characterized. SyNOS catalyzes the conversion of arginine to citrulline and nitric oxide (NO), and then 70% of the produced NO is rapidly oxidized to nitrate by an unusual globin domain in its 5'-terminus. In this study, we assessed whether SyNOS expression in plants affects N metabolism improving NUE and yield. Our results showed that transgenic Arabidopsis plants had higher primary shoot length and shoot branching when grown in N-deficient conditions and higher seed production in N-sufficient and -deficient conditions. Moreover, transgenic plants showed significantly increased NUE in both N conditions. No differences were observed in N uptake for SyNOS lines. However, SyNOS lines presented an increase in N assimilation/remobilization under low N conditions. In addition, SyNOS lines had greater N-deficiency tolerance compared to wt plants. Our results support that SyNOS expression generates a positive effect on N metabolism and seed production in Arabidopsis, and it might be envisaged as a strategy to improve productivity in crops under adverse N environments.
Silencing of oncogenic KRAS by mutant-selective small interfering RNA
Authors: Papke Bjoern , Azam Salma H. , Feng Anne Y. , Van Swearingen Amanda E. D. , Gutierrez-Ford Christina , Pallan Pradeep S. , Egli Martin , Cox Adrienne D. , Der Channing J. , Pecot Chad V. 
Published: October 2020

AbstractOncogenic mutations in theKRASgene are well-established drivers of cancer. While the recently developed KRASG12Cinhibitors offer a targeted KRAS therapy and have shown success in the clinic, KRASG12Crepresents only 11% of all KRAS mutations. Current therapeutic approaches for all other KRAS mutations are both indirect and non-mutant-selective, largely focusing on inhibition of downstream KRAS effectors such as MAP kinases. Inhibition of KRAS downstream signaling results in a system-wide down-modulation of the respective targets, raising concerns about systemic cell toxicity. Here, we describe a custom short interfering RNA (siRNA) oligonucleotide (EFTX-D1) designed to preferentially bind mRNA of the most commonly occurring KRAS missense mutations in codons 12 and 13. We determined that EFTX-D1 preferentially reduced the mutant KRAS sequence versus wild-type at the levels of both transcription and translation, and reversed oncogenic KRAS-induced morphologic and growth transformation. Furthermore, EFTX-D1 significantly impaired the proliferation of several KRAS mutant cancer cell lines in 2-D as well as 3-D assays. Taken together, our data indicate a novel use of RNA interference (RNAi) to target oncogenic KRAS-driven cancers specifically.
Discovery of novel putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in AML cells
Authors: Lenoir W. Frank , Morgado Micaela , DeWeirdt Peter C , McLaughlin Megan , Griffith Audrey L , Sangree Annabel K , Feeley Marissa N , Anvar Nazanin Esmaeili , Kim Eiru , Bertolet Lori L , Colic Medina , Dede Merve , Doench John G , Hart Traver 
Published: October 2020

AbstractCRISPR knockout screens in hundreds of cancer cell lines have revealed a substantial number of context-specific essential genes that, when associated with a biomarker such as lineage or oncogenic mutation, offer candidate tumor-specific vulnerabilities for targeted therapies or novel drug development. Data-driven analysis of knockout fitness screens also yields many other functionally coherent modules that show emergent essentiality or, in rarer cases, the opposite phenotype of faster proliferation. We develop a systematic approach to classify these suppressors of proliferation, which are highly enriched for tumor suppressor genes, and define a network of 145 genes in 22 discrete modules. One surprising module contains several elements of the glycerolipid biosynthesis pathway and operates exclusively in a subset of AML lines, which we call Fatty Acid Synthesis/Tumor Suppressor (FASTS) cells. The proliferation suppressor activity of genes involved in the synthesis of saturated fatty acids, coupled with a more severe fitness phenotype for the desaturation pathway, suggests that these cells operate at the limit of their carrying capacity for saturated fatty acids, which we confirmed biochemically. Overexpression of genes in this module is associated with a survival advantage in an age-matched cohort of AML patients, suggesting the gene cluster driving anin vitrophenotype may be associated with a novel, clinically relevant subtype.
Social isolation impairs the prefrontal-nucleus accumbens circuit subserving social recognition in mice
Authors: Park Gaeun , Ryu Changhyeon , Kim Soobin , Lee Yong-Seok , Kim Sang Jeong 
Published: October 2020

AbstractThe medial prefrontal cortex (mPFC) plays important roles in social behaviors, but it is not clear how early social experiences affect the mPFC and its subcortical circuit. We report that mice singly housed for 8 weeks immediately after weaning (SH mice) show a deficit in social recognition, even after 4 weeks of re-socialization. In SH mice, prefrontal infralimbic (IL) neurons projecting to the shell region of nucleus accumbens (NAcSh) showed decreased excitability compared to normally group housed (GH) mice. Furthermore, NAcSh-projecting IL neurons were activated when the mice encountered a familiar conspecific, which was not shown in SH mice. Chemogenetic inhibition of NAcSh-projecting IL neurons in normal mice selectively impaired social recognition without affecting social interaction, whereas activation of these neurons reversed social recognition deficit in SH mice. Therefore, mPFC IL-NAcSh projection is a novel brain circuit affected by early social experience; its activation is required for the social recognition.
Cytonemes with complex geometries and composition extend into invaginations of target cells
Authors: Wood Brent M. , Baena Valentina , Huang Hai , Terasaki Mark , Kornberg Thomas B. 
Published: October 2020

AbstractCytonemes are specialized filopodia that mediate paracrine signaling in Drosophila and other animals. Studies using fluorescence confocal microscopy (CM) established their general paths, cell targets, and essential roles in signaling. To investigate details unresolvable by CM, we used high pressure freezing and electron microscopy to visualize cytoneme structures, paths, contents, and contacts. We observed cytonemes previously seen by CM in the Drosophila wing imaginal disc system, including in disc, tracheal air sac primordium (ASP), and myoblast cytonemes, and identified cytonemes extending into invaginations of target cells and cytonemes connecting ASP cells and connecting myoblasts. Diameters of cytoneme shafts vary between wide (206 ± 51.8 nm) and thin (55.9 ±16.2 nm) segments at regular intervals. Actin, ribosomes, and membranous compartments are present throughout; rough endoplasmic reticulum and mitochondria are in wider proximal sections. These results reveal novel structural features of filopodia and provide a basis for understanding cytoneme cell biology and function.SummaryCytoneme signaling filopodia of Drosophila cells have regions defined by oscillating diameters, and contents that include ER, mitochondria and ribosomes, and form contacts along invaginations of target cell membranes.
Ultrasound-mediated mechanical forces selectively kill tumor cells
Authors: Tijore Ajay , Margadant Felix , Yao Mingxi , Hariharan Anushya , Chew Claire Alexandra Zhen , Powell Simon , Bonney Glenn Kunnath , Sheetz Michael 
Published: October 2020

AbstractUltrasound has been used to target tumors either through local heating or local nanobubbles but these methods damage surrounding normal cells in the target area. Recent studies show that tumor cells are susceptible to mechanical stresses and undergo calcium-dependent apoptosis under conditions that promote normal cell growth. Here we report that low-frequency ultrasound causes apoptosis of tumor cells by activating a calpain-dependent mitochondrial pathway that depends upon calcium entry through the mechanosensitive Piezo1 channels. This is a general property of all tumor cell lines tested so far irrespective of tissue origin. In animals, ultrasound irradiation causes tumor killing in the chick chorioallantoic membrane (CAM) model with relatively little damage to the chick embryos. Further, patient-derived pancreatic tumor organoids are killed by ultrasound treatment. Because low-level ultrasound causes apoptosis of tumor cells from many different tissues in different microenvironments, it may offer a safe non-invasive approach to augment tumor treatments.
Cancer methylomes characterization enabled by Rocker-meth
Authors: Benelli Matteo , Franceschini Gian Marco , Magi Alberto , Romagnoli Dario , Biagioni Chiara , Migliaccio Ilenia , Malorni Luca , Di Leo Angelo , Demichelis Francesca 
Published: October 2020

ABSTRACTDifferentially DNA methylated regions (DMRs) inform on the role of epigenetic changes in cancer. We present Rocker-meth, a computational method exploiting a heterogeneous hidden Markov model to detect DMRs across multiple experimental platforms. Its application to more than 6,000 methylation profiles across 14 tumor types provides a comprehensive catalog of tumor type-specific and shared DMRs, also amenable to single-cell DNA-methylation data. In depth integrative analysis including orthogonal omics shows the enhanced ability of Rocker-meth in recapitulating known associations, further uncovering the pan-cancer relationship between DNA hypermethylation and transcription factor deregulation depending on the baseline chromatin state.
E-cadherin is a structuring component of invadopodia in pancreatic cancer
Authors: Dobric Aurélie , Germain Sébastien , Silvy Françoise , Bonier Rénaté , Audebert Stéphane , Camoin Luc , Dusetti Nelson , Soubeyran Philippe , Iovanna Juan , Rigot Véronique , André Frédéric 
Published: October 2020

Graphical abstractBackgroundThe appearance of hybrid epithelial-mesenchymal (E/M) cells expressing E-cadherin is favourable for the establishment of pro-invasive function. However, the molecular mechanism and potential roles of E-cadherin in cancer cell invasion stay unexplored.MethodsWe used models of E/M hybrid cell lines, tissues sections and patient-derived xenografts from a multi-center clinical trial. E-cadherin involvement in invadopodia formation was assessed using a gelatin-FITC degradation assay. Mechanistic studies were performed by using proteomic analysis, siRNA strategy and proximity ligation assay.ResultsWe showed that E-cadherin is a critical component of invadopodia. This unexpected localization results from a synergistic trafficking of E-cadherin and MT1-MMP through Rab vesicle-dependent pathway. Modulation of E-cadherin expression or activation impacted invadopodia formation.Moreover, colocalization of E-cadherin and Actin in ―ring structures‖as precursor of invadopodia reveals that E-cadherin is required for invadopodia structuration.ConclusionE-cadherin, initially localized in the adherens junctions could be recycled to nascent invadopodia where it will interact with several components such as Arp2/3, Cortactin or MT1-MMP.The trans-adhesive properties of E-cadherin are therefore essential for structuringinvadopodia.
Origin and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages
Authors: Bain Calum C. , Gibson Douglas A. , Steers Nicholas , Boufea Katarina , Louwe Pieter A. , Docherty Catherine , Huici Victor , Gentek Rebecca , Magalhaes-Pinto Marlene , Bajenoff Marc , Benezech Cecile , Dockrell David , Saunders Philippa TK , Batada Nizar , Jenkins Stephen J 
Published: October 2020

AbstractMacrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the aetiology of pathologies including peritonitis, endometriosis and metastatic cancer thus understanding the factors that govern their behaviour is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover and function. We demonstrate that the sexually dimorphic replenishment of peritoneal macrophages from the bone marrow, which is high in males and very low in females, is driven by changes in the local microenvironment that arise upon sexual maturation. Population and single cell RNAseq revealed striking dimorphisms in gene expression between male and female peritoneal macrophages that was in part explained by differences in composition of these populations. By estimating the time of residency of different subsets within the cavity and assessing development of dimorphisms with age and in monocytopenic Ccr2−/− mice, we demonstrate that key sex-dependent features of peritoneal macrophages are a function of the differential rate of replenishment from the bone marrow while others are reliant on local microenvironment signals. Importantly, we demonstrate that the dimorphic turnover of peritoneal macrophages contributes to differences in the ability to protect against pneumococcal peritonitis between the sexes. These data highlight the importance of considering both sex and age in susceptibility to inflammatory and infectious disease.
Risks and issues: reactions of Vietnam and the experience to the world in the first wave of coronavirus pandemic
Authors: Dinh Hai Hong 
Published: October 2020

PurposeThis paper mentions the quick reactions of Vietnam to avoid explosive catastrophes before and during the first wave of the coronavirus pandemic. The work presented here has profound implications for future research of disaster response and preparation for future pandemics. In order to estimate the causal general effect of the pandemic, the authors have to do a quantitative survey at the end of the pandemic.Design/methodology/approachThe difference in damage caused by the pandemic between the great powers and Vietnam is the quick reaction. It plays a decisive role. In attempting to tackle emerging phenomena in the pandemic, this study is deliberately broad-based. Considerable attention is given to explaining each methodological choice. It centers on a core case of Vietnam. Using data from multiple methods, it adopts publish media and contemporary research during the pandemic as a way to draw out key themes within the core case.FindingsThe paper focuses on the lessons for the post-pandemic consist of the Buddhist conception (cause and effect) based on the quick reaction of the Vietnamese government and the adaptation of Vietnamese people. This is a key success for the future anti-pandemic process.Research limitations/implicationsThe paper is not exploring the pandemic within a larger scale of all nations to approach a general lesson for the world.Practical implicationsThe success of the first anti-pandemic phase does not guarantee that subsequent efforts will be successful. Respecting the “opponent” (the coronavirus) is the best way to avoid falling into the deadly subjective trap that some great powers have encountered.Social implicationsThis article highlights the rapid response of the Vietnamese before and during the coronavirus pandemic. From that, the article draws some lessons for the next similar disasters based on the cause and effect.Originality/valueA quick reaction is one of the most important ways to deal with any disaster. After a half year of the coronavirus pandemic spread, Vietnam has 408 infectious cases and no deaths within 96,208,984 people (The Ministry of Health of Vietnam on July 22nd, 2020). Vietnam achieved success with the least expensive price that should be finding in risks and issues in the future.
Loss of democracy in a cooperative kibbutz industry: ethical dilemmas – an Israeli case study
Authors: Moskovich Yaffa 
Published: October 2020

PurposeThis study aims to examine the changes in cooperative community and kibbutz industry that did not undergo privatization.Design/methodology/approachThis research was based on the case study method, combined with ethnographic interviews and document analysis.FindingsThe findings showed that the industry was highly successful economically, enabling the management to strengthen its authority without sharing information. The decision-making process, thus, became authoritarian, while the community's democratic mechanism was only nominal. This change was also accomplished by cultural transition from cooperative toward more capitalistic values. Management preferred to hire professional workers from the outside without any preference for kibbutz members, causing ethical dilemmas for certain elderly kibbutz members, who felt that the factory had abandoned socialistic ideas.Research limitations/implicationsThis research was conducted only on one kibbutz industry; further research is recommended.Practical implicationsManagement at cooperative organizations needs to realize that in a capitalistic environment, adaptation can cause the organization to lose its cooperative features. To prevent a cultural shift toward capitalistic values, managers need to be socialized and workers persuaded of the importance of cooperative values.Originality/valueThe study is innovative for its focus on loss of cooperative community and managerial style that has not been addressed sufficiently in the literature. This research sheds light on organizational conditions that can cause cooperative communities to lose their democratic and socialistic attributes.
Antecedents of employee alienation and its impact on individual work performance during post-merger integration (PMI)
Authors: Al Hosani Yousef , Jabeen Fauzia , Paul Justin , Stachowicz-Stanusch Agata 
Published: October 2020

PurposeThe objective of this study was to examine the significant factors leading to employee alienation in post-merger integration (PMI).Design/methodology/approachData were collected from 482 middle- and low-level employees in two organizations in the real estate and banking sectors in the United Arab Emirates. The analysis was carried out using structural equation modeling (SEM).FindingsOrganizational justice, employee commitment, organizational trust, perceived effectiveness of human resource (HR) initiatives and employee communication strategy played an important role in developing or mitigating a feeling of alienation among employees during PMI. Employee tenure in the organization affected individual work performance.Research limitations/implicationsThe study was limited to middle- and low-level employees and did not consider other organizational variables important in mergers. This study will help merger strategists to deliver appropriate HR practices during PMI, facilitating mitigation of uncertainties among employees and maximizing their trust and commitment.Originality/valueThe study results will help organizations understand employee trust, commitment and determinants in an emerging economy.