bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCN057, a Modulator of GSK3β, Induces KRAS G12D Mutant Pancreatic Cancer Cell Death
Authors: Singer Elizabeth M. , Chugh Rishi Man , Bhanja Payel , Gomez Adrian , Gao Lucy , Whitelegge Julian P. , McBride William H. , Saha Subhrajit , Norris Andrew J. 
Published: September 2021

AbstractEffective treatment for Pancreatic Cancer remains a major challenge due to its resistance to radiation/chemotherapy and poor drug permeability. Moreover, treatment induced normal tissue toxicity, mainly to the duodenum and gastrointestinal epithelium, is common and is a dose limiting event, while toxicity to the pancreas is relatively rare1–3. Gastrointestinal toxicity, however, often results in interruption, reduction or premature withdrawal of anti-cancer therapy which is a very significant factor impacting the overall survival of patients being treated. Therefore, development of a therapeutic strategy to selectively sensitize tumor tissue without inducing normal tissue toxicity is important. In this manuscript, we show that the novel small molecule BCN057 can modulate chemo-sensitivity of oncogenic RAS pancreatic cancer cells while conversely protecting normal intestinal epithelium from off target toxicity. In particular, BCN 057 protects Lgr5 positive intestinal stem cells, thereby preserving barrier function. Further, it is demonstrated that BCN057 inhibits GSK3β and thereby induces a pro-apoptotic phosphorylation pattern on c-Jun in KRAS G12D mutant pancreatic cancer cells (Panc-1) leading to the restoration of PTEN expression and consequent apoptosis. This appears to be a new mechanistic observation for the oncogenic RAS phenotype. Lastly, concurrent with its GSK3β inhibition, BCN057 is a small molecule inhibitor of PD-1 expression on human T-lymphocytes co-cultured with human pancreatic cancer cells. In summary, BCN057 can promote synthetic lethality specifically to malignant cells and therefore should be considered to improve the therapeutic ratio in pancreatic and epithelial cancer treatment in conjunction with chemotherapy and radiation.
Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment
Authors: Le Le Thi My , Thompson James Robert , Dang Phuoc Xuan , Bhandari Janarjan , Alam Amer 
Published: September 2021

AbstractThe peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to cellular fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive nervous system demyelination, and neurological impairments including the potentially fatal disease X-linked adrenoleukodystrophy (X-ALD). Molecular details underlying substrate recognition and transport by ABCD1 are poorly understood. Here we determined cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution that reveal key details of its transmembrane cavity and ATP dependent conformational transitions. We identify structural elements distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Together, our data support a transport mechanism where only the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane cavity while the acyl chains extend out into the surrounding membrane bilayer, help rationalize disease causing mutations, and provide a framework for ABCD1 targeted structure-based drug design.
Versatile, do-it-yourself, low-cost spinning disk confocal microscope
Authors: Halpern Aaron R. , Lee Min Yen , Howard Marco D. , Woodworth Marcus A. , Nicovich Philip R. , Vaughan Joshua C. 
Published: September 2021

AbstractConfocal microscopy is an invaluable tool for 3D imaging of biological specimens, however, accessibility is often limited to core facilities due to the high cost of the hardware. We describe an inexpensive do-it-yourself (DIY) spinning disk confocal microscope (SDCM) module based on a commercially fabricated chromium photomask that can be added on to a laser-illuminated epifluorescence microscope. The SDCM achieves strong performance across a wide wavelength range (~400-800 nm) as demonstrated through a series of biological imaging applications that include conventional microscopy (immunofluorescence, small-molecule stains, and fluorescence in situ hybridization) and super-resolution microscopy (single-molecule localization microscopy and expansion microscopy). This low-cost and simple DIY SDCM is well-documented and should help increase accessibility to confocal microscopy for researchers.
When development is constantly but weakly perturbed - Canalization by microRNAs
Authors: Lu GuangAn , Zhao Yixin , Chen Qingjian , Lin Pei , Tang Tian , Tang Zhixiong , Liufu Zhongqi , Wu Chung-I 
Published: September 2021

AbstractRecent studies have increasingly pointed to microRNAs (miRNAs) as the agent of GRN (gene regulatory network) stabilization as well as developmental canalization against constant but small environmental perturbations. Since the complete removal of miRNAs is lethal, we construct a Dicer-1 knockdown line (dcr-1KD) in Drosophila that modestly reduces all miRNAs. We hypothesize that flies with modest miRNA reductions will gradually deviate from the developmental norm, resulting in late-stage failures such as shortened longevity. In the optimal culture condition, the survival to adulthood is indeed normal in thedcr-1KD line but, importantly, adult longevity is reduced by ∼ 90%. When flies are stressed by high temperature,dcr-1KD induces lethality earlier in late pupation and, as the perturbations are shifted earlier, the affected stages are shifted correspondingly. We further show that the developmental failure is associated with GRN aberration in the larval stages even before phenotypic aberrations become observable. Hence, in late stages of development with deviations piling up, GRN would be increasingly in need of stabilization. In conclusion, miRNAs appear to be the genome’s solution to weak but constant environmental perturbations.
Robust de novo design of protein binding proteins from target structural information alone
Authors: Cao Longxing , Coventry Brian , Goreshnik Inna , Huang Buwei , Park Joon Sung , Jude Kevin M. , Marković Iva , Kadam Rameshwar U. , Verschueren Koen H.G. , Verstraete Kenneth , Walsh Scott Thomas Russell , Bennett Nathaniel , Phal Ashish , Yang Aerin , Kozodoy Lisa , DeWitt Michelle , Picton Lora , Miller Lauren , Strauch Eva-Maria , Halabiya Samer , Hammerson Bradley , Yang Wei , Benard Steffen , Stewart Lance , Wilson Ian A. , Ruohola-Baker Hannele , Schlessinger Joseph , Lee Sangwon , Savvides Savvas N. , Garcia K. Christopher , Baker David 
Published: September 2021

AbstractThe design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge. We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes and interactions, and then intensifies the search in the most promising regions. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of four of the binder-target complexes, and all four are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.
RNASeq analysis of a Pax3-expressing myoblast clone in-vitro and effect of culture surface stiffness on differentiation
Authors: Richardson Louise , Wang Dapeng , Hughes Ruth , Johnson Colin A , Peckham Michelle 
Published: September 2021

AbstractSkeletal muscle satellite cells cultured on soft surfaces (12kPa) show improved differentiation than cells cultured on stiff surfaces (approximately 100kPa). To better understand the reasons for this, we performed an RNA-Seq analysis for a single satellite cell clone (C1F) derived from the H2kb-tsA58 immortomouse, which differentiates into myotubes under tightly regulated conditions (withdrawal of γ-interferon, 37°C). As expected, the largest change in overall gene expression occurred at day 1, as cells switch from proliferation to differentiation. Surprisingly, further analysis showed that proliferating C1F cells express Pax3 and not Pax7, confirmed by immunostaining, yet their subsequent differentiation into myotubes is normal, and enhanced on softer surfaces, as evidenced by significantly higher expression levels of myogenic regulatory factors, sarcomeric genes, enhanced fusion and improved myofibrillogenesis. Levels of RNA encoding extracellular matrix structural constituents and related genes were consistently upregulated on hard surfaces, suggesting that a consequence of differentiating satellite cells on hard surfaces is that they attempt to manipulate their niche prior to differentiating. This comprehensive RNASeq dataset will be a useful resource for understanding Pax3 expressing cells.
Adipose deficiency and aberrant autophagy in a Drosophila model of MPS VII is corrected by pharmacological stimulators of mTOR
Authors: Basu Indrani , Bar Sudipta , Prasad Mohit , Datta Rupak 
Published: September 2021

AbstractMucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to β-glucuronidase (β-GUS) enzyme deficiency. Prominent clinical symptoms include hydrops fetalis, musculoskeletal deformities, neurodegeneration and hepatosplenomegaly leading to premature death in most cases. Apart from these, MPS VII is also characterized as adipose storage deficiency disorder although the underlying mechanism of this lean phenotype in the patients or β-GUS-deficient mice still remains a mystery. We addressed this issue using our recently developed Drosophila model of MPS VII (the CG2135-/- fly), which also exhibited a significant loss of adiposity. We report here that the lean phenotype of the CG2135-/- fly is due to fewer number of adipocytes, smaller lipid droplets and reduced adipogenesis. Our data further revealed that there is an abnormal accumulation of autophagosomes in the CG2135-/- larvae due to autophagosome-lysosome fusion defect. Decreased lysosome-mediated turnover also led to attenuated mTOR activity in the CG2135-/- flies. Interestingly, treatment of the CG2135-/- larvae with mTOR stimulators, 3BDO or glucose, led to the restoration of mTOR activity with simultaneous correction of the autophagy defect and adipose storage deficiency. Our finding thus established a hitherto unknown mechanistic link between autophagy dysfunction, mTOR downregulation and reduced adiposity in MPS VII.
ELeFHAnt: A supervised machine learning approach for label harmonization and annotation of single cell RNA-seq data
Authors: Thorner Konrad , Zorn Aaron M. , Chaturvedi Praneet 
Published: September 2021

AbstractAnnotation of single cells has become an important step in the single cell analysis framework. With advances in sequencing technology thousands to millions of cells can be processed to understand the intricacies of the biological system in question. Annotation through manual curation of markers based on a priori knowledge is cumbersome given this exponential growth. There are currently ~200 computational tools available to help researchers automatically annotate single cells using supervised/unsupervised machine learning, cell type markers, or tissue-based markers from bulk RNA-seq. But with the expansion of publicly available data there is also a need for a tool which can help integrate multiple references into a unified atlas and understand how annotations between datasets compare. Here we present ELeFHAnt: Ensemble learning for harmonization and annotation of single cells. ELeFHAnt is an easy-to-use R package that employs support vector machine and random forest algorithms together to perform three main functions: 1) CelltypeAnnotation 2) LabelHarmonization 3) DeduceRelationship. CelltypeAnnotation is a function to annotate cells in a query Seurat object using a reference Seurat object with annotated cell types. LabelHarmonization can be utilized to integrate multiple cell atlases (references) into a unified cellular atlas with harmonized cell types. Finally, DeduceRelationship is a function that compares cell types between two scRNA-seq datasets. ELeFHAnt can be accessed from GitHub at https://github.com/praneet1988/ELeFHAnt.
Infodemic surrounding COVID-19: Can LIS students recognize and categorize “problematic information” types on social media?
Authors: Yesmin Shamima , Ahmed S.M. Zabed 
Published: September 2021

Purpose
The purpose of this paper is to investigate Library and Information Science (LIS) students’ understanding of infodemic and related terminologies and their ability to categorize COVID-19-related problematic information types using examples from social media platforms.

Design/methodology/approach
The participants of this study were LIS students from a public-funded university located at the south coast of Bangladesh. An online survey was conducted which, in addition to demographic and study information, asked students to identify the correct definition of infodemic and related terminologies and to categorize the COVID-related problematic social media posts based on their inherent problem characteristics. The correct answer for each definition and task question was assigned a score of “1”, whereas the wrong answer was coded as “0”. The percentages of correctness score for total and each category of definition and task-specific questions were computed. The independent sample t-test and ANOVA were run to examine the differences in total and category-specific scores between student groups.

Findings
The findings revealed that students’ knowledge concerning the definition of infodemic and related terminologies and the categorization of COVID-19-related problematic social media posts was poor. There was no significant difference in correctness scores between student groups in terms of gender, age and study levels.

Originality/value
To the best of the authors’ knowledge, this is the first time an effort was made to understand LIS students’ recognition and classification of problematic information. The findings can assist LIS departments in revising and improving the existing information literacy curriculum for students.
Decoding the global trend of “vaccine tourism” through public sentiments and emotions: does it get a nod on Twitter?
Authors: Gulati Shruti 
Published: September 2021

Purpose
This paper aims to fill the major research gap prevalent in the tourism literature on the new form of tourism branching out from the COVID-19. While there are newspaper reports mentioning about the government’s reaction to vaccine tourism, there is no such study or report that tries to understand what the global masses feel about it; thus, a preliminary investigation of the social sentiment and emotion accruing around vaccine tourism on Twitter is carried out.

Design/methodology/approach
This exploratory study serves as a preliminary investigation of the social sentiment and emotion accruing around vaccine tourism on Twitter and tries to categorise them into eight basic emotions from Plutchik (1994) “wheel of emotions” as joy, disgust, fear, anger, anticipation, sadness, trust and surprise. The results are presented through data visualisation technique for analysis. The study makes use of R programming languages and the extensive packages offered on RStudio.

Findings
A total of 12,258 emotions were captured. It is evident that Vaccine Tourism has got maximum of positive sentiments (28.14%) which is almost double of the negative sentiment (14.05%). It is visible that the highest sentiment is “trust” (12.74%) and is followed by “fear” (8.97%). The least visible sentiment is “surprise” (4.32%). Polarity has been found for maximum tweets as positive (55.52%) which yet again surpasses negative polarity (33.7%), and neutral polarity is the least (10.67%).

Research limitations/implications
It can be said that people bear a positive emotion regarding vaccine tourism such as “trust” and “joy” which also denotes a positive sentiment score for testing polarity. But there are still concerns of high prices of the packages, fear-prevalent people to step out, and the uncertainty of right precautionary measures being taken still puts vaccine tourism under the radar of doubt with a fourth population having negative and neutral sentiments each. This is indicative with “fear” being the second highest emotion to the users. There are mixed emotions for vaccine tourism, but positive dominates the results.

Practical implications
The study attempts to see the global reaction on social media on vaccine tourism trend for giving food for thought to marketers. It can be said that Asians can be the target group.

Originality/value
To the best of the authors’ knowledge, there is no study that addresses the new trend of “Vaccine Tourism” or attempts to understand the emotions and sentiments of people globally.
Community work practices against children poverty in Southern Italy. Exploring experiences and perspectives in local welfare
Authors: Chiodo Emanuela 
Published: September 2021

PurposeThis paper has a dual purpose: on one side, it analyzes what types of solidarity and social relations are implemented as social support resources applied to actions aiming at the empowerment of children living in poverty. On the other, it investigates on the role of the community in the governance of local welfare practices and its ability to produce social innovations for municipal policies in favor of children and adolescents.Design/methodology/approachProximity, flexibility, generativity and territoriality are just some of the features that – in the framework of the scientific debate – characterize the social work in areas of social disadvantage. In the framework of the debate, this paper presents a qualitative research on the social ties and educational practices promoted and implemented by nonprofit organizations that attempt to counteract educational poverty and social exclusion of children and adolescents in the eastern peripheral neighborhoods of Naples, one of the poorest cities in the South of Italy.FindingsThe results of the analysis reveal a capacitating and generative role of the actions applied to social and educational practices for children and adolescents and their families in poor neighborhoods and peripheral areas; a role that is, however, also useful for community social policies targeting children and adolescents. Among local welfare policies enhancing community resources, such practices have indeed become an active resource of subsidiarity; they also ensure wider rights and empowerment for children and adolescents who live in poor communities and for their families as well.Originality/valueMore recent studies focusing on the role of social ties in deprived context and impoverishment processes, demonstrated that nonprofit organizations operate as crucial actors fostering inclusion and social cohesion, by means of “elective participation”; this guarantees access to protection and recognition resources that are an integral part of the social support these organizations provide in their areas of intervention. Despite the wide debate on the key role of the Third Sector in territorial welfare policies, further empirical studies on the role of these organizations in poor neighborhoods of the cities of the south of Italy are necessary. The value of this article is an attempt to provide to bridge this gap.
Shareholder risk-taking incentives in the presence of contingent capital
Authors: Fatouh Mahmoud , McCunn Ayowande A. 
Published: September 2021

Purpose
This paper aims to present a model of shareholders’ willingness to exert effort to reduce the likelihood of bank distress and the implications of the presence of contingent convertible (CoCo) bonds in the liabilities structure of a bank.

Design/methodology/approach
This study presents a basic model about the moral hazard surrounding shareholders willingness to exert effort that increases the likelihood of a bank’s success. This study uses a one-shot game and so do not capture the effects of repeated interactions.

Findings
Consistent with the existing literature, this study shows that the direction of the wealth transfer at the conversion of CoCo bonds determines their impact on shareholder risk-taking incentives. This study also finds that “anytime” CoCos (CoCo bonds trigger-able anytime at the discretion of managers) have a minor advantage over regular CoCo bonds, and that quality of capital requirements can reduce the risk-taking incentives of shareholders.

Practical implications
This study argues that shareholders can also use manager-specific CoCo bonds to reduce the riskiness of the bank activities. The issuance of such bonds can increase the resilience of individual banks and the whole banking system. Regulators can use restrictions on conversion rates and/or requirements on the quality of capital to address the impact of CoCo bonds issuance on risk-taking incentives.

Originality/value
To model the risk-taking incentives, authors generally modify the asset processes to introduce components that reflect asymmetric information between CoCo holders and shareholders and/or managers. This paper follows a simpler method similar to that of Holmström and Tirole (1998).
Active lane management for intelligent connected vehicles in weaving areas of urban expressway
Authors: Li Haijian , Zhang Junjie , Zhang Zihan , Huang Zhufei 
Published: September 2021

Purpose
This paper aims to use active fine lane management methods to solve the problem of congestion in a weaving area and provide theoretical and technical support for traffic control under the environment of intelligent connected vehicles (ICVs) in the future.

Design/methodology/approach
By analyzing the traffic capacities and traffic behaviors of domestic and foreign weaving areas and combining them with field investigation, the paper proposes the active and fine lane management methods for ICVs to optimal driving behavior in a weaving area. The VISSIM simulation of traffic flow vehicle driving behavior in weaving areas of urban expressways was performed using research data. The influence of lane-changing in advance on the weaving area was evaluated and a conflict avoidance area was established in the weaving area. The active fine lane management methods applied to a weaving area were verified for different scenarios.

Findings
The results of the study indicate that ICVs complete their lane changes before they reach a weaving area, their time in the weaving area does not exceed the specified time and the delay of vehicles that pass through the weaving area decreases.

Originality/value
Based on the vehicle group behavior, this paper conducts a simulation study on the active traffic management control-oriented to ICVs. The research results can optimize the management of lanes, improve the traffic capacity of a weaving area and mitigate traffic congestion on expressways.