bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting the HER2 status in esophageal cancer from tissue microarrays using convolutional neural networks
Authors: Pisula Juan I. , Datta Rabi R. , Börner Valdez Leandra , Avemarg Jan-Robert , Jung Jin-On , Plum Patrick , Löser Heike , Lohneis Philipp , Meuschke Monique , dos Santos Daniel Pinto , Gebauer Florian , Quaas Alexander , Bruns Christiane J. , Walch Axel , Lawonn Kai , Popp Felix C. , Bozek Katarzyna 
Published: May 2022

AbstractBackgroundFast and accurate diagnostics are key for personalized medicine. Particularly in cancer, precise diagnosis is a prerequisite for targeted therapies which can prolong lives. In this work we focus on the automatic identification of gastroesophageal adenocarcinoma (GEA) patients that qualify for a personalized therapy targeting epidermal growth factor receptor 2 (HER2). We present a deep learning method for scoring microscopy images of GEA for the presence of HER2 overexpression.MethodsOur method is based on convolutional neural networks (CNNs) trained on a rich dataset of 1,602 patient samples and tested on an independent set of 307 patient samples. We incorporated an attention mechanism in the CNN architecture to identify the tissue regions in these patient cases which the network has detected as important for the prediction outcome. Our solution allows for direct automated detection of HER2 in immunohistochemistry-stained tissue slides without the need for manual assessment and additional costly in situ hybridization (ISH) tests.ResultsWe show accuracy of 0.94, precision of 0.97, and recall of 0.95. Importantly, our approach offers accurate predictions in cases that pathologists cannot resolve, requiring additional ISH testing. We confirmed our findings in an independent dataset collected in a different clinical center.ConclusionsWe demonstrate that our approach not only automates an important diagnostic process for GEA patients but also paves the way for the discovery of new morphological features that were previously unknown for GEA pathology.
Modelling human and non-human animal network data in R using STRAND
Authors: Ross Cody T. , McElreath Richard , Redhead Daniel 
Published: May 2022

AbstractThere have been recent calls for wider application of generative modelling approaches in applied social network analysis. These calls have been motivated by the limitations of contemporary empirical frameworks, which have generally relied on post hoc permutation methods that do not actively account for interdependence in network data. At present, however, it remains difficult for typical end-users—e.g., field researchers—to apply generative network models, as there is a dearth of openly available software packages that make application of such methods as simple as other, permutation-based methods.Here, we outline the STRAND R package, which provides a suite of generative models for Bayesian analysis of human and non-human animal social network data that can be implemented using simple, base R syntax.To facilitate ease-of-use, we provide a tutorial demonstrating how STRAND can be used to model binary, count, or proportion data using stochastic blockmodels, social relations models, or a combination of the two modelling frameworks.
Borrelia burgdorferiengages mammalian type I interferon responses via the cGAS-STING pathway
Authors: Farris Lauren C. , Torres-Odio Sylvia , Adams L. Garry , West A. Phillip , Hyde Jenny A. 
Published: May 2022

ABSTRACTBorrelia burgdorferi, the etiologic agent of Lyme disease, is a spirochete that modulates numerous host pathways to cause a chronic, multi-system inflammatory disease in humans.B. burgdorferiinfection can lead to Lyme carditis, neurologic complications, and arthritis, due to the ability of specific borrelial strains to disseminate, invade, and drive inflammation.B. burgdorferielicits type I interferon (IFN-I) responses in mammalian cells and tissues that are associated with the development of severe arthritis or other Lyme-related complications. However, the innate immune sensors and signaling pathways controlling IFN-I induction remain unclear. In this study, we examined whether intracellular nucleic acid sensing is required for the induction of IFN-I toB. burgdorferi. Using fluorescence microscopy, we show thatB. burgdorferiassociates with mouse and human cells in culture and we document that internalized spirochetes co-localize with the pattern recognition receptor cyclic GMP-AMP synthase (cGAS). Moreover, we report that IFN-I responses in mouse macrophages and murine embryonic fibroblasts are significantly attenuated in the absence cGAS or its adaptor Stimulator of Interferon Genes (STING), which function to sense and respond to intracellular DNA. Longitudinal in vivo tracking of bioluminescentB. burgdorferirevealed similar dissemination kinetics and borrelial load in C57BL/6J wild-type, cGAS-deficient, or STING-deficient mice. However, infection-associated tibiotarsal joint pathology and inflammation were modestly reduced in cGAS-deficient compared to wild-type mice. Collectively, these results indicate that the cGAS-STING pathway is a critical mediator of mammalian IFN-I signaling and innate immune responses toB. burgdorferi.KEY POINTSB. burgdorferitriggers type I interferon responses in macrophages and fibroblastsCoiled spirochetes are observed in the cytosol and co-localize with cGAScGAS and STING mediateB. burgdorferi-induced type I interferon responses
An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility
Authors: Bosada Fernanda M. , van Duijvenboden Karel , Rivaud Mathilde R. , Uhm Jae-Sun , Verkerk Arie O. , Boukens Bastiaan J. , Christoffels Vincent M. 
Published: May 2022

AbstractHeart development and rhythm control are highly Tbx5 dosage-sensitive. TBX5 haploinsufficiency causes congenital conduction disorders, whereas increased expression levels of TBX5 in human heart samples has been associated with atrial fibrillation. We deleted the conserved mouse orthologues of two independent AF-associated genomic regions in the Tbx5 locus, one intronic (RE(int)-/-) and one downstream of Tbx5 (RE(down)-/-). In both lines we observed a modest (30%) increase of Tbx5 in the postnatal atria. To gain insight into the effects of slight dosage increase in vivo, we investigated the atrial transcriptional, epigenetic and electrophysiological properties of both lines. We observed induction of genes involved in development, ion transport and conduction, increased action potential duration and increased susceptibility to atrial arrhythmias. We identified an AF-associated variant in the human intronic regulatory region that increases transcriptional activity. Expression of the AF-associated transcription factor Prrx1 was induced in RE(int)-/- cardiomyocytes. We found that some of the transcriptional and functional changes in the atria caused by increased Tbx5 expression were normalized when reducing cardiac Prrx1 expression in RE(int)-/- mice, indicating an interaction between these two AF genes. We conclude that modest increases in expression of dose-dependent transcription factors, caused by common regulatory variants, significantly impact on the cardiac gene regulatory network and disease susceptibility.
KDM4A promotes the progression of neuroendocrine prostate cancer
Authors: Mak Celia Sze Ling , Zhu Ming , Liang Xin , Wang Feng , Yuan Fei , Hoang Anh G , Song Xingzhi , Shepherd Peter , Liang Derek , Suh Jessica , Pradhan Bijeta , Park Jiwon , Zhang Miao , Metzger Eric , Schüle Roland , Jain Abhinav K. , Karasik Ellen , Foster Barbara A. , Lee Min Gyu , Corn Paul , Logothetis Christopher J. , Aparicio Ana , Navone Nora , Troncoso Patricia , Tan Zhi , Zhang Jianhua , Lin Sue-Hwa , Wang Guocan 
Published: May 2022

ABSTRACTNeuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of prostate cancer (PCa) and lacks life-prolonging treatment. The incidence of NEPC is increased due to the widespread use of AR pathway inhibitors (ARPIs) in the treatment of non-metastatic CRPC and hormone-sensitive metastatic tumors. Here, we identified histone lysine demethylase KDM4A as a key player in NEPC progression and an effective therapeutic target. We found that KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Knockdown (KD) or knockout (KO) ofKDM4Ain NEPC cell lines suppressed cancer cell growthin vitroandin vivo. Mechanistically, we found that KDM4A promotes NEPC progression, in part, through direct transcriptional regulation ofMYC. We showed thatMYCis hyper-activated in human and mouse NEPC.KDM4AKD led to suppression of MYC signaling.MYCKD or inhibition profoundly suppressed NEPC cell proliferation. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growthin vitroandin vivo. Taken together, we demonstrated that KDM4A is an important regulator of NEPC progression and targeting KDM4A may potentially be an effective therapeutic strategy for NEPC.SignificanceNeuroendocrine prostate cancer (NEPC) is a highly aggressive prostate cancer subtype that is resistant to potent androgen receptor pathway inhibitors (ARPIs) and currently lacks effective therapeutic options. Histone lysine demethylase KDM4A is an important epigenetic regulator of gene expression in development and cancer. In this study, we show that KDM4A is highly expressed in NEPC and is required for NEPC proliferation, anchorage-independent growth, andin vivogrowth, which is in part mediated through the regulation of MYC expression. Importantly, we demonstrate that inhibition of KDM4A significantly impairs NEPC growth in preclinical models. Thus, our findings provide valuable insights into the molecular mechanisms underlying NEPC progression and offer a rationale for clinical trials with KDM4 inhibitor in NEPC patients.
Human Surfactant Protein D Facilitates SARS-CoV-2 Pseudotype Binding and Entry in DC-SIGN Expressing Cells, and Downregulates Spike protein Induced Inflammation
Authors: Beirag Nazar , Kumar Chandan , Madan Taruna , Shamji Mohamed H. , Bulla Roberta , Mitchell Daniel , Murugaiah Valarmathy , Neto Martin Mayora , Temperton Nigel , Idicula-Thomas Susan , Varghese Praveen M , Kishore Uday 
Published: May 2022

AbstractPattern recognition receptors are crucial for innate anti-viral immunity, including C-type lectin receptors. Two such examples are Lung surfactant protein D (SP-D) and Dendritic cell-specific intercellular adhesion molecules-3 grabbing non-integrin (DC-SIGN) which are soluble and membrane-bound C-type lectin receptors, respectively. SP-D has a crucial immune function in detecting and clearing pulmonary pathogens; DC-SIGN is involved in facilitating dendritic cell interaction as an antigen-presenting cell with naïve T cells to mount an anti-viral immune response. Both SP-D and DC-SIGN have been shown to interact with various viruses, including HIV-1, Influenza A virus and SARS-CoV-2. SARS-CoV-2 is an enveloped RNA virus that causes COVID-19. A recombinant fragment of human SP-D (rfhSP-D) comprising of α-helical neck region, carbohydrate recognition domain, and eight N-terminal Gly-X-Y repeats has been shown to bind SARS-CoV-2 Spike protein and inhibit SARS-CoV-2 replication by preventing viral entry in Vero cells and HEK293T cells expressing ACE2. DC-SIGN has also been shown to act as a cell surface receptor for SARS-CoV-2 independent of ACE2. Since rfhSP-D is known to interact with SARS-CoV-2 Spike protein and DC-SIGN, this study was aimed at investigating the potential of rfhSP-D in modulating SARS-CoV-2 infection. Coincubation of rfhSP-D with Spike protein improved the Spike Protein: DC-SIGN interaction. Molecular dynamic studies revealed that rfhSP-D stabilised the interaction between DC-SIGN and Spike protein. Cell binding analysis with DC-SIGN expressing HEK 293T and THP-1 cells and rfhSP-D treated SARS-CoV-2 Spike pseudotypes confirmed the increased binding. Furthermore, infection assays using the pseudotypes revealed their increased uptake by DC-SIGN expressing cells. The immunomodulatory effect of rfhSP-D on the DC-SIGN: Spike protein interaction on DC-SIGN expressing epithelial and macrophage-like cell lines was also assessed by measuring the mRNA expression of cytokines and chemokines. The RT-qPCR analysis showed that rfhSP-D treatment downregulated the mRNA expression levels of pro-inflammatory cytokines and chemokines such as TNF-α, IFN-α, IL-1β, IL-6, IL-8, and RANTES (as well as NF-κB) in DC-SIGN expressing cells challenged by Spike protein. Furthermore, rfhSP-D treatment was found to downregulate the mRNA levels of MHC class II in DC expressing THP-1 when compared to the untreated controls. We conclude that rfhSP-D helps stabilise the interaction of SARS-CoV-2 Spike protein and DC-SIGN and increases viral uptake by macrophages via DC-SIGN, suggesting an additional role for rfhSP-D in SARS-CoV-2 infection.
Sensorimotor decisions rely on the entanglement of evidence and motor accumulation processes
Authors: Verdonck Stijn , Loossens Tim , Philiastides Marios G. 
Published: May 2022

ABSTRACTMost contemporary theories of sensorimotor decision-making formalize the process leading up to a decision as a gradual accumulation of noisy stimulus information over time. The resulting evidence signal is thought to be continuously tested against an internal criterion representing the amount of evidence required to make the decision. In the currently prevailing view, the amount of accumulated evidence required for a decision is independent of the amount of sensory evidence presented by the stimulus, and once that level is reached, a choice is categorically communicated to the motor system to execute an overt response. Recent experimental research casts doubts on both of these assumptions. Using a Leaky Integrating Threshold model, we relax these assumptions specifying both an evidence accumulation and a motor accumulation process. The evidence accumulation signal feeds into a leaky motor accumulator, and it is on the level of the motor accumulation that the final decision criterion is set. This adaptation results in a markedly better description of choice-RT data, especially when it comes to urgency manipulations. We show that this alternative theory, which proposes that sensory evidence is doubly integrated before final evaluation, does not only describe the behavioral data better, but its neural correlates can also be readily derived from EEG signatures involving systems of both evidence and motor accumulation.
Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy
Authors: Bhatia Vipul , Kamat Nikhil V. , Pariva Tiffany E. , Wu Li-Ting , Tsao Annabelle , Sasaki Koichi , Wiest Lauren T. , Zhang Ailin , Rudoy Dmytro , Gulati Roman , Patel Radhika A. , Roudier Martine P. , True Lawrence D. , Haffner Michael C. , Nelson Peter S. , Priceman Saul J. , Ishihara Jun , Lee John K. 
Published: May 2022

SummarySix transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. We identified broad expression of STEAP1 (87% positive) in lethal metastatic prostate cancer, even more so than prostate-specific membrane antigen (PSMA, 60% positive) which is a clinically established diagnostic and therapeutic target. Second-generation chimeric antigen receptor (CAR) T cells were engineered for reactivity against STEAP1 and demonstrated substantial antitumor activity in metastatic human prostate cancer models in immunodeficient mice. Adoptive transfer of STEAP1 CAR T cells was associated with prolonged peripheral persistence and either disease eradication or substantial tumor growth inhibition with progressive disease demonstrating antigen loss. As STEAP1 CAR T cells were also highly active in antigen density conditions as low as ∼1,500 molecules/cell, we generated a human STEAP1 (hSTEAP1) knock-in (KI) mouse to evaluate the potential for on-target off-tumor toxicities. hSTEAP1-KI mice demonstrated a pattern of systemic hSTEAP1 expression akin to that observed in humans with the greatest expression found in the prostate gland. Mouse-in-mouse studies of STEAP1 CAR T cell therapy in immunocompetent hSTEAP1-KI mice engrafted with disseminated mouse prostate cancer showed preliminary safety without evidence of gross toxicity, cytokine storm, or architectural disruption and increased T cell infiltration at sites of systemic hSTEAP1 expression. Tumor responses and extension of survival were appreciated but antigen loss was identified in recurrent and progressive disease. In summary, we report the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, the generation of a STEAP1 CAR T cell therapy with promising potency and safety in preclinical studies of advanced prostate cancer, and antigen escape as a mechanism of resistance to effective STEAP1 CAR T cell therapy.
DoraHand: a novel dexterous hand with tactile sensing finger module
Authors: Wang Tao , Xie Zheng , Li Yuan , Zhang Yan , Zhang Hao , Kirchner Frank 
Published: May 2022

Purpose
This study aims to introduce the DoraHand, and the basic capability and performance have been verified in this paper. Besides the idea of sharing modular design and sensor design, the authors want to deliver an affordable and practical dexterous hand to the research area to contribute to the robotic manipulation area.

Design/methodology/approach
This paper introduced the DoraHand, a novel scalable and practical modular dexterous hand, which, adopting modular finger and palm design, fully actuated joint and tactile sensors, can improve the dexterity for robotic manipulation and lower the complexity of maintenance. A series of experiments are delivered to verify the performance of the hand and sensor module.

Findings
The parameters of the DoraHand are verified and suitable for the research of robotics manipulation area, the sensing capability has been tested with the static experiment and the slip prediction algorithm. And, the advantage of modular design and extensible interface have been verified by the real application.

Research limitations/implications
The authors continue improving the DoraHand and extend it to more different applications. The authors want to make the DoraHand as a basic research platform in the robotic manipulation area.

Practical implications
The DoraHand has been sent to more than ten different research institutes for different research applications. The authors continue working on this hand for better performance, easier usage and more affordability.

Social implications
This kind of dexterous hand can help researchers get rid of complex physical issues and pay more attention to the algorithm part; it can help to make robotic manipulation work more popular.

Originality/value
The key design in the DoraHand is the modular finger and sensing module. With the special design in mechanical and electrical parts, the authors build reliable hardware and can support the diversity requirement in the robotic manipulation area. The hand with tactile sensing capability can be used in more research and applications with its extensibility.
Controllers’ role ambiguity and work-related outcomes: exploring the influence of using performance measurement systems
Authors: Baraldi Stefano , Cifalinò Antonella , Lisi Irene Eleonora , Rizzo Marco Giovanni 
Published: May 2022

Purpose
Scholars have recognised that an inherent ambiguity underlines the roles of controllers, as they navigate multiple expectations of various organisational counterparts, including the control-type needs of corporate top managers and the decision-making needs of business managers. Role ambiguity (RA) is a form of psychological distress leading to dysfunctional work-related outcomes (WROs); therefore, the purpose of this study is to analyse whether the use of performance measurement systems (PMSs) by controllers influences their RA and, in turn, their job satisfaction and organisational commitment.

Design/methodology/approach
This study used data collected from a survey of 158 controllers to investigate whether controllers’ diagnostic and interactive uses of PMSs affect their RA and, indirectly, organisational commitment and job satisfaction.

Findings
The results show that an interactive use of PMSs by controllers decreases their RA, with positive effects on their commitment and satisfaction. On the contrary, PMS diagnostic use has no significant influence on either RA or WROs.

Originality/value
This study contributes to the body of literature on the psychological effects of PMSs related to RA, providing further empirical evidence to suggest that the adoption of PMSs may decrease individuals’ RA and, in turn, increase their WROs. In particular, this study enriches the existing literature with two elements of novelty: focus on controllers’ role instead of that of popular managers and focus on the behavioural effects of the diagnostic and interactive uses of PMSs.
Improving how we lead and manage in business marketing during and after a market crisis: the importance of perceived status, certainty, autonomy, relatedness and fairness
Authors: Hansen Jared M. , Hansen Joseph W. , Madsen Susan R. 
Published: May 2022

Purpose
The purpose of this research is to outline and investigate a set of five experience elements from neuroscience research labeled SCARF that could impact the quality of perception, evaluation and engagement of executives, managers and employees in business-to-business (B2B) companies during and after the COVID-19 pandemic. The proposed experience elements are perceived status, certainty, autonomy, relatedness and fairness. The authors demonstrate that all five elements are influential factors in B2B employees’ workplace environment during the COVID-19 pandemic. The authors outline several specific managerial implications and describe how companies can make better decisions related to several important market crisis decisions via a growth mindset built on the five experience elements. The authors also pay attention to implications to several B2B areas of research focus, including salesforce management and buying/supplier relationships.

Design/methodology/approach
The authors first examine existing B2B research to gauge if the five elements have been examined in B2B business contexts. They then analyze a combination of quantitative and qualitative survey data from 335 employees of different B2B companies to see if the five experience elements surface in discussion on how the pandemic has impacted their work experience and careers.

Findings
The authors find that several B2B research studies have looked at each of the individual components of the SCARF model, but none of them have yet included all five elements together in research or looked at them in the context of COVID-19. The results of analysis of surveys from employees in 335 B2B companies provide strong evidence that all five elements are influential factors in B2B employees workplace environment during the COVID-19 pandemic.

Originality/value
This study contributes to prior research focusing on how B2B companies can thrive during and after the COVID-19 pandemic. The research offers valuable practical insights and detailed examples of how to apply a set of five elements/experiences that industrial and business-to-business organization leaders should adopt in their conscious decision-making evaluation and in their communications with employees, suppliers and customers during and after the pandemic.