bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical modeling of surgery and steroid therapy for glioblastoma reveals changes in immunophenotype that are associated with tumor growth and outcome
Authors: Otvos Balint , Alban Tyler J. , Grabowski Mathew M. , Bayik Defne , Mulkearns-Hubert Erin E. , Radivoyevitch Tomas , Rabljenovic Anja , Johnson Sarah , Androjna Charlie , Mohammadi Alireza M. , Barnett Gene , Ahluwalia Manmeet S. , Vogelbaum Michael A. , Fecci Peter E. , Lathia Justin D. 
Published: August 2020

AbstractRecent advances in cancer immunotherapy have created a greater appreciation of potential anti-tumoral impacts by the immune system; however, individual patient responses have been variable. While immunotherapy is often given after standard-of-care treatment, the effects of initial interventions on the ability of the immune system to mount a response are not well understood and this may contribute to the variable response. For glioblastoma (GBM), initial disease management includes surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment. While new discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated to clinical trial design, the impact of surgical resection and steroids on the anti-tumor immune response has yet to be determined. Further, it is now accepted that steroid usage needs to be closely evaluated in the context of GBM and immunotherapy trials. To better model the clinical scenario in GBM, we developed a mouse model that integrates tumor resection and steroid treatment to understand how these therapies affect local and systemic immune responses. Using this model, we observed a systemic reduction in lymphocytes associated with surgical resection and identified a correlation between increased tumor volume and decreased circulating lymphocytes, a relationship that was obviated by dexamethasone treatment. Furthermore, we investigated the possibility of there being similar relationships in a cohort of patients with GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Lastly, correlating GBM patient data and outcomes demonstrated that peripherally circulating lymphocyte content varies with progression-free and overall survival, independent of tumor volume, steroid use, or tumor molecular profiles. These results highlight the systemic immunosuppressive effects that initial therapies can have on patients. Such effects should be considered when designing current and future immunotherapy clinical trials and underscore the importance of circulating lymphocytes as a possible correlate of GBM disease progression.
Learning an efficient hippocampal place map from entorhinal inputs using non-negative sparse coding
Authors: Lian Yanbo , Burkitt Anthony N. 
Published: August 2020

AbstractCells in the entorhinal cortex (EC) contain rich spatial information and projects strongly to the hippocampus where a cognitive map is supposedly created. These cells range from cells with structured spatial selectivity, such as grid cells in the medial entorhinal cortex (MEC) that are selective to an array of spatial locations that form a hexagonal grid, to weakly spatial cells, such as non-grid cells in the MEC and lateral entorhinal cortex (LEC) that contain spatial information but have no structured spatial selectivity. However, in a small environment, place cells in the hippocampus are generally selective to a single location of the environment, while granule cells in the dentate gyrus of the hippocampus have multiple discrete firing locations but lack spatial periodicity. Given the anatomical connection from the EC to the hippocampus, how the hippocampus retrieves information from upstream EC remains unclear. Here, we propose a unified learning model that can describe the spatial tuning properties of both hippocampal place cells and dentate gyrus granule cells based on non-negative sparse coding from EC input. Sparse coding plays an important role in many cortical areas and is proposed here to have a key role in the hippocampus. Our results show that the hexagonal patterns of MEC grid cells with various orientations, grid spacings and phases are necessary for the model to learn different place cells that efficiently tile the entire spatial environment. However, if there is a lack of diversity in any grid parameters or a lack of hippocampal cells in the network, this will lead to the emergence of hippocampal cells that have multiple firing locations. More surprisingly, the model can also learn hippocampal place cells even when weakly spatial cells, instead of grid cells, are used as the input to the hippocampus. This work suggests that sparse coding may be one of the underlying organising principles for the navigational system of the brain.Significance StatementThe brain can perform extremely complex spatial navigation tasks, but how it does this remains unclear. Here we show that the principle of sparse coding can be used to learn the hippocampal place map in a way that efficiently tiles the entire spatial environment using EC inputs, namely either grid cells or weakly spatial cells. This demonstrates that the hippocampus can retrieve spatial information from the entorhinal cortex using an efficient representation and that sparse coding may be one of the underlying principles of the navigational system of the brain.
Super-resolution imaging uncovers the nanoscopic segregation of polarity proteins in epithelia
Authors: Mangeol Pierre , Massey-Harroche Dominique , Richard Fabrice , Lenne Pierre-François , Le Bivic André 
Published: August 2020

AbstractEpithelial tissues acquire their integrity and function through the apico-basal polarization of their constituent cells. Proteins of the PAR and Crumbs complexes are pivotal to epithelial polarization, but the mechanistic understanding of polarization is challenging to reach, largely because numerous potential interactions between these proteins and others have been found, without clear hierarchy in importance. We identify the regionalized and segregated organization of members of the PAR and Crumbs complexes at epithelial apical junctions by imaging endogenous proteins using STED microscopy on Caco-2 cells, human and murine intestinal samples. Proteins organize in submicrometric clusters, with PAR3 overlapping with the tight junction (TJ) while PALS1-PATJ and aPKC-PAR6β form segregated clusters that are apical of the TJ and present in an alternated pattern related to actin organization. CRB3A is also apical of the TJ and weakly overlaps with other polarity proteins. This organization at the nanoscale level significantly simplifies our view on how polarity proteins could cooperate to drive and maintain cell polarity.
Foam cell induction activates AMPK but uncouples its regulation of autophagy and lysosomal homeostasis
Authors: LeBlond Nicholas D. , Nunes Julia R. C. , Smith Tyler K.T. , Robichaud Sabrina , Gadde Suresh , Cote Marceline , Kemp Bruce , Ouimet Mireille , Fullerton Morgan D. 
Published: August 2020

ABSTRACTThe dysregulation of macrophage lipid metabolism drives atherosclerosis. AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics and plays essential roles regulating macrophage lipid dynamics. Here, we investigated the consequences of atherogenic lipoprotein-induced foam cell formation on downstream immunometabolic signaling in primary mouse macrophages. A variety of atherogenic low-density lipoproteins (acetylated, oxidized and aggregated forms) activated AMPK signaling in a manner that was in part, due to CD36 and calcium-related signaling. In quiescent macrophages, basal AMPK signaling was crucial for maintaining markers of lysosomal homeostasis, as well as levels of key components in the lysosomal expression and regulation network. Moreover, AMPK activation resulted in targeted up-regulation of members of this network via transcription factor EB. However, in lipid-induced macrophage foam cells, neither basal AMPK signaling nor its activation affected lysosomal-associated programs. These results suggest that while the sum of AMPK signaling in cultured macrophages may be anti-atherogenic, atherosclerotic input dampens the regulatory capacity of AMPK signaling.
Optineurin promotes aggregation of mutant huntingtin and mutant ataxin-3, and reduces cytotoxicity of aggregates
Authors: Moharir Shivranjani C , Raghawan Akhouri Kishore , Swarup Ghanshyam 
Published: August 2020

AbstractOptineurin (OPTN), a cytoplasmic adaptor protein involved in cargo selective autophagy of bacteria, damaged mitochondria and mutant protein aggregates, is frequently seen in pathological structures containing protein aggregates, associated with several neurodegenerative diseases. However, the function of OPTN in these protein aggregates is not known. Here, we have explored the role of OPTN in mutant protein aggregation and in cytoprotection from toxicity of mutant proteins. Mutant huntingtin (mHtt) and mutant ataxin-3 (mAtax-3) showed reduced formation of aggregates inOptn−/−mouse embryonic fibroblasts as compared with wild type cells. Co-expression of OPTN enhanced aggregate formation by mHtt and mAtax-3 inOptn−/−cells. C-terminal domain of OPTN (412-577 amino acids) was necessary and sufficient to promote aggregate formation by these mutant proteins. The E478G mutant of OPTN, defective in ubiquitin-binding and autophagy, was also able to promote aggregation of mHtt and mAtax-3. OPTN and its C-terminal domain form a complex with the chaperone HSP70 known to promote mutant protein aggregation. Overexpression of mHtt or mAtax-3 induced more cell death inOptn−/−cells compared with wild type cells. Importantly, compared to wild type cells, Optn-deficient cells having mHtt or mAtax-3 aggregates showed higher level of cell death in neuronal (N2A) and non-neuronal cells. Our results show that OPTN promotes formation of mutant huntingtin and mutant ataxin-3 aggregates, and this function of OPTN might be mediated through interaction with HSP70 chaperones. Our results also show that OPTN reduces cytotoxicity caused by these mutant protein aggregates.Significance statementThe hallmark of several neurodegenerative diseases like amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease and Pick’s disease is the formation of pathological structures containing aggregated proteins, and OPTN is frequently observed in these structures. What role optineurin plays in those aggregates is not clear. Our results show that OPTN promotes aggregation of mutant huntingtin and mutant ataxin-3, and reduces cytotoxicity of aggregates in neuronal and non-neuronal cells. We suggest that OPTN provides cytoprotection in three different ways-by promoting mutant protein aggregation, by reducing cytotoxicity of aggregates and by autophagy-dependent clearance of aggregates reported earlier. These properties of OPTN provide a possible explanation for its association with various pathological structures containing protein aggregates seen in several neurodegenerative diseases.
The TPLATE subunit is essential for structural assembly of the endocytic TSET complex
Authors: Yperman Klaas , Wang Jie , Eeckhout Dominique , Winkler Joanna , Vu Lam Dai , Vandorpe Michael , Grones Peter , Mylle Evelien , Kraus Michael , Merceron Romain , Nolf Jonah , Mor Eliana , De Bruyn Pieter , Loris Remy , Potocký Martin , Savvides Savvas N. , De Rybel Bert , De Jaeger Geert , Van Damme Daniel , Pleskot Roman 
Published: August 2020

SummaryAll eukaryotic cells rely on endocytosis to regulate the plasma membrane proteome and lipidome. Most eukaryotic groups, with the exception of fungi and animals, have retained the evolutionary ancient TSET complex as a regulator of endocytosis. Despite the presence of similar building blocks in TSET, compared to other coatomer complexes, structural insight into this adaptor complex is lacking. Here, we elucidate the molecular architecture of the octameric plant TSET complex (TPLATE complex/TPC) using an integrative structural approach. This allowed us to describe a plant-specific connection between the TML subunit and the AtEH/Pan1 proteins and show a direct interaction between the complex and the plasma membrane without the need for any additional protein factors. Furthermore, we identify the appendage of TPLATE as crucial for complex assembly. Structural elucidation of this ancient adaptor complex vastly advances our functional as well as evolutionary insight into the process of endocytosis.Graphical abstract
Mesodermal FGF and BMP govern the sequential stages of zebrafish thyroid specification
Authors: Haerlingen Benoit , Opitz Robert , Vandernoot Isabelle , Molinaro Angelo , Shankar Meghna , Gillotay Pierre , Trubiroha Achim , Costagliola Sabine 
Published: August 2020

SummaryThyroid tissue is the site forde novosynthesis of thyroid hormones which are essential for vertebrate development and growth. Defects in embryonic thyroid morphogenesis are a predominant cause for congenital thyroid diseases but the molecular pathomechanisms are incompletely understood. The first molecularly recognizable step of thyroid development is the specification of thyroid precursors at a defined position in the anterior foregut endoderm. While recent studies identified FGF and BMP pathways as critical signaling factors for thyroid specification, the interplay between extrinsic signaling cues and thyroid transcription factor expression remained elusive. Here, we used zebrafish embryos to decipher the dynamics of thyroid transcription factor induction in relation to FGF and BMP signaling activities in pharyngeal endoderm. We first identified a previously unrecognized endodermal thyroid progenitor cell population expressing Pax2a but not Nkx2.4b. This cell population is characterized by enhanced FGF signaling but initially lacks detectable BMP signaling. A subpopulation of Pax2a-expressing progenitors differentiates subsequently into thyroid lineage-committed precursor cells co-expressing Pax2a and Nkx2.4b. We next combined pharmacological approaches with genetic models permitting inhibition or ectopic overactivation of signaling pathways to timely manipulate FGF and BMP activities. These experiments support a model where FGF signaling primarily regulates Pax2a expression whereas BMP signaling has dual functions in regulation of both Pax2a and Nkx2.4b expression. Collectively, our data allow us to formulate a refined model of thyroid cell specification from foregut endoderm.
Chondroitinase and antidepressants promote plasticity by releasing TRKB from dephosphorylating control of PTPσ in parvalbumin neurons
Authors: Lesnikova Angelina , Casarotto Plinio Cabrera , Fred Senem Merve , Voipio Mikko , Winkel Frederike , Steinzeig Anna , Antila Hanna , Umemori Juzoh , Biojone Caroline , Castrén Eero 
Published: August 2020

AbstractPerineuronal nets (PNNs) are an extracellular matrix structure rich in chondroitin sulphate proteoglycans (CSPGs) which preferentially encase parvalbumin-containing (PV+) interneurons. PNNs restrict cortical network plasticity but the molecular mechanisms involved are unclear. We found that reactivation of ocular dominance plasticity in the adult visual cortex induced by chondroitinase (chABC)-mediated PNN removal requires intact signaling by the neurotrophin receptor TRKB in PV+ neurons. Additionally, we demonstrate that chABC increases TRKB phosphorylation (pTRKB), while PNN component aggrecan attenuates BDNF-induced pTRKB in cortical neurons in culture. We further found that protein tyrosine phosphatase sigma (PTPσ, PTPRS), receptor for CSPGs, interacts with TRKB and restricts TRKB phosphorylation. PTPσ deletion increases phosphorylation of TRKBin vitroandin vivoin male and female mice, and juvenile-like plasticity is retained in the visual cortex of adult PTPσ deficient mice (PTPσ+/-). The antidepressant drug fluoxetine, which is known to promote TRKB phosphorylation and reopen critical period-like plasticity in the adult brain, disrupts the interaction between TRKB and PTPσ by binding to the transmembrane domain of TRKB. We propose that both chABC and fluoxetine reopen critical period-like plasticity in the adult visual cortex by promoting TRKB signaling in PV+ neurons through inhibition of TRKB dephosphorylation by the PTPσ-CSPG complex.Significance statementCritical period-like plasticity can be reactivated in the adult visual cortex through disruption of perineuronal nets (PNNs) by chondroitinase treatment, or by chronic antidepressant treatment. We now show that the effects of both chondroitinase and fluoxetine are mediated by the neurotrophin receptor TRKB in parvalbumin-containing (PV+) interneurons. We found that chondroitinase-induced visual cortical plasticity is dependent on TRKB in PV+neurons. Protein tyrosine phosphatase type S (PTPσ, PTPRS), a receptor for PNNs, interacts with TRKB and inhibits its phosphorylation, and chondroitinase treatment or deletion of PTPσ increases TRKB phosphorylation. Antidepressant fluoxetine disrupts the interaction between TRKB and PTPσ, thereby increasing TRKB phosphorylation. Thus, juvenile-like plasticity induced by both chondroitinase and antidepressant treatment is mediated by TRKB activation in PV+interneurons.
Does outsourcing affect agricultural productivity of farmer households? Evidence from China
Authors: Deng Xin , Xu Dingde , Zeng Miao , Qi Yanbin 
Published: August 2020

PurposePrevious studies focused on the influence of outsourcing (labor division) on productivity, especially in the industrial economy. However, few studies have focused on how labor division in agriculture affects agricultural productivity. To bridge this gap, this study uses survey data from 4864 farmer households in China to explore the impacts of outsourcing on agricultural productivity.Design/methodology/approachThis study employs an endogenous switching regression to account for selection bias and a counterfactual framework to measure the degree of influence. Thus, this study analyzes determinants of outsourcing and the impacts of outsourcing on agricultural productivity under the same framework.FindingsThe results revealed the following. (1) Farmer households with the below average productivity tended to outsource; conversely, farmer households with the above average productivity tended to cultivate the land by themselves. (2) Productivity increased by 25.61% for farmer households who choose to outsource. Moreover, if nonoutsourcing farmer households would choose to outsource, their productivity would increase by 10.86%.Originality/valueThis study furthers one’s understanding of how outsourcing affects agricultural productivity among farmer households.
The impact of board size on board demographic faultlines
Authors: Ali Muhammad , Ayoko Oluremi B. 
Published: August 2020

PurposeDemographic faultlines are associated with negative group processes and low performance. Little is known about the formation of faultlines in boards and how they can be weakened to capitalize on the positive effects of diversity.Design/methodology/approachThis study draws on social identity theory and faultlines theory to provide insights into how gender and age faultlines are formed in a board. Subsequently, it proposes and tests a U-shaped board size–faultlines strength relationship. Archival data were collected on 288 organizations listed on the Australian Securities Exchange.FindingsHierarchical regression analyses indicate that small- and large-sized boards experience stronger faultlines than medium-sized boards.Originality/valueThis study provides pioneering evidence for a U-shaped relationship between board size and demographic faultlines strength. These findings inform practice by suggesting an optimal board size.
The structural integrity of high-strength welded pipeline steels: a review
Authors: Singh Mayur Pratap , Shukla Dinesh Kumar , Kumar Rajneesh , Arora Kanwer Singh 
Published: August 2020

PurposeThe key purpose of conducting this review is to identify the issues that affect the structural integrity of pipeline structures. Heat affected zone (HAZ) has been identified as the weak zone in pipeline welds which is prone to have immature failuresDesign/methodology/approachIn the present work, literature review is conducted on key issues related to the structural integrity of pipeline steel welds. Mechanical and microstructural transformations that take place during welding have been systematically reviewed in the present review paper.FindingsKey findings of the present review underline the role of brittle microstructure phases, and hard secondary particles present in the matrix are responsible for intergranular and intragranular cracks.Research limitations/implicationsThe research limitations of the present review are new material characterization techniques that are not available in developing countries.Practical implicationsThe practical limitations are new test methodologies and associated cost.Social implicationsThe fracture of pipelines significantly affects the surrounding ecology. The continuous spillage of oil pollutes the land and water of the surroundings.Originality/valueThe present review contains recent and past studies conducted on welded pipeline steel structures. The systematic analysis of studies conducted so far highlights various bottlenecks of the welding methods.
Transformative marketing: health and well-being of Special Olympic athletes
Authors: McCullough Brian P. , Trail Galen T. 
Published: August 2020

PurposeTransformative marketing provides a way to encourage positive behaviors. This approach can be applied to community intervention organizations, such as the Special Olympics. Such organizations bring services to provide activity, healthy eating, proper healthcare and caretaker education. This study examines one campaign of the 2018 Special Olympics USA Summer Games focusing on health and wellness.Design/methodology/approachThe authors surveyed caretakers about these campaigns including their attitudes toward health and wellness and other basic psychographics (i.e. needs/values) to inform a transformative marketing campaign directed to engaging the caretakers.FindingsThe hierarchical regression shows us is that all the variables combined explain 26.9% of intentions to help their athlete eat as healthily as possible, with needs/values explaining the most variance, even after all of the other variables are in the model. The authors discuss their results and the practical applications of their findings to improve transformative marketing campaigns to achieve desirable social outcomes through the Special Olympics.Originality/valueThe authors identified what variables uniquely contributed to the intention by caretakers of ID athletes to engage in health and wellness campaigns that benefit their athletes. Future research can apply the results to developing similar sustainability (environmental, social or economic) campaigns using transformative marketing perspectives that will more positively benefit target markets in and through sport.