bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of novel single-source precursor of tin for deposition of tin oxide thin films for various applications
Authors: Sharma Priyanshu , Tripathi Santosh Kumar , Jaiswal Piyush
Published: June 2021

Novel single-source organometallic precursor, Triethanolamine Tin (II) (Sn-TEA), was synthesized by the reaction of SnCl2 and triethanolamine in the presence of Sodium acetate. TGA, FTIR, 1H characterize the Sn-TEA precursor, and 13C NMR was done to confirm its thermal stability and predict its molecular structure. The 1H and 13C NMR showed an organometallic molecule as TEA and acetate form a coordination sphere around the Sn atom in a stable structure. The TGA showed two thermal decomposition steps at ~206.14oC and ~750oC and residue at 800 °C. The precursor was pyrolyzed at 400oC, and the residual powder was characterized by FTIR, which indicated the formation of Tin Oxide. The precursr was then used to deposit SnO2 films by microwave-assisted solvothermal process on glass substrates. The films were characterized with XRD, FESEM and tested for conductivity. XRD confirmed the formation of SnO2 of the cubic lattice. The precursor concentration and microwave irradiation time on the film morphology, compositional analysis, and electrical conductivity were studied thoroughly. Sn-TEA complex proved to be a potential single-source precursor for SnO2 production, and it can be applied to develop highly pure/doped SnO2 films for gas sensing applications in a cost-effective manner
A novel design of bioinspired retinal vascular network based microchannel for LOC applications
Authors: Karbari Sudha R , Shetty Kiran Guruprasad
Published: June 2021

Microchannels are identified as important components that transfer liquids within a minute area for microfluidic applications. Pressure controlling is an efficient and most accurate way to introduce a certain velocity of equipment. In this study, we described the simulation analysis for microfluidic channels with three inlets and one outlet and went on to optimize it to two inlets and one outlet with appropriate velocity profiles and pressure profiles. The grooves in the microchannel draw inspiration from the vascular network of the retina which is a dynamically interconnected structure composed of three planar vascular layers with bends and grooves at its tip ends. Different fluids enter the inlets and are supposed to get mixed as much as possible before leaving the outlet. The geometry needs to be modified to increase the mixing of the two fluids within 0.05 sec. A passive approach to induce mixing of the biological samples is facilitated by increasing the distances. The fluids travel longer distances for mixing because of diffusive and inertial forces for which the volumetric fluids travel long before mixing takes place. The channel length is increased by introducing groove along the center of each channel to increase the length for the mixing.
Comparative Performance of Induction Motor Speed Controller System with Flux Weakening Control
Authors: Chelinia Erianda Putri Regina , Yusviar Feri
Published: June 2021

In general induction motor not work optimally because cannot reach the maximum speed of the rating. In this paper, simulation is used with several methods, named Maximum Torque Per Ampere (MTPA) and Field-weakening. Simulation of the methods used the function on MATLAB C-Mex and implemented on block of Simulink. The Field-weakening is control speed of the induction motor by decreased flux. The goal is to produce motor speed above the rating. The method of field-weakening control with addition of |iq
| used as reference

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, which will be used to limit

i

q

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. The result of the study is a comparison between the two methods to verify reliability. Simulations results showed that induction motor speed controller using field-weakening control with addition |iq
| better performance.
Supercapacitor Modeling for Conversion Systems and Power Supply in Electric Vehicles
Authors: Fadilah  , Feri Y
Published: June 2021

The main obstacle in an Electric Vehicle (EV) is the large torque requirement at the start. And in this case, it must be overcome with a battery that is bigger and heavier. However, a large battery will become a burden when moving and braking. The use of supercapacitors can make the vehicle move more powerful at the beginning of the movement because of its very fast energy release. This paper presents a supercapacitor modeling to support battery performance in an energy storage system. This research is focused on modeling the supercapacitor connected to the drive converter circuit by looking for a mathematical model in the form of a state-space equation, the results of which are simulated using the C Mex S function in Matlab / Simulink. From the modeling carried out, it is obtained a system that has a system response that is built and shows the system is working properly, the output voltage can follow the reference results.
Bioplastic Technology as Packaging Innovation
Authors: Ekawardhani Y A , Pasaribu C Y , Rohmah A N , Salsabila O
Published: June 2021

This study aims at explaining bioplastics’ use as a substitute for plastic base materials. Besides, it is also expected to help sustainable packaging innovation. The use of plastics continues to increase over time. Although plastic is difficult to decompose, its durability makes it still used for various product packaging. Contrary to its use, this resilience becomes an obstacle in protecting the environment from accumulating plastic waste. There are various solutions to replace plastic material with something more environmentally friendly. One of them is the use of bioplastics from cassava peels. This material, called bioplastic, is an innovation to protect the environment in environmentally friendly plastic. This innovation opens up opportunities to be used as a business that connects producers and customers through new technologies and products. The descriptive method used in this research was carried out in two stages: first, in the form of data collection techniques in the form of literature studies through internet resource searches. Second, based on the data obtained, it is used as a reference for determining visual information for packaging made from bioplastic. The visualization process uses Photoshop Creative Cloud 2018 software. The result is an illustration showing the characteristics of the bioplastic material derived from cassava peels and an environmentally friendly plastic material. An illustration in the form of information leads to the formation of conceptual businesses to increase buyer interest and the tendency to use bioplastics.
Internet of Things Cyber Security in Digital Era
Authors: Solihat M , Wulansari R V
Published: June 2021

This study aims to determine cybersecurity security in terms of data transfer in the digital era. This study used a descriptive qualitative approach, namely a literature study. The results of this study are to show that using the internet remains safe and avoids dangerous things. With the positive influence of digital technology on cybersecurity, it can be concluded that cybersecurity is to maintain security from technological crimes. This research is expected to serve as a warning to the public to be careful in using the internet.
Development of Fly Ash Coal/TiO2 Pored Composite Materials in The Making of Ceramic Membrane for Water Treatment Process
Authors: Apriyanti Eny , Susanto Heru , Nyoman Widiasa I
Published: June 2021

The ceramic membrane is a synthetic membrane, also called an inorganic membrane. The objectives of this study are to evaluate the characteristics of fly ash ceramic membrane and their performance for water treatment. The ceramic membrane fabrication process uses a printing process with a pressure of 1 atm with a burning temperature of 1100°C for 7 hours. The stages of this research include 1) composition optimization experiments with variations in the composition of fly ash and kaolin clay and temperature, 2) Characterization of ceramic membranes obtained by X-ray diffraction (XRD) and scanning electron microscope (SEM) tests. Optimization is carried out by varying the composition using a ratio of fly ash kaolin clay MB1: 40%: 20 %: 30%; MB2: 30%: 30%: 30%; MB3: 20%: 40%: 30% with a combustion temperature of 1100°C with a combustion process time of 7 hours. From the research results obtained, the porosity test results MB1 porosity 42%; The porosity of MB2 is 44%; The porosity MB3 is 50.22% from the porosity test results showing the higher composition of coal fly ash, the smaller porosity obtained. This phenomenon occurs during the combustion or sintering process to minimize the membrane pores. The structure of the membrane pores can be seen by the characterization test using SEM. SEM test results show that the MB1 ceramic membrane has delicate pores so that it has the potential to be applied. The experimental results showed that the utilization of fly ash for ceramic membrane material was promising for water treatment due to its excellent properties and filtration performance.
Cognitive Profile and Relationship with Quality of Life and Psychosocial Functioning in Mood Disorders
Authors: Zazula Robson , Mohebbi Mohammadreza , Dodd Seetal , Dean Olivia M , Berk Michael , Vargas Heber Odebrecht , Nunes Sandra Odebrecht Vargas
Published: June 2021

Background

Comparisons between healthy controls (HCs) and individuals with mood disorders have shown more cognitive dysfunction among the latter group, in particular in bipolar disorder (BD). This study aimed to characterize the pattern of cognitive function of BD and major depressive disorder (MDD) and compare them to HC using the (CogState Research Battery) CSRB™.

Method

Participants were tested, comprising the following domains: processing speed, attention, working memory, visual memory, executive functions, and verbal memory. Quality of life and functionality were also assessed. Multiple linear regression models were performed to examine the effect of demographic characteristics and functionality on cognitive outcomes separately for BD and MDD.

Results

Ninety individuals participated in the study, of which 32 had BD, 30 had MDD, and 28 were HC. Differences were found between both BD and MDD and HC for the composite cognitive score, with significant differences between BD and HC (Diff = −5.5, 95% CI = [−9.5, −1.5], p = 0.005), and MDD and HC (Diff = −4.6, 95% CI = [−8.6, −0.5], p = 0.025). There were overall significant differences in five cognitive domains: processing speed (p = 0.001 and p = 0.004), attention (p = 0.002), working memory (p = 0.02), visual memory (p = 0.021), and verbal memory (p = 0.007). BD also presented worse performance than both MDD and HC, and MDD presented better performance than BD but worse than HC in quality of life and functionality. Multiple linear regression models were significative for education (p < 0.001) and age (p = 0.004) for BD and education (p < 0.001) for MDD.

Conclusion

In general, cognition is more affected in BD than MDD, which could be associated with functional and quality of life impairment.
Contextual factors associated with knowledge and attitudes of HIV/AIDS among Malawian women of reproductive age
Authors: Nkoka Owen , Ntenda Peter A M , Chuang Kun-Yang
Published: June 2021

Background

Increasing the knowledge and attitude toward human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a key in the management of the condition. However, in Malawi, there is limited information regarding individual- and community-level factors associated with HIV/AIDS knowledge and attitudes. This study examined the contextual factors associated with HIV/AIDS knowledge and attitudes among women of childbearing age (WOCBA) (aged 15–49 years) in Malawi.

Methods

The 2015–16 Malawi demographic and health survey was used to analyze 24 562 WOCBA who were nested in 850 communities. Mixed effects logistic regression models were fitted to estimate the fixed and random effects of individual- and community-level factors on HIV/AIDS knowledge and attitudes.

Results

Approximately 30.9% of the participants had good HIV/AIDS knowledge while 80.5% had good HIV/AIDS attitudes. Among others, at the individual-level, woman’s age, educational level and household wealth were positively associated with both good HIV/AIDS knowledge and attitudes. At the community-level, those from communities with a high percentage of women complaining about the distance to health facility were less likely to have both good HIV/AIDS knowledge and attitudes.

Conclusions

Individual- and community-level factors have been shown to be associated with HIV/AIDS knowledge and attitudes among WOCBA in Malawi. Additionally, residual heterogeneity in terms of HIV/AIDS knowledge and attitudes across communities was observed. Therefore, thorough profiling of communities when designing public health programs and strategies may prove beneficial.
Methods for analyzing neuronal structure and activity in Caenorhabditis elegans
Authors: Emmons Scott W , Yemini Eviatar , Zimmer Manuel
Published: June 2021

The model research animal Caenorhabditis elegans has unique properties making it particularly advantageous for studies of the nervous system. The nervous system is composed of a stereotyped complement of neurons connected in a consistent manner. Here, we describe methods for studying nervous system structure and function. The transparency of the animal makes it possible to visualize and identify neurons in living animals with fluorescent probes. These methods have been recently enhanced for the efficient use of neuron-specific reporter genes. Because of its simple structure, for a number of years, C. elegans has been at the forefront of connectomic studies defining synaptic connectivity by electron microscopy. This field is burgeoning with new, more powerful techniques, and recommended up-to-date methods are here described that encourage the possibility of new work in C. elegans. Fluorescent probes for single synapses and synaptic connections have allowed verification of the EM reconstructions and for experimental approaches to synapse formation. Advances in microscopy and in fluorescent reporters sensitive to Ca2+ levels have opened the way to observing activity within single neurons across the entire nervous system.
Patenting in 4IR technologies and firm performance
Authors: Benassi Mario , Grinza Elena , Rentocchini Francesco , Rondi Laura
Published: June 2021

We investigate whether firm performance is related to the accumulated stock of technological knowledge associated with the Fourth Industrial Revolution (4IR) and, if so, whether the firm’s history in 4IR technology development affects such a relationship. We exploit a rich longitudinal matched patent-firm data set on the population of large firms that filed 4IR patents at the European Patent Office (EPO) between 2009 and 2014, while reconstructing their patent stocks from 1985 onward. To identify 4IR patents, we use a novel two-step procedure proposed by EPO (2020, Patents and the Fourth Industrial Revolution: The Global Technology Trends Enabling the Data-Driven Economy, European Patent Office), based on Cooperative Patent Classification codes and on a full-text patent search. Our results show a positive and significant relationship between firms’ stocks of 4IR patents and labor and total factor productivity. We also find that firms with a long history in 4IR patent filings benefit more from the development of 4IR technological capabilities than later applicants. Conversely, we find that firm profitability is not significantly related to the stock of 4IR patents, which suggests that the returns from 4IR technological developments may be slow to be cashed in. Finally, we find that the positive relationship with productivity is stronger for 4IR-related wireless technology and for artificial intelligence, cognitive computing, and big data analytics.
Deposition of Phosphorylated α-Synuclein and Activation of GSK-3β and PP2A in the PS19 Mouse Model of Tauopathy
Authors: Takaichi Yuta , Chambers James K , Ano Yasuhisa , Takashima Akihiko , Nakayama Hiroyuki , Uchida Kazuyuki
Published: June 2021

The simultaneous accumulation of multiple pathological proteins, such as hyperphosphorylated tau (hp-tau) and phosphorylated α-synuclein (p-αSyn), has been reported in the brains of patients with various neurodegenerative diseases. We previously demonstrated that hp-tau-dependent p-αSyn accumulation was associated with the activation of GSK-3β in the brains of P301L tau transgenic mice. To confirm the effects of another mutant tau on p-αSyn accumulation in vivo, we herein examined the brains of PS19 mice that overexpress human P301S mutant tau. Immunohistochemically, hp-tau and p-αSyn aggregates were detected in the same neuronal cells in the cerebrum and brain stem of aged PS19 mice. A semiquantitative analysis showed a positive correlation between hp-tau and p-αSyn accumulation. Furthermore, an activated form of GSK-3β was detected within cells containing both hp-tau and p-αSyn aggregates in PS19 mice. Western blotting showed a decrease in inactivated PP2A levels in PS19 mice. The present results suggest that the overexpression of human P301S mutant tau induces p-αSyn accumulation that is accompanied by not only GSK-3β, but also PP2A activation in PS19 mice, and highlight the synergic effects between tau and αSyn in the pathophysiology of neurodegenerative diseases that show the codeposition of tau and αSyn.
Partisan Bias of Perceived Incivility and its Political Consequences: Evidence from Survey Experiments in Hong Kong
Authors: Liang Hai , Zhang Xinzhi
Published: June 2021

Exposure to presumably uncivil content is neither a necessary nor a sufficient condition for perceptions of incivility and thus could lead to differential political consequences. To examine the emergence and consequences of perceived incivility in disagreement comments, the present study reports on two population-based online survey experiments in Hong Kong (N1 = 1,207, N2 = 611). The results indicate that individuals perceive a higher degree of incivility in disagreement comments directed to in-group members than in those directed to out-group members, regardless of content features. This bias perception is greater when respondents can easily identify the incivility in a comment. Furthermore, exposure to disagreement comments can only influence willingness to participate and affective polarization indirectly via perceived incivility, and such effects are conditional on whether respondents can easily identify the incivility in a comment.
Zero waste and Wastephilian ethics during COVID-19
Authors: Kahambing Jan Gresil S
Published: June 2021

Responsibility toward the planet becomes imperative during the pandemic. Among the pressing issues, this is the management of waste. Ethical considerations on waste pertain to the consistency of adopting viewpoints that confront waste and its reality. Zero waste prospects remain to be an ideal in the perceived sustainable futures. The ethics of wastephilia or wastephilian ethics can reimagine sustainability in terms of waste management. While acknowledging the spectral or circular character of waste, wastephilian ethics confronts this reality by living-with waste.
A novel model to assess disease activity in Takayasu arteritis based on 18F-FDG-PET/CT: a Chinese cohort study
Authors: Ma Ling-Ying , Wu Bing , Jin Xue-Juan , Sun Ying , Kong Xiu-Fang , Ji Zong-Fei , Chen Rong-Yi , Cui Xiao-Meng , Shi Hong-Cheng , Jiang Lin-Di
Published: June 2021

Objective

To investigate the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in assessing disease activity in Takayasu arteritis (TA).

Methods

Ninety-one patients with TA were recruited from a Chinese cohort. Clinical data, acute-phase reactants and 18F-FDG-PET/CT findings were simultaneously recorded. The value of using 18F-FDG-PET/CT to identify active disease was evaluated, using ESR as a reference. Disease activity assessment models were constructed and concordance index (C-index), net reclassification index (NRI), and integrated discrimination index (IDI) were evaluated to compare the benefits of the new modes with ESR and the Kerr score.

Results

In total, 64 (70.3%) cases showed active disease. Higher levels of ESR and CRP, and lower IL-2 receptor (IL-2R) levels were observed in active cases. 18F-FDG-PET/CT parameters measured by determining the standard uptake value (SUV), including SUVmean, SUVratio1, SUVratio2, sum of SUVmean and sum of SUVmax, were significantly higher in active disease groups. The C-index threshold of ESR to indicate active disease was 0.78 (95% CI: 0.69, 0.88). The new activity assessment model combining ESR, sum of SUVmean and IL-2R showed significant improvement in C-index over the ESR method (0.96 vs 0.78, P < 0.01; NRI 1.63, P < 0.01; and IDI 0.48, P < 0.01). The new model also demonstrated modest superiority to the Kerr score assessment (0.96 vs 0.87, P = 0.03; NRI 1.19, P < 0.01; and IDI 0.33, P < 0.01).

Conclusions

A novel 18F-FDG-PET/CT-based method that involves combining the sum of SUVmean with ESR score and IL-2R levels demonstrated superiority in identifying active TA compared with conventional methods.
Antipsychotics Effects on Network-Level Reconfiguration of Cortical Morphometry in First-Episode Schizophrenia
Authors: Jiang Yuchao , Wang Yingchan , Huang Huan , He Hui , Tang Yingying , Su Wenjun , Xu Lihua , Wei Yanyan , Zhang Tianhong , Hu Hao , Wang Jinhong , Yao Dezhong , Wang Jijun , Luo Cheng
Published: June 2021

Cortical thickness reductions are evident in schizophrenia (SZ). Associations between antipsychotic medications (APMs) and cortical morphometry have been explored in SZ patients. This raises the question of whether the reconfiguration of morphological architecture by APM plays potential compensatory roles for abnormalities in the cerebral cortex. Structural magnetic resonance imaging was obtained from 127 medication-naive first-episode SZ patients and 133 matched healthy controls. Patients received 12 weeks of APM and were categorized as responders (n = 75) or nonresponders (NRs, n = 52) at follow-up. Using surface-based morphometry and structural covariance (SC) analysis, this study investigated the short-term effects of antipsychotics on cortical thickness and cortico-cortical covariance. Global efficiency was computed to characterize network integration of the large-scale structural connectome. The relationship between covariance and cortical thinning was examined by SC analysis among the top-n regions with thickness reduction. Widespread cortical thickness reductions were observed in pre-APM patients. Post-APM patients showed more reductions in cortical thickness, even in the frontotemporal regions without baseline reductions. Covariance analysis revealed strong cortico-cortical covariance and higher network integration in responders than in NRs. For the NRs, some of the prefrontal and temporal nodes were not covariant between the top-n regions with cortical thickness reduction. Antipsychotic effects are not restricted to a single brain region but rather exhibit a network-level covariance pattern. Neuroimaging connectomics highlights the positive effects of antipsychotics on the reconfiguration of brain architecture, suggesting that abnormalities in regional morphology may be compensated by increasing interregional covariance when symptoms are controlled by antipsychotics.
A Golgi lipid signaling pathway that controls neural stem cell polarity in the developing neocortex
Authors: Bankaitis Vytas , Xie Zhigang
Published: June 2021

The Golgi apparatus is a central regulator of membrane trafficking and cell polarity in mammalian cells. I will discuss our recent work in a murine embryonic neural stem cell (NSC) model demonstrating that a Golgi phosphatidylinositol 4‐phosphate (PI4P)‐dependent pathway promotes loading of the Golgi system into NSC apical processes. The physiological significance of this mechanism is demonstrated by defects in apical loading of the Golgi system resulting in cell‐autonomous disruption in NSC polarity and, when imposed on a tissue‐wide scale, catastrophic failure in development of the neocortex. This pathway requires the action of a pair of phosphatidylinositol transfer proteins (PITPNA and (PITPNB) to promote PI4P production on Golgi membranes, and the actions of downstream effector proteins that respond to PI4P signaling. These effectors include GOLPH3, the nonconventional myosin Myo18A, and the ceramide transfer protein CERT. Finally, we find the PI4P‐dependent regulation of Golgi apical positioning is transmitted to the differentiated progeny of the affected NSCs and influences later steps in development of the embryonic mouse neocortex. Taken together, we have identified a novel mechanism by which PITPs, PI4P, and Golgi apparatus position regulate cell polarity and stem cell biology in the developing mammalian forebrain.

Support or Funding Information

This research was funded by NIH grant R01‐GM112591 and grant BE‐0017 from the Robert A. Welch Foundation.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mechanisms of Concanavalin A‐induced mediators of hepatocyte damage in hepatic stellate cells: A dual role of interferon regulatory factor‐1
Authors: Rani Richa , Kumar Sudhir , Gandhi Chandrashekhar R.
Published: June 2021

Concanavalin A (ConA)‐induced liver injury in mice has been used extensively as a model to understand the role of immune cells. However, perisinusoidal hepatic stellate cells (HSCs), the primary cell type of liver fibrosis, were recently found to orchestrate ConA‐induced liver damage directly and by influencing recruitment and characteristics of immune cells. HSC‐released interferon‐β (IFNβ) and increased hepatic expression of a transcription factor, interferon regulatory factor 1 (IRF1), were determined to be major components of ConA‐induced liver injury. The aim of this study was to delineate the mechanisms of the actions of ConA on HSCs with specific focus on IRF1/IFNβ axis. HSCs and hepatocytes isolated from WT and IRF1−/− mice were used. HSCs were found to rapidly internalize FITC‐labeled ConA; internalized ConA was greatly concentrated in the perinuclear region. ConA increased the expression and nuclear translocation of IRF1 and NF‐κB in wild type (WT) HSCs and the expression of TNFα, IFNβ and CXCL1. These effects of ConA were abrogated in HSCs isolated from IRF1−/− mice. ConA induced JAK/STAT signaling in HSCs, and inhibitors of this signaling pathway ameliorated ConA‐induced IRF1 expression/nuclear translocation as well as cytokine/chemokine production. Finally, ConA‐stimulated WT but not IRF1−/− HSCs induced apoptosis of WT hepatocytes. Conversely, ConA‐stimulated WT HSCs were unable to induce apoptosis of IRF1−/− hepatocytes. Our findings suggest that IRF1 plays a dual role in ConA‐induced liver injury. On the one hand, ConA stimulates the synthesis of the mediators of hepatocyte injury through JAK/STAT signaling involving IRF1. On the other hand, IRF1 nuclear translocation in hepatocytes induced by ConA‐stimulated HSCs instigates apoptosis. While this mechanistic evaluation is performed using ConA, the findings could be relevant to liver injury due to lectins in the food products. In conclusion, HSC can be a potential therapeutic target for acute liver damage of various etiologies including lectins.

Support or Funding Information

This work was supported by a VA Merit Review Award 1IO1BX001174 to CRG.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regulation of pancreatic islet cell fates
Authors: Sussel Lori
Published: June 2021

The regulation of lineage specification is a challenging problem in organogenesis. Our studies are focused on identifying the gene regulatory networks underlying cell fate decisions in the pancreas, with an emphasis on the endocrine islet cell lineages. To this end, we have identified a number of coding and non‐coding genes that are essential for the specification of islet cell fates. In particular, Nkx2.2 is an essential transcriptional regulatory protein that is important for the formation and function of several islet cell lineages. Furthermore, Nkx2.2 continues to be essential for the active maintenance of both beta cell identity and function in the adult. Deletion of Nkx2.2 in mature beta cells caused these cells to acquire non‐beta cell endocrine features resulting in populations of reprogrammed cells. These studies demonstrate that Nkx2.2 is a conserved master regulatory protein that controls the acquisition and maintenance of beta cell identity by directly activating critical beta cell genes and actively repressing genes that specify the alternative islet endocrine cell lineages. These studies have been instrumental in understanding normal pancreatic cell differentiation processes during embryonic development and underscored the need to continually maintain these cell specific gene regulatory programs in the adult organ. Our findings have also demonstrated the existence of remarkable plasticity in adult pancreatic lineages.

Support or Funding Information

NIH R01 DK082590

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regulation of Functional Proteome by the Heat Shock Response and Proteostasis Network
Authors: Morimoto Richard I.
Published: June 2021

Cellular health and proteome function is maintained by the proteostasis network (PN) comprised of molecular chaperones, transport pathways, the ubiquitin‐dependent proteasome, and autophagy clearance mechanisms. The dynamic properties of the PN are regulated by cell stress responses including the heat shock response (HSR) and the unfolded protein responses of the endoplasmic reticulum (UPRER) and mitochondria (UPRMITO). To understand the biology of organismal proteostasis, we have examined the properties of the PN in different tissues throughout the lifespan of C. elegans. The transition from development through reproduction into adulthood and aging places a tremendous demand on quality control processes and protein biogenesis. In early development, heat shock transcription factor HSF‐1 is essential, and target gene expression is co‐regulated with the cell cycle factor, E2F, to control a small subset of chaperone and PN genes involved in rapid anabolic growth. HSF‐1 is also involved in suppression of protein degradation pathways in early development. At reproductive maturity, the HSR is inhibited in somatic tissues by signals from the germ line stem cells that place repressive H3K27me3 chromatin marks at HS gene loci, repressing HSF‐1 DNA binding and transcription of chaperone genes, leading to the collapse of proteostasis in aging. These inhibitory signals on organismal proteostasis can be reversed genetically by overexpression of the jumonji demethylase, inhibition of germ line signaling, or induction of mitochondrial stress, either by mild downregulation of components of the electron transport chain, xenobiotics, and certain pathogenic bacteria to prevent the proteostasis collapse that occurs in early adult aging. These observations reveal that the regulation of molecular chaperones and other components of the PN by cell stress response pathways in aging is the basis for increased risk for misfolding and aggregation as occurs in neurodegenerative diseases and other protein conformational diseases.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial Cell IQGAP1 is Required to Support Efficient Leukocyte Transmigration both In Vitro and In Vivo
Authors: Sullivan David P. , Dalal Prarthana J. , Muller William A.
Published: June 2021

Inflammation is the body's fundamental response to tissue insult and damage. When operating correctly, it allows the organism to fight infection, repair injuries, and return the body to homeostasis. When the response is incorrectly directed, whether insufficient, excessive, or against an improper target, it contributes to and even directly causes numerous human pathologies. One of the critical components of inflammation is the recruitment of leukocytes to the target site. This process is a carefully choreographed series of sequential steps that leads to the net efflux of leukocytes out of the blood stream and into tissue. In the culminating and putative committed stage, the leukocyte squeezes between adjacent endothelial cells in a process commonly referred to as transendothelial migration (TEM). TEM is a critical step that requires several intercellular interactions and thus represents an attractive therapeutic target for regulating aberrant inflammation. During TEM, endothelial cells direct the lateral border recycling compartment (LBRC), a sub‐junctional membrane network, to the site of leukocyte migration to facilitate its passage. All manipulations that affect the function and delivery of the LBRC substantially reduce leukocyte efflux.

To better understand the molecular components and function of the LBRC, we recently conducted a screen for LBRC‐interacting proteins and identified IQGAP1. IQGAP1 is a large multi‐domain cytoplasmic protein that is reported to bind several signaling proteins in other systems. Knockdown of endothelial cell IQGAP1 disrupted the directed movement of the LBRC and substantially reduced leukocyte TEM. To determine which domains of IQGAP1 are required for its function in TEM, we expressed a series of truncated constructs and examined their ability to rescue the knockdown of endogenous IQGAP1. We found that the actin‐binding domain of IQGAP1 is required for its localization to endothelial borders. Furthermore, both the actin‐binding domain and the IQ‐motifs are required for its function in TEM. We extended these studies in vivo by generating bone marrow chimeras, in which IQGAP1 knockout animals were reconstituted with wild‐type leukocytes. These studies show that IQGAP1 in endothelium is required for efficient TEM in vivo in two different inflammatory models. Together these findings detail a novel function for IQGAP1 in TEM that involves both its actin‐binding domain and IQ motifs which together coordinate the directed movement of the LBRC to the site of TEM.

Support or Funding Information

Funding Support: R01HL046849, R01HL064774

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reduced RON Expression, DM1 resistance and MRP1 Upregulation Contributes to Resistance in Colon Cancer Cells against anti‐RON Antibody‐Drug Conjugate Zt/g4‐DM1
Authors: suthe sreedhar reddy , Yao Hang‐Ping , wang ming‐hai
Published: June 2021

Zt/g4‐DM1 is an antibody‐drug conjugate that specifically delivers the potent cytotoxic payload maytansinoid (DM1) to RON receptor‐positive cells. Despite its impressive preclinical efficacy in the initial stages of treatment in xenograft models, tumors‐mediated by colon and PDAC cells were only partially inhibited by Zt/g4‐DM1. In light of these findings, we wanted to investigate mechanisms involved in Zt/g4‐DM1 resistance. As part of this work, we developed anti‐RON Zt/g4‐SMCC‐DM1 resistant colon cancer HT29, HCT116, SW620 cells derived from tumors by continuous treatment at lower doses followed by incremental dose increases. Approximately 100–200 fold resistance to Zt/g4‐DM1 developed in these cells and cross‐resistance was observed other ADCs containing drugs with similar mechanism of action. Reduced RON expression, DM1 resistance and increased expression of the ABCC1 (MRP1) drug exporter compared to parental cells were primary mediators of resistance. Interestingly we found a small percentage of RON positive population in resistant cells, when isolated these RON+ clones from three cell lines exhibited stable drug refractoriness and altered intracellular trafficking as a unique underlying mechanism of resistance to Zt/g4‐DM1. HT29R, HCT116R, SW620R cell lines showed resistance to unconjugated DM1 but not to other chemotherapeutic agents. Tumors derived from HT29R, HCT116R, SW620R grew in mice and were refractory to Zt/g4‐DM1 compared with parental cells. Hence, acquired resistance to Zt/g4‐DM1 was generated from cells derived from tumors by continuous drug exposure, and either increased ABCC1 protein or reduced RON expression and defective intracellular trafficking in case of RON+ resistant cells were primary mediators of resistance. These resistant cell models retained sensitivity to chemotherapeutics, suggesting that alternative therapies may help in overcoming acquired resistance.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
TIMP‐2 Inhibits Tumor Growth in Murine Model of Lung Cancer through EGFR signaling
Authors: Kumar Sarvesh , Jensen Sandra M. , Chowdhury Ananda , Peeney David , Wei Beiyang , Shih Joanna , Caterina John J. , Stetler‐Stevenson William G.
Published: June 2021

The tissue inhibitor of metalloproteinase family of proteins (TIMPs 1–4) function as natural MMP inhibitors, and have been shown to play a role in maintenance and remodeling of the ECM as well as other cellular processes including proliferation, apoptosis and angiogenesis. TIMP‐2 is widely expressed in the stromal compartment of normal tissues, and has been shown to possess many MMP‐independent functions within the tumor microenvironment including inhibition of tumor growth and angiogenesis, reduced vascular permeability, and decreased tumor cell migration and invasion. In the current study, we used congenic mutant TIMP‐2 mice (mT2) with a loss of function mutation in the Timp‐2 gene to study TIMP‐2 associated effects in mice following intratracheal installation of Lewis Lung carcinoma cells labeled with luciferase (LL2‐Luc). The bioluminescence (BLI) data on 28 days post installation revealed a higher tumor burden in mT2 mice compared to wild type (wt) littermates, suggesting that loss of function mutation in Timp‐2 gene increases tumor growth (p<0.05), as well as an increase in the lung/body weight ratio (p<0.01). In agreement with these findings, Kaplan‐Meier analysis exhibited significantly higher mortality in mT2 mice compared to wt controls (p<0.01). Histologic analysis of H&E stained lung sections revealed a significant increase in the number of tumor nodules in mT2 mice compared to wt controls (p<0.01). In addition, we found that daily treatment (intraperitoneal injection) with exogenous recombinant TIMP2 (rTIMP2) protein (200ug/kg/day) significantly inhibited tumor growth (p<0.05) and lung/body weight ratio (p<0.01) in both mT2 and wt mice. Furthermore, both normal and tumor tissues from mice harboring the TIMP‐2 loss of function mutation demonstrated increased levels of EGFR phosphorylation (Tyr‐1068) by western blot analysis. In support of these findings, treatment of Lewis lung carcinoma cells by rTIMP‐2 inhibited EGF‐induced phosphorylation of EGFR (Tyr‐1068) in a dose dependent manner. In conclusion, these data indicate that the loss of function Timp‐2 mutation accelerates lung tumorigenesis, and that exogenous rTIMP‐2 treatment inhibits LL2 tumor growth via inhibition of EGFR signaling.

Support or Funding Information

This work is supported by center for cancer research, intramural research program, NCI/NIH research grants ZIA BC011204 & ZIA SC 009179 to WGSS.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Desmosomal Cadherins Desmoglein‐2 or Desmocollin‐2 Regulate Intestinal Epithelial Barrier Function and Mucosal Repair
Authors: Kusters Dennis , Flemming Sven , Luissint Anny‐Claude , Hilgarth Roland , Parkos Charles , Nusrat Asma
Published: June 2021

The intestinal epithelial barrier plays a pivotal role in controlling mucosal homeostasis. In a number of pathological states such as inflammatory bowel disease, epithelial damage with disruption of the mucosal barrier results in a compromised intestinal mucosal homeostasis. To avoid chronic mucosal damage, efficient wound repair is critical in re‐establishing epithelial barrier properties and homeostasis. Epithelial barrier properties are achieved by intercellular junction proteins in the apical junctional complex and desmosomes. Intestinal epithelial cells express desmosomal cadherins, desmoglein 2 (Dsg2) and desmocollin 2 (Dsc2). To analyze contribution of these cadherins in controlling epithelial adhesion and homeostasis we generated mice with inducible intestinal epithelial specific (VillinCre‐ERT2) deletion of Dsg2 or Dsc2. Inducible downregulation of Dsg2 or Dsc2 resulted in compromised epithelial barrier function as assessed by paracellular FITC dextran flux using an intestinal loop model. Additionally, perturbation of these cadherins increased susceptibility to dextran sodium sulfate induced acute colitis.

In addition to controlling epithelial barrier function, intercellular junction proteins have been reported to regulate signaling events involved in mediating repair. We therefore determined if desmosomal cadherins control intestinal mucosal repair. Knock‐down of either Dsg2 or Dsc2 delayed colonic mucosal wound repair in a murine biopsy induced colonic injury model. Since epithelial wound closure is mediated by collective migration of cells which coordinates forward movement of the epithelial sheet to cover denuded surfaces, we analyzed adhesive and migratory properties of in vitro model intestinal epithelial cells lacking Dsg2 or Dsc2. These studies revealed that down regulation of Dsg2 or Dsc2 decreased cohesiveness of cells and affected adhesion to the matrix, thereby suggesting an important role of Dsg2 and Dsc2 in controlling adhesion and homeostatic properties of intestinal epithelial cells.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Genetic Influences on Craniofacial Morphology
Authors: Sherwood Richard J. , Duren Dana L. , Subedi Janardan , Williams‐Blangero Sarah , Mahaney Michael C.
Published: June 2021

Disorders of the craniofacial complex are among the most common congenital defects. Studies of these disorders have been confounded by a high level of genetic heterogeneity with single gene defects producing a variety of dysmorphisms or, conversely, by a variety of gene defects independently producing a similar phenotype. The identification of the underlying normal phenotypic variation, and its genetic basis, is critical to understanding the epidemiology of craniofacial anomalies. We have investigated the genetic architecture of traits from the craniofacial complex in three unique populations, including two human groups (the Fels Longitudinal Study, and the Jiri Dental Study) as well as an animal model (Papio hamadryas). Our ultimate objective is to elucidate fundamental aspects of the genetic architecture of the human craniofacial and dentognathic complexes.

We captured a wide variety of quantitative phenotypes describing craniofacial and dentognathic morphology from lateral cephalographs and dental casts. A maximum‐likelihood variance components‐based method (as implemented in SOLAR) was used to estimate heritability, and conduct multipoint linkage analysis, and genomewide association analysis (GWA). All traits were significantly heritable and were generally of moderate magnitude for skeletal traits (~35–60%) and somewhat higher for dental traits (~70–90%). Linkage analyses identified a number of significant QTL for quantitative traits from cephalographs for both human and baboon crania.

GWA analyses for the Jiri Dental Study have recently identified 46 SNPs for which there was at least suggestive evidence (P ≤ 1.60E‐6) for association with 31 different orofacial and dental traits; 9 of the 46 associations exhibited genome‐wide significance (P ≤ 2.74E‐7). Several of the implicated genes are associated with normal and abnormal growth and development of head and neck: ACAN, ERAP2, GPX3, NR2C2, & RORA. Pathway analysis revealed the gene harboring the strongest association, micro‐RNA locus MIRLET7D, regulates six genes that are in a tooth development pathway.

The combination of human and non‐human primate genetic studies of the craniofacial complex are providing insight on novel pathways for both normal morphology and congenital disorders of this important region.

Support or Funding Information

Supported by the National Institute of Dental and Craniofacial Research/NIH R01DE018497, R01DE016692, R21 DE016408, and National Institute of Allergy and Infectious Diseases/NIH R01AI037091, R01AI044406.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Constraints and Catalysts in Cerebellar Evolution
Authors: Wingate Richard
Published: June 2021

The cerebellum comprises a remarkably stereotyped neural circuit, elements of which, such as the granule cell‐Purkinje cell synapse, are highly conserved across vertebrates. It functions as an adaptive filter that can be employed in regulating feed forward control of movement, but has a wider range of functions including in mammals, a demonstrable role in cognitive development. The range of neural functions modulated by cerebellar activity is a product of its output connections. In many species these are mediated by cerebellar nuclei whose number and projections vary systematically across major classes of vertebrates. Notably, the connection of cerebellar nuclei to the thalamus and hence the ability of the cerebellum to participate in forebrain activity is a mammalian innovation. Cerebellum size is also a key adaptive variable amongst different species with some species of both fish and mammals displaying relatively large, elaborately foliated cerebellum. Different strategies for generating large numbers of cells are adopted by different classes of vertebrates. In particular, the appearance of a transient, external granule cell layer (EGL) in cerebellar development is a tetrapod innovation. In some reptiles, birds and mammals, the EGL becomes a proliferative layer, which leads to a rapid clonal expansion of granule cells and the potential for foliation. Both the diversification of connectivity (cerebellar nuclei) and transit amplification (in the EGL) are adaptive properties within derivatives of a single defined pool of progenitors at the embryonic “rhombic lip”. Different derivatives are generated within distinct cohorts. Within these cohorts the heterochronic shift in the expression of a small number of genes appears to be responsible for generating the key changes in cerebellar development in vertebrates.

Support or Funding Information

Medical Research Council, UK

BBSRC

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.