bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted degradation of microtubule-associated protein tau using an engineered nanobody-E3 ubiquitin ligase adapter fusion
Authors: Wang Shiyao , Jiang Shaowei , Zheng Guoan , Cho Yong Ku 
Published: September 2022

AbstractReducing the level of microtubule-associated protein tau has recently emerged as a promising therapeutic approach for a range of neurodegenerative diseases. Among the various approaches, targeted protein degradation provides a reversible means to rapidly reduce and specifically target disease-relevant forms of tau. However, in aging cells, the protein turnover activity is generally weakened, reducing the efficacy of protein degradation. A potential solution to this is to harness the nuclear proteasomal activity. The nucleus has a high proteasomal content and the degradation activity remains relatively unaffected even in aged cells. Here we show that an E3 ligase F-box domain from the nuclear protein human speckle type BTB/POZ protein (SPOP) is effective in degrading the microtubule-associated protein tau in primary mouse hippocampal neurons. Using EGFP-tagged tau and a GFP-binding nanobody fused to SPOP, we found that the native nuclear localization signal in SPOP causes nuclear sequestration of the target protein. However, degradation of the sequestered target proteins is incomplete, resulting in nuclear accumulation. Replacing the native SPOP nuclear localization signal (NLS) with variants having altered nuclear localization efficiency dramatically affects in the degree of nuclear accumulation of the target protein. Interestingly, nanobody-SPOP with no NLS was more efficient than that with a NLS in reducing overall tau level, causing an approximately 50% reduction in ectopically expressed human tau in mouse neurons. These results show the potential for harnessing the nuclear proteasomal activity for targeted tau degradation in cells and demonstrate a new modality of regulating intracellular protein degradation.
Role of astroglial ACBP in energy metabolism flexibility and feeding responses to metabolic challenges in male mice
Authors: Bouyakdan K. , Manceau R. , Robb J. , Rodaros D. , Fulton S. , Alquier T. 
Published: September 2022

ABSTRACTAcyl-CoA Binding Protein (ACBP), also known as Diazepam Binding Inhibitor (DBI), has recently emerged as a hypothalamic and brainstem gliopeptide regulating energy balance. Previous work has shown that the ACBP-derived octadecaneuropeptide exerts strong anorectic action via POMC neuron activation and the melanocortin-4 receptor. Importantly, targeted ACBP loss-of-function in astrocytes promotes hyperphagia and diet-induced obesity while its overexpression in arcuate astrocytes reduces feeding and body weight. Despite this knowledge, the role of astroglial ACBP in adaptive feeding and metabolic responses to acute metabolic challenges has not been investigated. Using different paradigms, we found that ACBP deletion in Glial Fibrillary Acidic Protein (GFAP)-positive astrocytes does not affect diet-induced weight loss in obese male mice nor metabolic parameters in chow-fed mice (e.g. energy expenditure, body temperature) during fasting, cold exposure and at thermoneutrality. In contrast, astroglial ACBP deletion impairs meal pattern and feeding responses during refeeding after a fast and during cold exposure, thereby showing that ACBP is required to mount an appropriate feeding response in states of increased energy demand. These findings challenge the general view that astroglial ACBP exerts anorectic effects and suggest that regulation of feeding by ACBP is dependent on metabolic status.
Size-tunable ICG-based contrast agent platform for targeted near-infrared photoacoustic imaging
Authors: Singh Shrishti , Giammanco Giovanni , Hu Chih-Hsiang , Bush Joshua , Cordova Leandro Soto , Lawrence Dylan J , Moran Jeffrey L , Chitnis Parag V , Veneziano Remi 
Published: September 2022

AbstractNear-infrared photoacoustic imaging (NIR-PAI) combines the advantages of optical and ultrasound imaging to provide anatomical and functional information of tissues with high resolution. Although NIR-PAI is promising, its wide application is hindered by the limited availability of NIR contrast agents. J-aggregates (JA) made of indocyanine green dye (ICG) represents an attractive class of biocompatible contrast agents for PAI. Here, we present a facile synthesis method that combines ICG and ICG-azide dyes for producing contrast agent with tunable size down to 230 nm and direct functionalization with targeting moieties. The ICG-JA platform has a detectable PA signalin vitrothat is two times stronger than whole blood and high photostability. The targeting ability of ICG-JA was measuredin vitrousing HeLa cells. The ICG-JA platform was then injected into mice andin vivoNIR-PAI showed enhanced visualization of liver and spleen for 90 minutes post-injection with a contrast-to-noise ratio of 2.42.
Effect of time spent on active learning on exam performance: A controlled case study on a course with different instructors but identical teaching materials
Authors: Cen Xinjian , Lee Rachel J. , Contreras Christopher , Owens Melinda T. , Maloy Jeffrey 
Published: September 2022

AbstractActive learning, including student thinking and discussion in class, has been shown to increase student learning gains. However, it is less clear how variations in how instructors implement active learning affect student gains. Our study aims to investigate the extent to which the time spent on individual episodes of active learning activities influences student performance. We hypothesized that instructors who let students spend more time on peer discussion and individual thinking on practice problems associated with particular learning objectives will have better student exam scores on exam questions addressing those objectives. To test this hypothesis, we obtained a large data set of classroom recordings and student exam scores from an introductory biology course at a large four-year university, where three instructors shared identical teaching materials and exams for different course offerings.Contrary to our hypothesis, although the three instructors spent significantly different amounts of time on episodes of thinking and peer discussion, there was no correlation between the total time spent on active learning activities and student performance on exam questions. Linear mixed-effects modeling of the effect of length of episodes of student thinking and discussion on exam score found that the amount of course time spent on active learning activities did not reliably predict student performance on associated exam questions. This result held true even when only considering learning objectives with high variations in performance between offerings, difficult exam questions, exam questions requiring higher-order thinking skills, or within-instructor performance. Although our study was only conducted in one course, our results imply that time spent per individual episode of student thinking or peer discussion may not be the primary factor explaining the positive effects of active learning and that it may be worthwhile to explore other factors.
An endogenous lentivirus in the germline of a rodent
Authors: Kambol Roziah , Gatseva Anna , Gifford Robert J. 
Published: September 2022

ABSTRACTLentiviruses (genus Lentivirus) are complex retroviruses that infect a broad range of mammals, including humans. Unlike many other retrovirus genera, lentiviruses have only rarely been incorporated into the mammalian germline. However, a small number of endogenous retrovirus (ERV) lineages have been identified, and these rare genomic “fossils” can provide crucial insights into the long-term history of lentivirus evolution. Here, we describe a previously unreported endogenous lentivirus lineage in the genome of the South African springhare (Pedetes capensis), demonstrating that the host range of lentiviruses has historically extended to rodents (order Rodentia). Furthermore, through comparative and phylogenetic analysis of lentivirus and ERV genomes, considering the biogeographic and ecological characteristics of host species, we reveal broader insights into the long-term evolutionary history of the genus.
Application of Data-Driven computing to patient-specific simulation of brain neuromodulation
Authors: Salahshoor Hossein , Ortiz Michael 
Published: September 2022

AbstractWe present a class of model-free Data-Driven solvers that effectively enable the utilization ofin situandin vivoimaging datadirectlyin full-scale calculations of the mechanical response of the human brain to sonic and ultrasonic stimulation, entirely bypassing the need for analytical modeling or regression of the data. The well-posedness of the approach and its convergence with respect to data are proven analytically. We demonstrate the approach, including its ability to make detailed spatially-resolved patient-specific predictions of wave patterns, using public-domain MRI images, MRE data and commercially available solid-mechanics software.
Is evolutionary conservation a useful predictor for cancer long noncoding RNAs? Insights from the Cancer lncRNA Census 3
Authors: Vancura Adrienne , Gutierrez Alejandro H. , Hennig Thorben , Pulido-Quetglas Carlos , Slack Frank , Johnson Rory , Häfliger Simon 
Published: September 2022

AbstractEvolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census, we observed an inverse relationship between year of discovery and evolutionary conservation. This observation is specific to cancer over other diseases, implying a sampling bias in selection of lncRNA candidates and casting doubt on the value of evolutionary metrics for prioritisation of cancer-related lncRNAs.
Myelin plasticity in ventral tegmental area is required for opioid reward
Authors: Yalçın Belgin , Pomrenze Matthew B. , Malacon Karen , Chau Isabelle J. , Taylor Kathryn R. , Ni Lijun , Contreras-Esquivel Daniel , Malenka Robert C. , Monje Michelle 
Published: September 2022

AbstractAll drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Here, we demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation or by morphine administration specifically within the reward center ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens NAc dopamine release dynamics, which is critical for reward learning, and impairs behavioral conditioning to morphine. Our findings identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.One-Sentence SummaryActivity-dependent myelin plasticity in the ventral tegmental area modulates dopaminergic circuit function and opioid reward
Roots fuel cell produces and stores clean energy
Authors: Shlosberg Yaniv , Huang Ailun , Tóth Tünde N. , Kaner Richard B. 
Published: September 2022

AbstractIn recent years, extensive scientific efforts have been conducted to develop clean bio-energy technologies. A promising approach that has been under development for more than a hundred years is the microbial fuel cell (MFC) which utilizes exo-electrogenic bacteria as an electron source in a bio-electrochemical cell. The viability of bacteria in soil MFCs can be maintained by integrating plant roots which release organic materials that feed the bacteria. In this work, we show that rather than organic compounds, roots also release redox species that can produce electricity in a bio-fuel cell. We first study the reduction of the electron acceptor Cytochrome C by green onion roots. We integrate green onion roots into a bio-fuel cell to produce a continuous bias-free electric current for more than 24 h in the dark. This current is enhanced upon irradiation of light on the onion’s leaves. We apply cyclic voltammetry and 2D-fluorescence measurements to show that NADH and NADPH act as major electron mediators between the roots and the anode, while their concentration in the external root matrix is increased upon irradiation of the leaves. Finally, we show that roots can contribute to energy storage by charging a supercapacitor.
Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1 (DMT1): Preclinical Efficacy Against Iron Overload and Safety Evaluation
Authors: Cutts Alison , Chowdhury Sultan , Ratkay Laszlo G , Eyers Maryanne , Young Clint , Namdari Rostam , Cadieux Jay A , Chahal Navjot , Grimwood Michael , Zhang Zaihui , Lin Sophia , Tietjen Ian , Xie Zhiwei , Robinette Lee , Sojo Luis , Waldbrook Matthew , Hayden Michael , Mansour Tarek , Pimstone Simon , Goldberg Y. Paul , Webb Michael , Cohen Charles J. 
Published: September 2022

ABSTRACTDivalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of non-heme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or β-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 (hDMT1) inhibitors. Dimeric constructs were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary iron uptake in both rats and pigs, yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiological function of DMT1.SIGNIFICANCE STATEMENTThis report introduces methodology to develop potent, gut-restricted inhibitors of DMT1 and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.
Recovering birds and mammals across Europe continue to be negatively impacted by threats but benefit from conservation measures
Authors: Gray Claudia , McRae Louise , Deinet Stefanie , Ledger Sophie , Benham Charlotte , Burfield Ian J. , Eaton Mark , Scott-Gatty Kate , Puleston Hannah , Rutherford Claire , Staneva Anna , Schepers Frans , Freeman Robin 
Published: September 2022

AbstractEven during ongoing global biodiversity losses and extinctions, numerous species have shown recoveries in terms of increased abundance and/or range extent. Understanding the mechanisms that contribute to, or limit, these recoveries is critical not just to ensure they continue, but to promote similar recoveries across broader ecosystems. Here, we explore the changes in abundance and range extent of selected 47 recovering species (24 mammals and 23 birds) in Europe using official data reported by EU Member States and supplemented using the Living Planet Index database. We investigate how the diversity of ongoing threats and conservation measures contribute to the likelihood and extent of recoveries. For birds, long-term recoveries were less likely among species impacted by a greater diversity of threats, although this may be mitigated by the diversity of conservation measures in place. Similarly, for mammals, populations with reported threats recovered less quickly while those with management actions in place recovered more quickly. To achieve the aims of the UN Decade on Restoration, we need to ensure, even for recovering species, that threats continue to be reduced and that conservation management actions are ongoing and effective.
Multiple climate change factors jointly increase the competitiveness of a C4 grass against its C3 competitor
Authors: Hsu Gen-Chang , Ke Po-Ju , Ho Chuan-Kai 
Published: September 2022

AbstractC3 and C4 plants are the two major terrestrial plant groups that respond differently to temperature, water, and CO2. Although much research has focused on the individual effect of warming, water availability, and elevated CO2 on biomass production and competitive interactions between C3 and C4 plants, the joint effects of these factors remain underexplored. We grew naturally co-occurring C3 (Oplismenus composites) and C4 (Paspalum conjugatum) grass under three temperature warming scenarios (control, +2°C, and +4°C), two water supply intervals (normal 2 days vs. prolonged 7 days [drought]), and two CO2 concentrations (ambient 400 ppm vs. elevated 800 ppm) in growth chambers and measured their above- and below-ground dry biomass in monoculture and mixture to quantify their biomass performances and competitive responses. Warming and elevated CO2 together enhanced the above- and/or below-ground biomass of both C3 and C4 grass. Moreover, temperature, water, and CO2 interacted to increase the below-ground biomass of the C4 grass. Surprisingly, the C3 grass performed worse under interspecific competition (mixture biomass) relative to intraspecific competition (monoculture biomass) at elevated CO2 compared to ambient CO2, while the reverse is true for the C4 grass. Furthermore, the C4 grass was most competitive against the C3 grass under simultaneous 4°C warming, drought, and elevated CO2. Taken together, our results suggest that the competitive balance could potentially shift in favor of C4 plants under the projected temperature warming, increased drought frequencies, and rising atmospheric CO2, with an increase in C4 relative abundance in future plant communities.
Identification of a novel HASPIN inhibitor and its synergism with the PLK1 inhibitor
Authors: Kwon Eun-Ji , Mashelkar Karishma K. , Seo Juhee , Shin Yoonze , Sung Kisu , Jang Sung Chul , Cheon Sang Won , Lee Haeseung , Han Byung Woo , Lee Sang Kook , Jeong Lak Shin , Cha Hyuk-Jin 
Published: September 2022

SummaryBackgroundHASPIN, a mitotic kinase for Histone H3, is a promising target for anti-cancer therapy. However, as HASPIN is an atypical kinase with low similarity to eukaryotic protein kinases, development of a HASPIN inhibitor from the conventional pharmacophore of kinase inhibitors would be technically challenging.MethodsChemical modifications of a cytotoxic 4’-thioadenosine analogue with high genotoxicity and multiple kinomescan profiles were performed to produce a novel non-genotoxic kinase inhibitor, LJ4827. The mode of action of this inhibitor with clear anti-cancer activity was inferred based on transcriptomic and chemical similarity to known drugs.ResultsThe specificity and potency of LJ4827 as a HASPIN inhibitor were validated by in vitro kinase screening and subsequent X-ray crystallography. As predicted, LJ4827 treatment delayed mitosis by clear inhibition of the recruitment of Aurora B at the centromere in cancer cells, without a genotoxic response. Through transcriptome analysis of lung cancer patients, PLK1 was predicted as a druggable synergistic partner to complement HASPIN inhibition. Cotreatment with the PLK1 inhibitor BI2536 and LJ4827 led to pronounced cytotoxicity of lung cancers in vitro and in vivo.ConclusionSimultaneous inhibition of both HASPIN and PLK1 is a promising therapeutic strategy for lung cancers.
The locus coeruleus mediates behavioral flexibility
Authors: McBurney-Lin Jim , Yang Hongdian 
Published: September 2022

AbstractBehavioral flexibility refers to the ability to adjust behavioral strategies in response to changing environmental contingencies. A major hypothesis in the field posits that the activity of neurons in the locus coeruleus (LC) plays an important role in mediating behavioral flexibility. To test this hypothesis, we developed a novel context-dependent bilateral tactile detection task where mice responded to left and right whisker deflections in a rule-dependent manner and exhibited varying degrees of flexible switching behavior. Recording from optogenetically-tagged neurons in the LC during task performance revealed a prominent graded correlation between baseline LC activity and behavioral flexibility, where higher baseline activity following a rule change was associated with faster behavioral switching to the new rule. Increasing baseline LC activity with optogenetic activation improved task performance and accelerated task switching. Overall, our study provides strong evidence to demonstrate that LC activity mediates behavioral flexibility.
Gell: A GPU-powered 3D hybrid simulator for large-scale multicellular system
Authors: Du Jiayi , Zhou Yu , Jin Lihua , Sheng Ke 
Published: September 2022

AbstractAs a powerful but computationally intensive method, hybrid computational models study the dynamics of multicellular systems by evolving discrete cells in reacting and diffusing extracellular microenvironments. As the scale and complexity of studied biological systems continuously increase, the exploding computational cost starts to limit large-scale cell-based simulations. To facilitate the large-scale hybrid computational simulation and make it feasible on easily accessible computational devices, we develop a fast and memory-efficient open-source GPU-based hybrid computational modeling platform Gell (GPU Cell), for large-scale system modeling. We fully parallelize the simulations on GPU for high computational efficiency and propose a novel voxel sorting method to further accelerate the modeling of massive cell-cell mechanical interaction with negligible additional memory footprint. As a result, Gell efficiently handles simulations involving tens of millions of cells on a personal computer. We compare the performance of Gell with a state-of-the-art paralleled CPU-based simulator on a hanging droplet spheroid growth task and further demonstrate Gell with a ductal carcinoma in situ (DCIS) simulation. Gell affords ~150X acceleration over the paralleled CPU method with one-tenth of the memory requirement.Author SummaryNumerical cell simulations provide indispensable insight into the cell-to-tumor tissue transition and help reduce biological experimental variables. However, the availability and practicality of large-scale cell simulation tools have been limited by high computational cost, slow performance, or proprietary. Recent developments in open-source simulation codes and GPU implementation have partially addressed the challenge. We further optimized the cell simulation platform for GPU implementation in this work. As a result, benchmark cell simulation experiments can be performed efficiently on a personal computer with a modern GPU. We made the platform open source to encourage community adoption and collective development.