bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variation in Dental Tissues: Using Bayesian Multilevel Modelling to Explore Intra- and Inter-Individual Dental Variation
Authors: Fernee Christianne , Zakzewski Sonia , Robson Brown Kate 
Published: May 2023

AbstractObjectivesDental variation within populations and, even more so, within individuals is far less well understood than variation between populations. This is problematic as a single tooth type is often used as a representative of the whole dentition, despite a lack of understanding of intra-tooth type relationships. This research investigates the variation of dental tissues and proportions within and between individuals.Materials and MethodsUpper and lower first incisor to second premolar tooth rows were obtained from 30 individuals (n=300), from 3 archaeological samples. The teeth were micro-CT scanned and surface area and volumetric measurements were obtained from the surface meshes extracted. Dental variation of these measurements on a tooth and individual level was studied using Bayesian Multilevel Modelling.ResultsThe individual and tooth level variation differed by dental measurement, ranging between 9.5%-47.5% and 52.6-90.5% respectively. Enamel volume had the highest degree of individual-level variation in contrast to coronal dentine volume that had the lowest of individual-level variation. Tooth type, isomere, and position in field all showed a significant effect on the dental measurements examined in this study.DiscussionTooth selection and sampling strategies should consider individual and tooth-level variation, with at least one tooth from each type and isomere included in analyses. This will ensure that any population-level differences are not masked by variability between teeth. The low level of coronal dentine volume individual variation indicates that it is particularly useful in studies with small sample sizes.
Building the vector in? Construction practices contribute to the invasion and persistence ofAnopheles stephensiin Jigjiga, Ethiopia
Authors: Yared Solomon , Gebresilassie Araya , Aklilu Esayas , Abdulahi Elyas , Kirstein Oscar D. , Gonzalez-Olvera Gabriela , Che-Mendoza Azael , Bibiano-Marin Wilbert , Waymire Elizabeth , Lines Jo , Lenhart Audrey , Kitron Uriel , Carter Tamar , Manrique-Saide Pablo , Vazquez-Prokopec Gonzalo M. 
Published: May 2023

AbstractAnopheles stephensiis a major vector of malaria in Asia and the Arabian Peninsula, and its recent invasion into Africa poses a significant threat to malaria control and elimination efforts on the continent. The mosquito is well-adapted to urban environments, and its presence in Africa could potentially lead to an increase in malaria transmission in cities. Most of the knowledge aboutAn. stephensiecology in Africa has been generated from studies conducted during the rainy season, when vectors are most abundant. Here, we provide evidence from the peak of the dry season in the city of Jigjiga, Ethiopia, and report the finding ofAn. stephensiimmature stages infesting predominantly water reservoirs made to support construction operations (in construction sites or associated with brick manufacturing businesses). Political and economic changes in Ethiopia (and particularly the Somali Region) have fueled an unprecedented construction boom since 2018 that, in our opinion, has been instrumental in the establishment, persistence and propagation ofAn. stephensivia the year-round availability of perennial larval habitats associated with construction. We argue that larval source management during the dry season may provide a unique opportunity for focused control ofAn. stephensiin Jigjiga and similar areas.
Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer
Authors: Cárdenas Emilio L. , O’Rourke Rachel L. , Menon Arya , Meagher Jennifer , Stuckey Jeanne , Garner Amanda L. 
Published: May 2023

ABSTRACTEukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to the m7GpppX-cap at the 5′ terminus of coding mRNAs to initiate cap-dependent translation. While all cells require cap-dependent translation, cancer cells become addicted to enhanced translational capacity, driving the production of oncogenic proteins involved in proliferation, evasion of apoptosis, metastasis, and angiogenesis among other cancerous phenotypes. eIF4E is the rate-limiting translation factor and its activation has been shown to drive cancer initiation, progression, metastasis, and drug resistance. These findings have established eIF4E as a translational oncogene and promising, albeit challenging, anti-cancer therapeutic target. Although significant effort has been put forth towards inhibiting eIF4E, the design of cell-permeable, cap-competitive inhibitors remains a challenge. Herein, we describe our work towards solving this long-standing challenge. By employing an acyclic nucleoside phosphonate prodrug strategy, we report the synthesis of cell-permeable inhibitors of eIF4E binding to capped mRNA to inhibit cap-dependent translation.
Mifepristone decreases nicotine intake in dependent and non-dependent adult rats
Authors: Chellian Ranjithkumar , Behnood-Rod Azin , Bruijnzeel Adriaan W. 
Published: May 2023

AbstractAddiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders. The aim of these studies was to investigate if glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine. The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent (3 days per week) or daily access (7 days per week) for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine if the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded. The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access, but only the rats with daily access to nicotine showed signs of dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the total distance traveled and rearing in the open field test and operant responding for food pellets. These findings indicate that mifepristone decreases the reinforcing effects of nicotine and food, but it might also be somewhat sedative.
Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway
Authors: Koumoundourou Artemis , Rannap Märt , Bruyckere Elodie De , Nestel Sigrun , Reißner Carsten , Egorov Alexei V. , Liu Pentao , Missler Markus , Heimrich Bernd , Draguhn Andreas , Britsch Stefan 
Published: May 2023

AbstractThe transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapsesin vivoandin vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.
Quantitative Geometric Modeling of Blood Cells from X-ray Histotomograms of Whole Zebrafish Larvae
Authors: Yakovlev Maksim A. , Liang Ke , Zaino Carolyn R. , Vanselow Daniel J. , Sugarman Andrew L. , Lin Alex Y. , La Riviere Patrick J. , Zheng Yuxi , Silverman Justin D. , Leichty John C. , Huang Sharon X. , Cheng Keith C. 
Published: May 2023

AbstractTissue phenotyping is foundational to understanding and assessing the cellular aspects of disease in organismal context and an important adjunct to molecular studies in the dissection of gene function, chemical effects, and disease. As a first step toward computational tissue phenotyping, we explore the potential of cellular phenotyping from 3-Dimensional (3D), 0.74 µm isotropic voxel resolution, whole zebrafish larval images derived from X-ray histotomography, a form of micro-CT customized for histopathology. As proof of principle towards computational tissue phenotyping of cells, we created a semi-automated mechanism for the segmentation of blood cells in the vascular spaces of zebrafish larvae, followed by modeling and extraction of quantitative geometric parameters. Manually segmented cells were used to train a random forest classifier for blood cells, enabling the use of a generalized cellular segmentation algorithm for the accurate segmentation of blood cells. These models were used to create an automated data segmentation and analysis pipeline to guide the steps in a 3D workflow including blood cell region prediction, cell boundary extraction, and statistical characterization of 3D geometric and cytological features. We were able to distinguish blood cells at two stages in development (4- and 5-days-post-fertilization) and wild-type vs.polA2 huli hutu(hht) mutants. The application of geometric modeling across cell types to and across organisms and sample types may comprise a valuable foundation for computational phenotyping that is more open, informative, rapid, objective, and reproducible.
A single cell transcriptomic fingerprint of stressed premature, imbalanced differentiation of embryonic stem cells
Authors: Ruden Ximena , Singh Aditi , Marben Teya , Tang Wen , Awonuga Awoniyi , Ruden Douglas M. , Puscheck Elizabeth , Feng Hao , Rappolee Daniel 
Published: May 2023

AbstractCultured naïve pluripotent ESC differentiate into first lineage, XEN or second lineage, formative pluripotency. Hyperosmotic stress (sorbitol), like retinoic acid, decreases naive pluripotency and increases XEN in two ESC lines, as reported by bulk and scRNAseq, analyzed by UMAP. Sorbitol overrides pluripotency in two ESC lines as reported by bulk and scRNAseq, analyzed by UMAP. UMAP analyzed the effects of 5 stimuli - three stressed (200-300mM sorbitol with leukemia inhibitory factor +LIF) and two unstressed (+LIF, normal stemness-NS and -LIF, normal differentiation-ND). Sorbitol and RA decrease naive pluripotency and increase subpopulations of 2-cell embryo-like and XEN sub-lineages; primitive, parietal, and visceral endoderm (VE). Between the naïve pluripotency and primitive endoderm clusters is a stress-induced cluster with transient intermediate cells with higher LIF receptor signaling, with increased Stat3, Klf4, and Tbx3 expression. Sorbitol, like RA, also suppresses formative pluripotency, increasing lineage imbalance. Although bulk RNAseq and gene ontology group analyses suggest that stress induces head organizer and placental markers, scRNAseq reveals few cells. But VE and placental markers/cells were in adjacent clusters, like recent reports. UMAPs show that dose-dependent stress overrides stemness to force premature lineage imbalance. Hyperosmotic stress induces lineage imbalance, and other toxicological stresses, like drugs with RA, may cause lineage imbalance, resulting in miscarriages or birth defects.
Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer’s Disease mice
Authors: Hafycz Jennifer M. , Strus Ewa , Naidoo Nirinjini N. 
Published: May 2023

AbstractAlzheimer’s disease (AD) is a debilitating neurodegenerative disorder that is pervasive among the aging population. Two distinct phenotypes of AD are deficits in cognition and proteostasis, including chronic activation of the unfolded protein response (UPR) and aberrant Aβ production. It is unknown if restoring proteostasis by reducing chronic and aberrant UPR activation in AD can improve pathology and cognition. Here, we present data using an APP knock-in mouse model of AD and several protein chaperone supplementation paradigms, including a late-stage intervention. We show that supplementing protein chaperones systemically and locally in the hippocampus reduces PERK signaling and increases XBP1s, which is associated with increased ADAM10 and decreased Aβ42. Importantly, chaperone treatment improves cognition which is correlated with increased CREB phosphorylation and BDNF. Together, this data suggests that chaperone treatment restores proteostasis in a mouse model of AD and that this restoration is associated with improved cognition and reduced pathology.One-sentence summaryChaperone therapy in a mouse model of Alzheimer’s disease improves cognition by reducing chronic UPR activity
Theoretical framework and experimental solution for the air-water interface adsorption problem in cryoEM
Authors: Kang Joon S. , Zhou Xueting , Liu Yun-Tao , Wang Kaituo , Zhou Z. Hong 
Published: May 2023

AbstractAs cryogenic electron microscopy (cryoEM) gains traction in the structural biology community as a method of choice for determining atomic structures of biological complexes, it has been increasingly recognized that many complexes that behave well under conventional negative-stain electron microscopy tend to have preferential orientation, aggregate or simply mysteriously “disappear” on cryoEM grids, but the reasons for such misbehavior are not well understood, limiting systematic approaches to solving the problem. Here, we have developed a theoretical formulation that explains these observations. Our formulation predicts that all particles migrate to the air-water interface (AWI) to lower the total potential surface energy — rationalizing the use of surfactant, which is a direct solution to reducing the surface tension of the aqueous solution. By conducting cryogenic electron tomography (cryoET) with the widely-tested sample, GroEL, we demonstrate that, in a standard buffer solution, nearly all particles migrate to the AWI. Gradual reduction of the surface tension by introducing surfactants decreased the percentage of particles exposed to the surface. By conducting single-particle cryoEM, we confirm that applicable surfactants do not damage the biological complex, thus suggesting that they might offer a practical, simple, and general solution to the problem for high-resolution cryoEM. Application of this solution to a real-world AWI adsorption problem with a more challenging membrane protein, namely, the ClC-1 channel, has led to its first near-atomic structure using cryoEM.
HNF4α mediated QPRT expression in the kidney facilitates resilience against acute kidney injury
Authors: Clark Amanda J. , Saade Marie Christelle , Vemireddy Vamsidhara , Vu Kyle Q. , Flores Brenda Mendoza , Etzrodt Valerie , Ciampa Erin J. , Huang Huihui , Takakura Ayumi , Zandi-Nejad Kambiz , Zsengellér Zsuzsanna K. , Parikh Samir M. 
Published: May 2023

ABSTRACTNicotinamide adenine dinucleotide (NAD+) levels decline in experimental models of acute kidney injury (AKI). Attenuated enzymatic conversion of tryptophan to NAD+ in tubular epithelium may contribute to adverse cellular and physiological outcomes. Mechanisms underlying defense of tryptophan-dependent NAD+ production are incompletely understood. Here we show that regulation of a bottleneck enzyme in this pathway, quinolinate phosphoribosyltransferase (QPRT) may contribute to kidney resilience. Expression of QPRT declined in two unrelated models of AKI. Haploinsufficient mice developed worse outcomes compared to littermate controls whereas novel, conditional gain-of-function mice were protected from injury. Applying these findings, we then identified hepatocyte nuclear factor 4 alpha (HNF4α) as a candidate transcription factor regulating QPRT expression downstream of the mitochondrial biogenesis regulator and NAD+ biosynthesis inducer PPARgamma coactivator-1-alpha (PGC1α). This was verified by chromatin immunoprecipitation. A PGC1a-HNF4α -QPRT axis controlled NAD+ levels across cellular compartments and modulated cellular ATP. These results propose that tryptophan-dependent NAD+ biosynthesis via QPRT and induced by HNF4α may be a critical determinant of kidney resilience to noxious stressors.
Differential Contribution of Sensorimotor Cortex and Subthalamic Nucleus to Unimanual and Bimanual Hand Movements
Authors: Merrick Christina M. , Doyle Owen N. , Gallegos Natali E. , Irwin Zachary T. , Olson Joseph W. , Gonzalez Christopher L. , Knight Robert T. , Ivry Richard B. , Walker Harrison C. 
Published: May 2023

AbstractWhy does unilateral subthalamic nucleus deep brain stimulation improve motor function bilaterally? To address this clinical observation, we collected parallel neural recordings from sensorimotor cortex and the subthalamic nucleus during repetitive ipsilateral, contralateral, and bilateral hand movements in patients with Parkinson’s disease undergoing subthalamic nucleus deep brain stimulation. We used a cross-validated electrode-wise encoding model to map EMG data to the neural signals. Electrodes in the subthalamic nucleus encoded movement in a comparable manner for both hands during unimanual and bimanual movements, whereas sensorimotor cortex electrodes displayed a strong contralateral bias. To examine representational overlap in encoding across the two hands, we trained the model with data from one condition (contralateral hand) and used the trained weights to predict neural activity for movements produced with the other hand (ipsilateral hand). Overall, between-hand generalization was poor and this limitation was evident in both SMC and STN. A similar method was used to probe representational overlap across different task contexts (unimanual vs. bimanual). Task context was more important for the STN compared to the SMC indicating that neural activity in the STN showed greater divergence between the unimanual and bimanual conditions. These results indicate that whereas SMC activity is strongly lateralized and relatively context-free, STN integrates contextual information with the ongoing behavior.Significance StatementUnilateral subthalamic nucleus deep brain stimulation (DBS) improves both contralateral and ipsilateral motor symptoms of Parkinson’s disease. To explore mechanisms for bilateral improvement, parallel neural recordings from the sensorimotor cortex (SMC) and subthalamic nucleus (STN) were recorded in patients with Parkinson’s disease undergoing DBS. Neural activity and muscle activity from the hands were collected while patients performed unimanual and bimanual repetitive hand movements. Activity in SMC primarily encoded contralateral movements and was relatively context-free. In contrast, STN encoded movements in a comparable manner for both hands and was sensitive to the behavioral context.
Structural Visualization of HECT-E3 Ufd4 accepting and transferring Ubiquitin to Form K29/K48-branched Polyubiquitination on N-degron
Authors: Mao Junxiong , Ai Huasong , Wu Xiangwei , Zheng Qingyun , Cai Hongyi , Liang Lujun , Tong Zebin , Pan Man , Liu Lei 
Published: May 2023

SummaryProteins with destabilizing N-terminal residues are degraded via K48-linked ubiquitination-dependent N-degron pathway, during which the HECT-type E3 ligase Ufd4 can further augment polyubiquitination events on these proteins to accelerate their degradation. How Ufd4 increase polyubiquitination on ubiquitinated N-degrons remains unclear. Here, we biochemically determined that Ufd4 preferentially ubiquitinates the proximal ubiquitin in K48-linked ubiquitin chain in K29-linkage specific manner and revealed high-resolution cryo-EM structures of Ufd4 accepting (E2-to-E3 state, 3.52 Å) and transferring ubiquitin-thioester (E3-to-substrate state, 3.31 Å), respectively. The N-terminal ARM region and HECT domain C-lobe of Ufd4 were identified and characterized as key structural elements that together recruit K48-linked diUb and orient Lys29 of its proximal Ub to the active cysteine of Ufd4 for K29-linked branched ubiquitination. These structures not only provide mechanistic insights into the architecture of the Ufd4 complex but also show the full picture of the Ub transferring cascades of HECT-type E3 ligase.
Study protocol for a randomised controlled trial investigating the effects of Mindfulness Based Stress Reduction on stress regulation and associated neurocognitive mechanisms in stressed university students: The MindRest study
Authors: Kogias Nikos , Geurts Dirk E. M. , Krause Florian , Speckens Anne E. M. , Hermans Erno J. 
Published: May 2023

AbstractBackground:Stress-related disorders are a growing public health concern. While stress is a natural and adaptive process, chronic exposure to stressors can lead to dysregulation and take a cumulative toll on physical and mental well-being. One approach to coping with stress and building resilience is through Mindfulness-Based Stress Reduction (MBSR). By understanding the neural mechanisms of MBSR, we can gain insight into how it reduces stress and what drives individual differences in treatment outcomes. This study aims to establish the clinical effects of MBSR on stress regulation in a population that is susceptible to develop stress-related disorders (i.e., university students with mild to high self-reported stress), to assess the role of large-scale brain networks in stress regulation changes induced by MBSR, and to identify who may benefit most from MBSR.Methods:This study is a longitudinal two-arm randomised, wait-list controlled trial to investigate the effects of MBSR on a preselected, Dutch university student population with elevated stress levels. Clinical symptoms are measured at baseline, post-treatment, and three months after training. Our primary clinical symptom is perceived stress, with additional measures of depressive and anxiety symptoms, alcohol use, stress resilience, positive mental health, and stress reactivity in daily life. We investigate the effects of MBSR on stress regulation in terms of behaviour, self- report measures, physiology, and brain activity. Repetitive negative thinking, cognitive reactivity, emotional allowance, mindfulness skills, and self-compassion will be tested as potential mediating factors for the clinical effects of MBSR. Childhood trauma, personality traits and baseline brain activity patterns will be tested as potential moderators of the clinical outcomes.DiscussionThis study aims to provide valuable insights into the effectiveness of MBSR in reducing stress-related symptoms in a susceptible student population and crucially, to investigate its effects on stress regulation, and to identify who may benefit most from the intervention.Trial registrationRegistered on September 15, 2022, at clinicaltrials.gov,NCT05541263.https://clinicaltrials.gov/ct2/show/study/NCT05541263