bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stimulation of platelet P2Y1 receptors by different endogenous nucleotides leads to functional selectivity via biased signalling
Authors: Arkless Kate L , Pan Dingxin , Shankar-Hari Manu , Amison Richard T. , Page Clive P. , Rahman Khondaker Miraz , Pitchford Simon C. 
Published: August 2022

AbstractBackground and PurposePlatelet function during inflammation is dependent on activation by endogenous nucleotides. Non-canonical signalling via the P2Y1 receptor is important for these non-thrombotic functions of platelets. However, apart from ADP, the role of other endogenous nucleotides acting as agonists at P2Y1 receptors is unknown. This study compared the effects of ADP, Ap3A, NAD+, ADP-ribose, and Up4A on platelet functions contributing to inflammation or haemostasis.Experimental ApproachPlatelets obtained from healthy human volunteers were incubated with ADP, Ap3A, NAD+, ADP-ribose or Up4A, with aggregation and fibrinogen binding measured (examples of function during haemostasis) or before exposure to fMLP to measure platelet chemotaxis (an inflammatory function). In silico molecular docking of these nucleotides to the binding pocket of P2Y1 receptors was then assessed.Key ResultsPlatelet aggregation and binding to fibrinogen induced by ADP was not mimicked by NAD+, ADP-ribose, and Up4A. However, these endogenous nucleotides induced P2Y1-dependent platelet chemotaxis, an effect that required RhoA and Rac-1 activity, but not canonical PLC activity. Analysis of molecular docking of the P2Y1 receptor revealed distinct differences of amino acid interactions and depth of fit within the binding pocket by Ap3A, NAD+, ADP-ribose or Up4A compared to ADP.Conclusion and ImplicationsPlatelet function (aggregation vs motility) can be differentially modulated by biased-agonist activation of P2Y1 receptors. This may be due to the character of the ligand-binding pocket interaction. This has implications for future therapeutic strategies aimed to suppress platelet activation during inflammation without affecting haemostasis as is the requirement of current ant-platelet drugs.
Cola Subgenus Disticha subg. nov. (Malvaceae-Sterculiaceae) of tropical Africa, a synoptic taxonomic revision with seven new species
Authors: Cheek Martin 
Published: August 2022

SummaryA new subgenus, Subg. Disticha is erected for 14 species of simple-leaved Cola sharing unique characters within the genus which are presumed synapomorphies: distichous phyllotaxy; petioles lacking pulvini; petioles of uniformly short length, <10 mm long; male flowers with short androphores <1(– 2) mm long; stamens 4 – 5; stem indumentum where present, dominated by short simple translucent hairs (except in C. philipi-jonesii where stellate), and in many species dark purple to black stems with contrasting bright white lenticels. All species have fruit with small globose, unsculptured orange mericarps c. 1 cm diam. (where fruits are known). The species of this subgenus range from SE Nigeria in the west to coastal Kenya and Tanzania in the east and Malawi in the south, but are absent from the Congo basin. Species diversity is highest in the Cross-Sanaga and Eastern Arc-Coastal Forest biogeographic areas, consistent with these taxa being Pleistocene refuge species. The species are mainly monoecious, but dioecy cannot yet be ruled out in some species. In two species where sufficient material was available for investigation (Cola chlorantha, C. roy), the simple cymes were found to be bisexual, the terminal flower being female, the two lateral flowers often being male, a pattern previously unreported in the genus. All species are understorey shrubs or small trees of evergreen lowland or submontane forest, except C. uloloma of coastal semi-deciduous forest in E Africa and which is unique in showing xerophilic characteristics. The species can be divided into group A: five species mainly in E Africa with rapidly glabrescent or glabrous stems, conspicuously asymmetric leaves, few-flowered, pedunculate cymes (C. uloloma, C. chlorantha, C. roy sp.nov., C.”udzungwa”, C. asymmetrica sp. nov.); group B: in Lower Guinea (Atlantic coast of Africa) with hairy stems, symmetric or inconspicuously asymmetric leaves, sessile, fasciculate inflorescences: (Cola mayimbensis, C. philipi-jonesii, C. metallica, C.moussavoui, C. stigmatosa, C. takamanda sp.nov. C. toyota sp. nov, C. “campo-ma’an”, C. zanaga sp. nov.). Of the seven new species to science, two are named informally since the material is so incomplete (sterile), and five are formally named. Species diversity is highest in Cameroon and Tanzania, each with four species, followed by Gabon with three species. It is expected that additional new species will be found in poorly-surveyed surviving evergreen forest habitat in each of these three countries. Conservation assessments are given for each species using the IUCN 2012 standard. All species are considered threatened, with ten species being Critically Endangered (the highest category of threat), each known from a single location, with their forest habitat threatened mainly by clearance for agriculture.
Are Deep Learning Structural Models Sufficiently Accurate for Free Energy Calculations? Application of FEP+ to AlphaFold2 Predicted Structures
Authors: Beuming Thijs , Martín Helena , Díaz-Rovira Anna M. , Díaz Lucía , Guallar Victor , Ray Soumya S. 
Published: August 2022

ABSTRACTThe availability of AlphaFold2 has led to great excitement in the scientific community - particularly among drug hunters - due to the ability of the algorithm to predict protein structures with high accuracy. However, beyond globally accurate protein structure prediction, it remains to be determined whether ligand binding sites are predicted with sufficient accuracy in these structures to be useful in supporting computationally driven drug discovery programs. We explored this question by performing free energy perturbation (FEP) calculations on a set of well-studied protein-ligand complexes, where AlphaFold2 predictions were performed by removing all templates with >30% identity to the target protein from the training set. We observed that in most cases, the ΔΔG values for ligand transformations calculated with FEP, using these prospective AlphaFold2 structures, were comparable in accuracy to the corresponding calculations previously carried out using X-ray structures. We conclude that under the right circumstances, AlphaFold2 modeled structures are accurate enough to be used by physics-based methods such as FEP, in typical lead optimization stages of a drug discovery program.
Large-scale network metrics improve the classification performance of rapid-eye-movement sleep behavior disorder patients
Authors: Roascio Monica , Turrisi Rosanna , Arnaldi Dario , Famà Francesco , Mattioli Pietro , Nobili Flavio , Barla Annalisa , Arnulfo Gabriele 
Published: August 2022

AbstractClinical decision support systems based on machine-learning algorithms are largely applied in the context of the diagnosis of neurodegenerative diseases (NDDs). While recent models yield robust classifications in supervised two classes-problems accurately separating Parkinson’s disease (PD) from healthy control (HC) subjects, few works looked at prodromal stages of NDDs. Idiopathic Rapid-eye Movement (REM) sleep behavior disorder (iRBD) is considered a prodromal stage of PD with a high chance of phenoconversion but with heterogeneous symptoms that hinder accurate disease prediction. Machine learning (ML) based methods can be used to develop personalized trajectory models, but these require large amounts of observational points with homogenous features significantly reducing the possible imaging modalities to non-invasive and cost-effective techniques such as high-density electrophysiology (hdEEG). In this work, we aimed at quantifying the increase in accuracy and robustness of the classification model with the inclusion of network-based metrics compared to the classical Fourier-based power spectral density (PSD). We performed a series of analyses to quantify significance in cohort-wise metrics, the performance of classification tasks, and the effect of feature selection on model accuracy.We report that amplitude correlation spectral profiles show the largest difference between iRBD and HC subjects mainly in delta and theta bands. Moreover, the inclusion of amplitude correlation and phase synchronization improves the classification performance by up to 11% compared to using PSD alone. Our results show that hdEEG features alone can be used as potential biomarkers in classification problems using iRBD data and that large-scale network metrics improve the performance of the model. This evidence suggests that large-scale brain network metrics should be considered important tools for investigating prodromal stages of NDD as they yield more information without harming the patient, allowing for constant and frequent longitudinal evaluation of patients at high risk of phenoconversion.HighlightsNetwork-based features are important tools to investigate prodromal stages of PDAmplitude correlation shows the largest difference between two groups in 9/30 bandsAmplitude correlation improved up to 11% the performance compared to PSD aloneClassification robustness increases when we use both network-based EEG featuresClassifier performance worsens when PSD is added to network-based EEG features
ATG9 vesicles comprise the seed membrane of mammalian autophagosomes
Authors: Olivas Taryn J. , Wu Yumei , Yu Shenliang , Luan Lin , Choi Peter , Nag Shanta , De Camilli Pietro , Gupta Kallol , Melia Thomas J. 
Published: August 2022

AbstractDuring autophagosome biogenesis, the incorporation of transmembrane proteins into the expanding phagophore is not readily observed. In addition, the membrane surface area of the organelle expands rapidly, while the volume of the autophagosome is kept low. Several recent studies have suggested a model of membrane expansion that explains how these attributes are maintained. The autophagosome expands predominantly through the direct protein-mediated transfer of lipids through the lipid transfer protein ATG2. As these lipids are only introduced into the cytoplasmic-facing leaflet of the expanding phagophore, full membrane growth also requires lipid scramblase activity. ATG9 has been demonstrated to harbor scramblase activity and is essential to autophagosome formation, however if and when it is integrated into mammalian autophagosomes remains unclear. Here we show that in the absence of lipid transport, ATG9 vesicles are already fully competent to collect proteins normally found on mature autophagosomes, including LC3-II. Further, through the novel use of styrene-maleic acid lipid particles as a nanoscale interrogation of protein organization on intact membranes, we show that ATG9 is fully integrated in the same membranes as LC3-II, even on maturing autophagosomes. The ratios of these two proteins at different stages of maturation demonstrate that ATG9 proteins are not continuously integrated, but rather are present on the seed vesicles only and become diluted in the rapidly expanding autophagosome membrane. Thus, ATG9 vesicles are the seed membrane from which mammalian autophagosomes form.
Spatial confinement modulates macrophage response in microporous annealed particle (MAP) scaffolds
Authors: Liu Yining , Suarez-Arnedo Alejandra , Riley Lindsay , Miley Tasman , Xia Jingyi , Segura Tatiana 
Published: August 2022

AbstractMacrophages are essential in the initiation, maintenance, and transition of inflammatory processes like foreign body response and wound healing. Mounting evidence suggests that physical factors also modulate macrophage activationin vitroandin vivo. 2Din vitrosystems have demonstrated that constraining macrophages to small areas or channels modulates their phenotypes and changes their responses to known inflammatory agents such as lipopolysaccharide. However, how dimensionality and pore size affect macrophage phenotype is less explored. In this work, we studied the change in M1/M2 polarization when macrophages were confined in microporous annealed particle scaffolds (MAP), which are granular hydrogels generated from annealed spherical microgels. We engineered three types of MAP gels comprising 40, 70, and 130 µm diameter particle sizes, respectively. Particles sizes were selected using outputs from software LOVAMAP that analyzes the characteristics of 3-D pores in MAP gels. Since the size of building block particle correlates with pore size inside the final scaffolds, our three scaffold types allowed us to study how the degree of spatial confinement modulated the behavior of embedded macrophages. Spatially confining macrophages in scaffolds with pore size on the scale of cells led to a reduced level of the inflammatory response, which was correlated with a change in cell morphology and motility.
The bed nucleus of the stria terminalis mediates the expression of proactive defensive behavior
Authors: Guerra Diana P. , Wang Wei , de Souza Karienn A. , Moscarello Justin M. 
Published: August 2022

AbstractThe bed nucleus of the stria terminalis (BNST) is a forebrain region implicated in aversive responses to uncertain threat. Much of the work on the role of BNST in defensive behavior has used Pavlovian paradigms in which the subject reacts to aversive stimuli delivered in a pattern determined entirely by the experimenter. Here, we report that BNST also mediates proactive defensive responses in a task that allows subjects to prevent the delivery of an aversive outcome. In a standard two-way signaled active avoidance paradigm, male rats learned to shuttle during a tone to avoid shock. Our data demonstrate that chemogenetic inhibition (hM4Di) of BNST attenuates the expression of the avoidance response, whereas chemogenetic activation (hM3Dq) of BNST potentiates the response by extending the period of tone-evoked shuttling. This effect was specific to the BNST, as inactivation of the neighboring medial septum produced no effect on the expression of avoidance. These data support the novel conclusion that BNST mediates two-way avoidance behavior in male rats.
RNA localization to the mitotic spindle regulated by kinesin-1 and dynein is essential for early development of the sea urchin embryo
Authors: Remsburg Carolyn M. , Konrad Kalin D. , Song Jia L. 
Published: August 2022

AbstractMitosis is a fundamental and highly regulated process that acts to faithfully segregate chromosomes into two identical daughter cells. Transcript localization of genes involved in mitosis to the mitotic spindle may be an evolutionarily conserved mechanism to ensure that mitosis occurs in a timely manner. We identified many RNA transcripts that encode proteins involved in mitosis localized at the mitotic spindles in dividing sea urchin embryos and mammalian cells. Disruption of microtubule polymerization, kinesin-1, or dynein results in lack of spindle localization of these transcripts in the sea urchin embryo. Further, results indicate that the cytoplasmic polyadenylation element (CPE) within the 3’UTR of Aurora B, a recognition sequence of CPEB, is essential for RNA localization to the mitotic spindle. Blocking this sequence results in arrested development during early cleavage stages, suggesting that RNA localization to the mitotic spindle may be a regulatory mechanism of cell division that is important for early development.
Nanosecond pulsed electric field ablates rabbit VX2 liver tumors in a non-thermal manner versus radiofrequency ablation
Authors: Li Qing-Gang , Liu Zhen-Guo , Sun Ying , Zou Ya-Wen , Chen Xiao-Long , Wu Bin , Chen Xin-Hua , Ren Zhi-Gang 
Published: August 2022

AbstractBackgroundLiver tumor remains an important cause of cancer-related death. Nanosecond pulsed electric fields (nsPEFs) are advantageous in the treatment of melanoma and pancreatic cancer, but their therapeutic application on liver tumors need to be further studied.MethodsHep3B cells were treated with nsPEFs. The biological behaviors of cells were detected by Cell Counting Kit-8, 5-ethynyl-20-deoxyuridine, and transmission electron microscopy (TEM) assays. In vivo, rabbit VX2 liver tumor models were ablated by ultrasound-guided nsPEFs and radiofrequency ablation (RFA). Contrast-enhanced ultrasound (CEUS) was used to evaluate the ablation effect. HE staining and Masson staining were used to evaluate the tissue morphology after ablation. Immunohistochemistry was performed to determine the expression of Ki67, proliferating cell nuclear antigen, and α-smooth muscle actin at different time points after ablation.ResultsThe cell viability of Hep3B cells was continuously lower than that of the control group within 3 days after pulse treatment. The proliferation of Hep3B cells was significantly affected by nsPEFs. TEM showed that Hep3B cells underwent significant morphological changes after pulse treatment. In vivo, CEUS imaging showed that nsPEFs could completely ablate model rabbit VX2 liver tumors. After nsPEFs ablation, the area of tumor fibrosis and the expression of Ki67, proliferating cell nuclear antigen, and α-smooth muscle actin were decreased. However, after RFA, rabbit VX2 liver tumor tissue showed complete necrosis, but the expression of PCNA and α-smooth muscle actin did not decrease compared to the tumor group.ConclusionsnsPEFs can induce Hep3B cells apoptosis and ablate rabbit VX2 liver tumors in a non-thermal manner versus RFA. The ultrasound contrast agent can monitor immediate effect of nsPEF ablation. This study provides a basis for the clinical study of nsPEFs ablation of liver cancer.
Experience-dependent plasticity of gustatory insular cortex circuits and taste preferences
Authors: Schiff Hillary C. , Kogan Joshua F. , Isaac Maria , Czarnecki Lindsey A. , Fontanini Alfredo , Maffei Arianna 
Published: August 2022

AbstractEarly experience with food influences taste preference in adulthood. How gustatory experience influences development of taste preferences and refinement of cortical circuits has not been investigated. Here we exposed weanling mice to an array of tastants and determined the effects on the preference for sweet in adulthood. We demonstrate an experience-dependent shift in sucrose preference persisting several weeks following the termination of exposure. A shift in sucrose palatability, altered neural responsiveness to sucrose, and inhibitory synaptic plasticity in the gustatory portion of the insular cortex (GC) were also induced. The modulation of sweet preference occurred within a restricted developmental window, but restoration of the capacity for inhibitory plasticity in adult GC reactivated the sensitivity of sucrose preference to taste experience. Our results establish a fundamental link between gustatory experience, sweet-preference, inhibitory plasticity, and cortical circuit function, and highlight the importance of early life experience in setting taste preferences.
Novel gene-intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy: A new mechanism for motor neuron degeneration
Authors: Cutrupi Anthony N. , Narayanan Ramesh K. , Perez-Siles Gonzalo , Grosz Bianca R. , Lai Kaitao , Boyling Alexandra , Ellis Melina , Lin Ruby CY , Neumann Brent , Mao Di , Uesugi Motonari , Nicholson Garth A. , Vucic Steve , Saporta Mario A. , Kennerson Marina L. 
Published: August 2022

AbstractDistal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and 4 disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild type full length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic C. elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.
Reshuffling of the coral microbiome during dormancy
Authors: Brown Anya L , Sharp Koty , Apprill Amy 
Published: August 2022

AbstractQuiescence, or dormancy, is a response to stressful conditions in which an organism slows or halts physiological functioning. Although most species that undergo dormancy maintain complex microbiomes, there is little known about how dormancy influences and is influenced by the host’s microbiome, including in the temperate coral, Astrangia poculata. Northern populations of A. poculata undergo winter quiescence. Here, we characterized wild A. poculata microbiomes in a high-resolution sampling time series before, during, and after quiescence using 16S ribosomal RNA gene sequencing on active (RNA) and present (DNA) microbiomes. We observed a restructuring of the coral microbiome during quiescence that persisted after re-emergence. Upon entering quiescence, corals shed copiotrophic microbes, including putative pathogens, suggesting removal of these taxa as corals cease normal functioning. During and after quiescence, bacteria and archaea associated with nitrification were enriched, suggesting the quiescent microbiome may replace essential functions through supplying nitrate to corals and/or microbes. Overall, this study demonstrates that key microbial groups related to quiescence in A. poculata may play a role in the onset or emergence from dormancy, and long-term regulation of the microbiome composition. The predictability of dormancy in A. poculata provides an ideal natural manipulation system to further identify factors that regulate host-microbial associations.ImportanceUsing a high-resolution sampling time series, we are the first to demonstrate a persistent microbial community shift with quiescence (dormancy) in a marine organism, the temperate coral, Astrangia poculata. Furthermore, during this period of community turnover, there is a shedding of putative pathogens and copiotrophs and an enhancement of the ammonia-oxidizing bacteria (Nitrosococcales) and archaea (Ca. Nitrosopumilus). Our results suggest that quiescence represents an important period during which the coral microbiome can “reset,” shedding opportunistic microbes and enriching for the re-establishment of beneficial associates, including those that may contribute nitrate while the coral animal is not actively feeding. We suggest this work provides foundational understanding of the interplay of microbes and the host’s dormancy response in marine organisms.