bluuebunny/crossref_metadata_2025_split huggingface dataset:
GIP receptor reduces osteoclast activity and improves osteoblast survival by activating multiple signaling pathways
Authors: Hansen Morten S. , Søe Kent , Christensen Line L. , Fernandez-Guerra Paula , Hansen Nina W. , Wyatt Rachael A. , Martin Claire , Hardy Rowan S. , Andersen Thomas L. , Olesen Jacob B. , Overgaard Søren , Hartmann Bolette , Rosenkilde Mette M. , Kassem Moustapha , Rauch Alexander , Gorvin Caroline M. , Frost Morten 
Published: July 2022

AbstractBone is a dynamic tissue that is remodeled throughout life by bone resorbing osteoclasts and bone forming osteoblasts, to adapt to physiological or mechanical demands. These processes are impaired in osteoporosis, and understanding how bone remodeling is regulated could improve anti-osteoporotic treatments. Clinical investigations show that short-term treatment with glucose-dependent insulinotropic polypeptide (GIP) acutely decreases serum markers of bone resorption and may increase bone formation. However, evidence for direct effects of GIP intracellular signaling and functions in mature human osteoclasts and osteoblasts have not been investigated. We report that the GIP receptor (GIPR) is robustly expressed in mature human osteoclasts. Exposure of osteoclasts to GIP inhibits osteoclastogenesis, delays bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways (cAMP, Src, Akt, calcium, p38) to impair nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) and nuclear factor-κB (NFκB). Human osteoblasts also express GIPR, and GIP improves osteoblast survival via cAMP and Akt-mediated pathways. GIP treatment of co-cultures of osteoclasts and osteoblasts also decreased bone resorption. Antagonizing GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoclasts and osteoblasts. This study demonstrates that GIP inhibits bone resorption and improves survival of human osteoblasts, which could increase bone mass and strength, supporting clinical investigations of the effect of GIP on bone. Moreover, this study demonstrates that GIPR agonism could be beneficial in the treatment of disorders of bone remodeling, such as osteoporosis.One-sentence SummaryGIP acts directly on bone cells to regulate bone remodeling
Single-Cell Transcriptome Dynamics of the Autotaxin-Lysophosphatidic Acid Axis During Muscle Regeneration Reveal Proliferative Effects in Mesenchymal Fibro-Adipogenic Progenitors
Authors: Contreras Osvaldo , Harvey Richard P. 
Published: July 2022

AbstractLysophosphatidic acid (LPA) is a growth factor-like bioactive phospholipid recognising LPA receptors (LPARs) and mediating signalling pathways that regulate embryonic development, wound healing, carcinogenesis, and fibrosis, via effects on cell migration, proliferation and differentiation. Extracellular LPA is generated from lysophospholipids by the secreted hydrolase - ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2; also, AUTOTAXIN / ATX) and metabolised by different membrane-bound phospholipid phosphatases (PLPPs). Here, we use public bulk and singlecell RNA sequencing datasets to explore the gene expression ofLpar1-6,Enpp2, andPlppgenes under skeletal muscle homeostasis and regeneration conditions. We show that the skeletal muscle system dynamically expresses theEnpp2-Lpar-Plppgene axis, withLpar1being the highest expressed member among LPARs.Lpar1was expressed by mesenchymal fibro-adipogenic progenitors (FAPs) and tenocytes, whereas FAPs mainly expressedEnpp2. Clustering of FAPs identified populations representing distinct cell states with robustLpar1andEnpp2transcriptome signatures in homeostatic cells expressing higher levels of markersDpp4andHsd11b1. However, tissue injury induced transient repression ofLpargenes andEnpp2. The role of LPA in modulating the fate and differentiation of tissue-resident FAPs has not yet been explored. Ex vivo, LPAR1/3 and ENPP2 inhibition significantly decreased the cell-cycle activity of FAPs and impaired fibro-adipogenic differentiation, implicating LPA signalling in the modulation of the proliferative and differentiative fate of FAPs. Together, our results demonstrate the importance of the ENPP2-LPAR-PLPP axis in different muscle cell types and FAP lineage populations in homeostasis and injury, paving the way for further research on the role of this signalling pathway in skeletal muscle homeostasis and regeneration, and that of other organs and tissues, in vivo.SummaryOur reanalysis of single-cell transcriptomics revealed the involvement and temporally dynamic expression of the ENPP2-LPAR-PLPP axis in response to skeletal muscle regeneration.
Electrical spiking of psilocybin fungi
Authors: Gandia Antoni , Adamatzky Andrew 
Published: July 2022

AbstractPsilocybin fungi, aka “magic” mushrooms, are well known for inducing colourful and visionary states of mind. Such psychoactive properties and the ease of cultivating their basidiocarps within low-tech setups make psilocybin fungi promising pharmacological tools for mental health applications. Understanding of the intrinsic electrical patterns occurring during the mycelial growth can be utilised for better monitoring the physiological states and needs of these species. In this study we aimed to shed light on this matter by characterising the extra-cellular electrical potential of two popular species of psilocybin fungi: Psilo-cybe tampanensis and P. cubensis. As in previous experiments with other common edible mushrooms, the undisturbed fungi have shown to generate electric potential spikes and trains of spiking activity. This short analysis provides a proof of intrinsic electrical communication in psilocybin fungi, and further establishes these fungi as a valuable tool for studying fungal electro-physiology.
Chemical Proteomics Reveals Protein Tyrosination Extends Beyond the Alpha-Tubulins in Human Cells
Authors: Makarov Dmytro , Kielkowski Pavel 
Published: July 2022

AbstractTubulin detyrosination-tyrosination cycle regulates the stability of microtubules. Thus far described on α-tubulins, the tyrosination level is maintained by a single tubulin-tyrosine ligase (TTL). However, the precise dynamics and tubulin isoforms which undergo (de)tyrosination in neurons are unknown. Here, we exploit the substrate promiscuity of the TTL to introduce an O-propargyl-L-tyrosine in neuroblastoma cells and neurons. Mass spectrometry-based chemical proteomics in neuroblastoma cells using the O-propargyl-L-tyrosine probe revealed previously discussed tyrosination of TUBA4A, MAPRE1, and other non-tubulin proteins. This finding was further corroborated in differentiating neurons. Together we present the method for tubulin tyrosination profiling in living cells. Our results show that detyrosination-tyrosination is not restricted to α-tubulins with coded C-terminal tyrosine and is thus involved in fine-tuning of the tubulin and non-tubulin proteins during neuronal differentiation.
Sampling globally and locally correct RNA 3D structures using ERNWIN, SPQR and experimental SAXS data
Authors: Thiel Bernhard C. , Bussi Giovanni , Poblete Simón , Hofacker Ivo L. 
Published: July 2022

AbstractThe determination of the three-dimensional structure of large RNA macromolecules in solution is a challenging task that often requires the use of several experimental and computational techniques. Small-angle X-ray spectroscopy can provide insight into some geometrical properties of the probed molecule, but this data must be properly interpreted in order to generate a three-dimensional model. Here, we propose a multiscale pipeline which introduces SAXS data into modelling the global shape of RNA in solution, which can be hierarchically refined until reaching atomistic precision in explicit solvent. The low-resolution helix model (ERNWIN) deals with the exploration of the huge conformational space making use of the SAXS data, while a nucleotide-level model (SPQR) removes clashes and disentangles the proposed structures, leading the structure to an all-atom representation in explicit solvent. We apply the procedure on five different structures up to 126 nucleotides with promising results.
Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission
Authors: Cuhadar Ulku , Calzado-Reyes Lorenzo , Pascual-Caro Carlos , Aberra Aman S. , Ritzau-Jost Andreas , Aggarwal Abhi , Ibata Keiji , Podgorski Kaspar , Yuzaki Michisuke , Geis Christian , Hallerman Stefan , Hoppa Michael B. , de Juan-Sanz Jaime 
Published: July 2022

AbstractThe fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how the landscape of trans-synaptic bridges dynamically remodels to reflect functional states of the synapse. Here we developed novel optical tools to visualize in firing synapses the molecular behavior of a particular secreted trans-synaptic protein, LGI1, and its presynaptic receptor, ADAM23, and discovered that neuronal activity acutely rearranges the abundance of these proteins at the synaptic cleft. Surprisingly, LGI1 in synapses was not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitated the formation of trans-synaptic connections proportionally to the history of activity of the synapse, adjusting excitatory transmission to synaptic firing rates. Thus, our findings reveal that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as a critical point of activity-dependent control of synaptic function.Highlights– Neuronal activity translocates LGI1 and ADAM23 to the presynaptic surface– LGI1 and ADAM23 are not located in synaptic vesicles– Stable cleft localization of LGI1 depends on the history of synaptic activity– LGI1 abundance at the synaptic cleft controls glutamate release
CHILDHOOD DEATHS, DEPRIVATION, AND MODIFIABLE FACTORS: FINDINGS FROM THE NATIONAL CHILD MORTALITY DATABASE
Authors: Odd David , Stoianova Sylvia , Williams Tom , Odd Dawn , Kurinczuk Jennifer J , Wolfe Ingrid , Luyt Karen 
Published: July 2022

ABSTRACTObjectivesThe aim of this analysis is to identify and report the patterns of social deprivation in relation to childhood mortality; and identify potential points where public health, social and education interventions or health policy may be best targeted.DesignDecile of deprivation and underlying population distribution was derived using Office for National Statistics (ONS) data. The risk of death was then derived using a Poisson regression model, calculating the increasing risk of death for each increasing deprivation decile.SettingEnglandParticipants2688 childhood deaths in England reviewed between the April 2019 and March 2020.Main Outcome MeasuresThe relationship between deprivation and risk of death; for deaths with, and without modifiable factors.ResultsThere was evidence of increasing mortality risk with increase in deprivation decile (RR 1.08 (1.07 to 1.10)), with the gradient of risk stronger in children who died with modifiable factors than those without (RR 1.12 (1.09 to 1.15)) vs (RR 1.07 (1.05 to 1.08)). Deprivation sub-domains of Employment, Adult Education, Barriers to Housing and Services, and Indoor Living Environments appeared to be the most important predictors of child mortalityConclusionsThere is a clear gradient of increasing child mortality across England as measures of deprivation increase; with a striking finding that this varied little by area, age or other demographic factor. Over a fifth of all child deaths may be avoided if the most deprived half of the population had the same mortality as the least deprived. Children dying in more deprived areas may have a greater proportion of avoidable deaths. Adult employment and education, and improvements to housing, may be the most efficient place to target resources to reduce these inequalities.
Effects of Physical Exercises on Emotion Regulation: A Meta-Analysis
Authors: Liu Jie , Gao Shuqing , Zhang Liancheng 
Published: July 2022

AbstractBackgroundAt present, there are inconsistent results in the research on the effect of physical exercise on emotion regulation ability, and there is no relevant research on how to exercise scientificlc. Therefore, on the basis of previous research, this study conducted a meta-analysis on the theme of physical exercise affecting emotion regulation ability according to the statement of PRISMA, and added relevant moderator variables to clarify the effect of physical exercise on emotion regulation ability.ObjectiveWe identified physical exercise studies and randomized controlled trials (RCTs) of emotion regulation ability that reported overall effect, heterogeneity, and publication bias of physical exercises on emotion regulation ability.MethodsWe searched for RCT s of exercise interventions on emotion regulation ability from databases including PubMed, Web of Science, Ebsco, The Cochrane Library, CNKI (China National Knowledge Infrastructure), and Wanfang, from January 1 2000 to January 1 2022. We performed methodological quality evaluations on the included literature and graded evidence with a meta-analysis using Review Manager 5.3 software.ResultsIn total, 10 RCT s were included; the overall results of the meta-analysis (936participants) indicated that physical exercises improved emotion regulation ability (standardized mean difference (SMD) = 0.47; 95% confidence interval (CI) 0.21 to 0.72; p < 0.05), sensory arousal ability (SMD = 0.70; 95% CI 0.14 to 1.27; p < 0.05), and emotion regulation strategies (SMD = 0.46; 95% CI 0.04 to 0.87; p < 0.05); Subgroup analysis showed that a single exercise of more than 30 minutes can improve emotional regulation ability, which is not affected by exercise intensity, period and the health status of the participants.ConclusionPhysical exercises can effectively improve the emotion regulation ability. The effects are considered as moderate effect sizes. While single exercise time should be at least 30 minutes.Limited by the quantity and quality of the included studies, the above conclusions need to be verified with more high-quality studies.PROSPERO registration number: CRD42021217978
Efficacy of Anakinra in the Management of Patients with COVID-19 Infection: A Randomized Clinical Trial
Authors: Elmekaty Eman Zeyad I. , Maklad Aya , Abouelhassan Rawan , Munir Waqar , Mohamed Ibrahim Mohamed Izham , Nair Arun , Alibrahim Rim , Iqbal Fatima , Bishawi Ahmad Al , Abdelmajid Alaaeldin , Aboukamar Mohamed , Khattab Mohammed Abu , Soub Hussam Al , Maslamani Muna Al 
Published: July 2022

AbstractBackgroundThe global pandemic of COVID-19 infections continues to grow worldwide, with rising number of deaths day by day. The hyperinflammation state contributes to the multiorgan failure associated with COVID-19 infections. This study aims to explore the efficacy and safety of anakinra in COVID-19 patients with both respiratory distress and cytokine release syndromes.MethodsThis was an open-label, multicenter, randomized clinical trial. Patients were randomized in 1:1 ratio to receive standard of care (SOC) alone, or anakinra plus SOC. Adults with confirmed COVID-19 infection with evidence of both respiratory distress and cytokine release syndrome were included. The primary outcome was treatment success at day 14, defined as WHO clinical progression score of ≤3. The primary analysis was based on intention-to-treat population, with p-value of <0.05.ResultsA total of 80 patients were enrolled in the study. The mean age was 49.9 years (SD=11.7), with 82.5% (n=66) male patients. The primary outcome was not statistically different (87.5% (n=35) in anakinra group vs. 92.5% (n=37) in SOC group, p=0.712). The majority of reported adverse events were mild in severity and not related to the study treatment. Increased aspartate aminotransferase was the only significant adverse event (35% (n=14) in anakinra group vs. 15% (n=6) in SOC group, p=0.039); yet, was not associated with treatment discontinuation.ConclusionIn patients with severe COVID-19 infection, the addition of anakinra to SOC treatment was not associated with significant improvement in the WHO clinical progression scale. Further studies investigating patients’ subgroups that might benefit from anakinra are warranted. The trial was registered at ClinicalTrials.gov (NCT04643678).
Phylogeny analysis of whole protein-coding genes in metagenomic data detected an environmental gradient for the microbiota
Authors: Satoh Soichirou , Tanaka Rei , Yokono Makio , Endoh Daiji , Yabuki Tetsuo , Tanaka Ayumi 
Published: July 2022

AbstractEnvironmental factors affect the growth of microorganisms and therefore alter the composition of microbiota. Correlative analysis of the relationship between metagenomic composition and the environmental gradient can help elucidate key environmental factors and establishment principles for microbial communities. However, a reasonable method to quantitatively compare whole metagenomic data and identify the primary environmental factors for the establishment of microbiota has not been reported so far. In this study, we developed a method to compare whole proteomes deduced from metagenomic shotgun sequencing data, and quantitatively display their phylogenetic relationships as metagenomic trees. We called this method Metagenomic Phylogeny by Average Sequence Similarity (MPASS). We also compared one of the metagenomic trees with dendrograms of environmental factors using a comparison tool for phylogenetic trees. The MPASS method correctly constructed metagenomic trees of simulated metagenomes and soil and water samples. The topology of the metagenomic tree of samples from the Kirishima hot springs area in Japan was highly similarity to that of the dendrograms based on previously reported environmental factors for this area. The topology of the metagenomic tree also reflected the dynamics of microbiota at the taxonomic and functional levels. Our results strongly suggest that MPASS can successfully classify metagenomic shotgun sequencing data based on the similarity of whole protein-coding sequences, and will be useful for the identification of principal environmental factors for the establishment of microbial communities.
Development of amidase-dependent pyrazinoic acid prodrugs with activity against pyrazinamide resistant Mycobacterium tuberculosis
Authors: Levine Carly , Jadhav Ravindra , Pan Yan , Tsotetsi Kholiswa , Wang Xin , Awasthi Divya , Grady Courtney , Shelke Anil , Daher Samer S. , Richmann Todd , Shrestha Riju , Sukheja Paridhi , Patel Jimmy , Barnett Pamela R. , Dikdan Ryan J. , Kim Thomas , Russo Riccardo , Hanna Jennifer , Zimmerman Matthew , Dartois Véronique , Freundlich Joel S. , Alland David , Kumar Pradeep 
Published: July 2022

ABSTRACTRapid emergence of drug resistance in Mycobacterium tuberculosis (Mtb) is one of the most significant healthcare challenges of our time. The cause of drug resistance is multifactorial, with the long course anti-tubercular therapy required to treat tuberculosis (TB) constituting a major contributing factor. Introduction of pyrazinamide (PZA) resulted in shortening of TB treatment from twelve to six months and consequently played a critical role in curbing drug resistance that developed over long course therapy. Nevertheless, because PZA is a prodrug activated by a nonessential amidase, PncA, resistance to PZA develops and frequently results in treatment failure. Here, we leveraged a whole cell drug screening approach to identify anti-tuberculars with unconventional mechanisms of action or activation that could be further developed into compounds effective at killing Mtb resistant to PZA. We discovered an amide containing prodrug, DG160, that was activated by the amidase, Rv2888c (AmiC). This amidase was capable of metabolizing a variety of amide containing compounds including a novel pyrazinoic acid-isoquinolin-1-amine prodrug, JSF-4302, which we developed as a potential PncA-independent replacement for PZA. As predicted, AmiC activation of JSF-4302 led to the generation of POA in Mtb including in a PZA resistant clinical isolate, thereby successfully delivering the active component of PZA while bypassing the need for activation by PncA. This work provides a framework for a new approach to drug development and prodrug activation in Mtb.SIGNIFICANCEPyrazinamide (PZA) is a vital component of Mycobacterium tuberculosis (Mtb) treatment since its inclusion shortened tuberculosis therapy by six months. However, PZA is a prodrug and resistance develops at a high frequency due to mutations in its activator PncA. Here, we present the discovery of amide-containing anti-tubercular prodrugs that are activated intracellularly by the Mtb amidase, AmiC. Taking advantage of this finding, we successfully designed and synthesized pyrazinoic acid (POA) prodrugs that were activated by AmiC and found that these compounds delivered intracellular POA to PZA- resistant Mtb isolates that contained a nonfunctional PncA. This new approach to prodrug development provides a method for delivering conjugated drugs into Mtb with the potential to overcome clinical drug resistance.
Adaptive delayed feedback control disrupts unwanted neuronal oscillations and adjusts to network synchronization dynamics
Authors: de Castro Domingos Leite , Aroso Miguel , Aguiar A. Pedro , Grayden David B. , Aguiar Paulo 
Published: July 2022

AbstractAdaptive neuronal stimulation has a strong therapeutic potential for neurological disorders such as Parkinson’s disease and epilepsy. However, standard stimulation protocols mostly rely on continuous open-loop stimulation. We implement here, for the first time in neuronal populations, two different Delayed Feedback Control (DFC) algorithms and assess their efficacy in disrupting unwanted neuronal oscillations. DFC is a well-established closed-loop control technique but its use in neuromodulation has been limited so far to models and computational studies. Leveraging on the high spatiotemporal monitoring capabilities of specialized in vitro platforms, we show that standard DFC in fact worsens the neuronal population oscillatory behaviour and promotes faster bursting, which was never reported in silico. Alternatively, we present adaptive DFC (aDFC) that monitors ongoing oscillation periodicity and self-tunes accordingly. aDFC disrupts collective neuronal oscillations and decreases network synchrony. Furthermore, we show that the intrinsic population dynamics have a strong impact in the susceptibility of networks to neuromodulation. Experimental data was complemented with computer simulations to show how this network controllability might be determined by specific network properties. Overall, these results support aDFC as a better candidate for therapeutic neurostimulation and provide new insights regarding the controllability of neuronal systems.