bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibiting Succinate Release Worsens Cardiac Reperfusion Injury by Enhancing Mitochondrial Reactive Oxygen Species Generation
Authors: Milliken Alexander S. , Nadtochiy Sergiy M. , Brookes Paul S. 
Published: June 2022

Background
The metabolite succinate accumulates during cardiac ischemia. Within 5 minutes of reperfusion, succinate returns to baseline levels via both its release from cells and oxidation by mitochondrial complex II. The latter drives reactive oxygen species (ROS) generation and subsequent opening of the mitochondrial permeability transition (PT) pore, leading to cell death. Targeting succinate dynamics (accumulation/oxidation/release) may be therapeutically beneficial in cardiac ischemia–reperfusion (IR) injury. It has been proposed that blocking MCT1 (monocarboxylate transporter 1) may be beneficial in IR injury, by preventing succinate release and subsequent engagement of downstream inflammatory signaling pathways. In contrast, herein we hypothesized that blocking MCT1 would retain succinate in cells, exacerbating ROS generation and IR injury.

Methods and Results
Using the mitochondrial ROS probe mitoSOX and a custom‐built murine heart perfusion rig built into a spectrofluorometer, we measured ROS generation in situ during the first moments of reperfusion. We found that acute MCT1 inhibition enhanced mitochondrial ROS generation at reperfusion and worsened IR injury (recovery of function and infarct size). Both of these effects were abrogated by tandem inhibition of mitochondrial complex II, suggesting that succinate retention worsens IR because it drives more mitochondrial ROS generation. Furthermore, using the PT pore inhibitor cyclosporin A, along with monitoring of PT pore opening via the mitochondrial membrane potential indicator tetramethylrhodamine ethyl ester, we herein provide evidence that ROS generation during early reperfusion is upstream of the PT pore, not downstream as proposed by others. In addition, pore opening was exacerbated by MCT1 inhibition.

Conclusions
Together, these findings highlight the importance of succinate dynamics and mitochondrial ROS generation as key determinants of PT pore opening and IR injury outcomes.
How the History of Changing Environments Affects Traits of Evolvable Robot Populations
Authors: Miras Karine , Eiben A. E. 
Published: June 2022

Abstract
The environment is one of the key factors in the emergence of intelligent creatures, but it has received little attention within the Evolutionary Robotics literature. This article investigates the effects of changing environments on morphological and behavioral traits of evolvable robots. In particular, we extend a previous study by evolving robot populations under diverse changing-environment setups, varying the magnitude, frequency, duration, and dynamics of the changes. The results show that long-lasting effects of early generations occur not only when transitioning from easy to hard conditions, but also when going from hard to easy conditions. Furthermore, we demonstrate how the impact of environmental scaffolding is dependent on the nature of the environmental changes involved.
Evaluation of lung function and clinical features of interlaminar cervical epidural steroid injections: a randomized controlled trial
Authors: Chae Ji Seon , Kim Won-joong , Lee Gi Year , Choi Yong Ju 
Published: June 2022

Objective Interlaminar cervical epidural steroid injections (ICESIs) are commonly used to treat axial neck pain and cervical radicular pain. However, local anesthetics can spread to and block the phrenic nerve and upper segments of the thoracic spinal cord where the sympathetic innervation of the lungs emerges. Therefore, changes in lung function may occur following ICESIs. Methods The primary outcome measure was the pulmonary function test (PFT) result 30 minutes before and after ICESI with ropivacaine (0.1875% or 0.25%). The secondary outcome measure was the comparison of the pain scores and functional disability between the two concentrations of ropivacaine 4 weeks after the ICESIs. Results Fifty patients were randomly assigned to either the R1 (0.1875% ropivacaine) or R2 (0.25% ropivacaine) group. No significant difference was observed between the pre-ICESI and 30-minute post-ICESI PFT results within each group, and no difference was observed between the two groups. After 4 weeks of treatment, both groups showed a significant decrease in pain scores and functional disability; however, no significant differences were observed between the two groups. Conclusions This study showed no significant change in lung function after ICESIs in either group and no local anesthetic concentration-based difference in the clinical efficacy of the ICESIs.
Tools for local health in all policies implementation: evidence from an explanatory case study of Kuopio, Finland
Authors: Guglielmin Maria , Shankardass Ketan , Bayoumi Ahmed , O’campo Patricia , Kokkinen Lauri , Muntaner Carles 
Published: June 2022

Aims: This paper describes the use of three governance tools for health in all policies utilised to facilitate implementation in the municipality of Kuopio, Finland: impact assessments, a city mandate (the Kuopio strategy), and shared budgets. Methods: An explanatory case study was used. Data sources included semistructured interviews with 10 government employees and scholarly literature. Realist scientific methods were used to reveal mechanisms underlying the use of tools in health in all policies. Results: Strong evidence was found supporting initial and new theory/hypotheses regarding the use of each tool in achieving positive implementation outcomes. Impact assessments facilitated health in all policies by enhancing understanding of health implications. The Kuopio strategy aided in implementation by giving credence to health in all policies work via formal authority. Shared budgets promoted intersectoral discussions and understanding, and a sense of ownership, in addition to allowing time to be spent on health in all policies work and not financial deliberation. Conclusions: Findings confirm the efficacious use of three governance tools in implementing health in all policies in Kuopio. Knowledge and evidence-based guidelines on local health in all policies implementation are needed as this policy approach continues to be recognised and adopted as a means to promote population health and health equity.
Grandviewite redefinition, new formula Cu3Al2(SO4)(OH)10⋅H2O, and crystal-structure determination
Authors: Sejkora Jiří , Steciuk Gwladys , Marquez-Zavalia Maria Florencia , Plášil Jakub , Dolníček Zdeněk 
Published: June 2022

AbstractGrandviewite is redefined on the basis of a reinvestigation of the holotype specimen from the Grandview mine, Arizona, USA, and additional specimens found in the Restauradora vein at the Capillitas mine, northwestern Argentina. Grandviewite from the Capillitas mine forms globular masses up to a couple of millimetres in diameter, formed by very thin platy to acicular lath-like crystals, greenish-pale blue in colour, pleochroic (X = colourless, Y = very pale blue and Z = greenish-pale blue), with pale blue streak and silky to a satiny lustre. Results of an electron-microprobe study and crystal-structure determination lead to the new ideal formula Cu3Al2(SO4)(OH)10⋅H2O, which requires (in wt.%) CuO 45.13, Al2O3 19.28, SO3 15.14, and H2O 20.45, total 100.00. Its empirical formulas are (Cu2.96Mn0.01)Σ2.97Al2.03(SO4)0.97(SiO4)0.03(AsO4)0.01(OH)9.97Cl0.01⋅H2O (Grandview mine) and Cu2.97(Al2.03Fe0.01)Σ2.04(SO4)0.95(SiO4)0.03(AsO4)0.01(PO4)0.01(OH)9.97Cl0.01⋅H2O (Capillitas mine). Grandviewite is triclinic, P$\bar{1}$, with unit-cell parameters refined from powder X-ray diffraction data: a = 5.713(2), b = 10.1374(8), c = 10.9791(9) Å, α = 72.240(6)°, β = 82.79(2)°, γ = 86.07(2)°, V = 600.5(3) Å3 and Z = 2 (Grandview mine); and a = 5.749(3), b = 10.1388(13), c = 10.9656(16) Å, α = 72.344(1)°, β = 82.83(4)°, γ = 86.77(3)°, V = 604.2(3) Å3 and Z = 2 (Capillitas mine). The crystal structure of grandviewite from the Capillitas mine was solved by 3-dimensional electron diffraction analysis (R(obs)/wR(obs) = 0.1304/0.1316 for 6401/31007 observed reflections with I ≥ 3σ(I). Grandviewite contains infinite AlO6–Cu1–AlO6 slabs along a connected on both ends to Cu2 [4 + 1]–SO4 chains. The SO4 tetrahedra form a disordered chain along a connected to the Cu2 pyramids on one side and are otherwise stabilised by strong hydrogen bonds to surrounding units. The Raman and infrared spectra for samples from both occurrences are identical. The redefinition (new chemical formula and triclinic symmetry) has been approved by the Commission on New Minerals, Nomenclature and Classification of the International Mineralogical Association (number 21-K).
STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion
Authors: Li Juan , Williams Matthew J. , Park Hyun Jung , Bastos Hugo P. , Wang Xiaonan , Prins Daniel , Wilson Nicola K. , Johnson Carys , Sham Kendig , Wantoch Michelle , Watcham Sam , Kinston Sarah J. , Pask Dean C. , Hamilton Tina L. , Sneade Rachel , Waller Amie K. , Ghevaert Cedric , Vassiliou George S. , Laurenti Elisa , Kent David G. , Göttgens Berthold , Green Anthony R. 
Published: June 2022

Abstract
Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal downstream mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but little is known about the role of STAT1 in regulating homeostatic hematopoietic stem/progenitor cells (HSPCs). Here, we show that loss of STAT1 altered the steady state HSPC landscape, impaired HSC function in transplantation assays, delayed blood cell regeneration following myeloablation, and disrupted molecular programs that protect HSCs, including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated major histocompatibility complex class II (MHCII) expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis and was refractory to 5-fluorouracil–induced myeloablation. Conversely, MHCIIlo HSCs displayed increased megakaryocytic potential and were preferentially expanded in CALR mutant mice with thrombocytosis. Similar to mice, high MHCII expression is a feature of human HSCs residing in a deeper quiescent state. Our results therefore position STAT1 at the interface of stem cell heterogeneity and the interplay between stem cells and the adaptive immune system, areas of broad interest in the wider stem cell field.
GGCX mutants that impair hemostasis reveal the importance of processivity and full carboxylation to VKD protein function
Authors: Rishavy Mark A. , Hallgren Kevin W. , Wilson Lee A. , Hiznay James M. , Runge Kurt W. , Berkner Kathleen L. 
Published: June 2022

Abstract
γ-Glutamyl carboxylase (GGCX) generates multiple carboxylated Glus (Glas) in vitamin K–dependent (VKD) proteins that are required for their functions. GGCX is processive, remaining bound to VKD proteins throughout multiple Glu carboxylations, and this study reveals the essentiality of processivity to VKD protein function. GGCX mutants (V255M and S300F) whose combined heterozygosity in a patient causes defective clotting and calcification were studied using a novel assay that mimics in vivo carboxylation. Complexes between variant carboxylases and VKD proteins important to hemostasis (factor IX [FIX]) or calcification (matrix Gla protein [MGP]) were reacted in the presence of a challenge VKD protein that could potentially interfere with carboxylation of the VKD protein in the complex. The VKD protein in the complex with wild-type carboxylase was carboxylated before challenge protein carboxylation occurred and became fully carboxylated. In contrast, the V255M mutant carboxylated both forms at the same time and did not completely carboxylate FIX in the complex. S300F carboxylation was poor with both FIX and MGP. Additional studies analyzed FIX- and MGP-derived peptides containing the Gla domain linked to sequences that mediate carboxylase binding. The total amount of carboxylated peptide generated by the V255M mutant was higher than that of wild-type GGCX; however, the individual peptides were partially carboxylated. Analysis of the V255M mutant in FIX HEK293 cells lacking endogenous GGCX revealed poor FIX clotting activity. This study shows that disrupted processivity causes disease and explains the defect in the patient. Kinetic analyses also suggest that disrupted processivity may occur in wild-type carboxylase under some conditions (eg, warfarin therapy or vitamin K deficiency).
The identification of TCF1+ progenitor exhausted T cells in THRLBCL may predict a better response to PD-1/PD-L1 blockade
Authors: Tabanelli Valentina , Melle Federica , Motta Giovanna , Mazzara Saveria , Fabbri Marco , Agostinelli Claudio , Calleri Angelica , Del Corvo Marcello , Fiori Stefano , Lorenzini Daniele , Cesano Alessandra , Chiappella Annalisa , Vitolo Umberto , Derenzini Enrico , Griffin Gabriel K. , Rodig Scott J. , Vanazzi Anna , Sabattini Elena , Tarella Corrado , Sapienza Maria Rosaria , Pileri Stefano A. 
Published: June 2022

Abstract
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B-cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL due to its peculiar cellular composition (&lt;10% neoplastic B cells interspersed in a cytotoxic T-cell/histiocyte-rich background). A significant percentage of THRLBCL is refractory to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-based regimens and to chimeric antigen receptor T-cell therapy; thus, the development of a specific therapeutic approach for these patients represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, and further corroborated our findings in an extended in silico set. Gene coexpression network analysis identified the predominant role of the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of 48 genes related to the functional exhaustion of T cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly suggest that THRLBCL may be responsive to anti–PD-1 therapy but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we validated our results by immunohistochemistry, identifying a subset of TCF1+ (T cell–specific transcription factor 1, encoded by the TCF7 gene) progenitor exhausted T cells enriched in patients with THRLBCL. This subset of TCF1+ exhausted T cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti–PD-1 response in patients with THRLBCL.
Refining the migration and engraftment of short-term and long-term HSCs by enhancing homing-specific adhesion mechanisms
Authors: Al-Amoodi Asma S. , Li Yanyan , Al-Ghuneim Arwa , Allehaibi Hanaa , Isaioglou Ioannis , Esau Luke E. , AbuSamra Dina B. , Merzaban Jasmeen S. 
Published: June 2022

AbstractIn contrast to the short-term (ST) CD34+ stem cells, studies have suggested that long-term (LT) hematopoietic stem cells (HSCs) found in the CD34− stem cell pool have trouble migrating and engrafting when introduced through IV. To understand why these deficiencies exist, we set out to fully elucidate the adhesion mechanisms used by ST and LT-HSCs to migrate to the bone marrow(BM). Specifically focusing on murine ST-HSCs (Flk2−CD34+) and LT-HSCs (Flk2−CD34−), we observed a distinctive expression pattern of BM homing effectors necessary for the first step, namely sialyl Lewis-X (sLex) (ligand for E-selectin), and the second step, namely CXCR4 chemokine receptor (receptor for SDF-1). sLex expression was higher on Flk2−CD34+ ST-HSCs (&gt;60%) compared with Flk2−CD34− LT-HSCs (&lt;10%), which correlated to binding to E-selectin. Higher concentrations of CXCR4 were observed on Flk2−CD34+ ST-HSCs compared with Flk2−CD34− LT-HSCs. Interestingly, the expression of CD26, a peptidase known to deactivate chemokines (ie, SDF-1), was higher on Flk2−CD34− LT-HSCs. Given that both E-selectin–binding and CXCR4-mediated migration are compromised in Flk2−CD34− LT-HSCs, we aimed to enhance their ability to migrate using recombinant human fucosyltransferase 6 (rhFTVI) and the CD26 inhibitor, Dip A (diprotin A). To this end, we observed that although LT-HSCs expressed low concentrations of sLex, they were able to engraft when transplanted into recipient mice. Moreover, although both CD26 inhibition and fucosylation enhanced migration of both HSC populations in vitro, only pretreatment of LT-HSCs with Dip A enhanced engraftment in vivo after transplantation into recipient mice. Remarkably, fucosylation of Flk2−CD34+ ST-HSCs consistently led to their ability to transplant secondary recipients. These data suggest that using fucosylation and Dip A to overcome the molecular disparity in adhesion mechanisms among ST-HSCs and LT-HSCs differentially influences their abilities to migrate and engraft in vivo and promotes the ability of ST-HSCs to engraft secondary recipient mice, the gold standard for testing functionality of LT-HSCs.
Upregulated lncARAT in Schwann cells promotes axonal regeneration by recruiting and activating proregenerative macrophages
Authors: Yin Gang , Lin Yaofa , Wang Peilin , Zhou Jun , Lin Haodong 
Published: June 2022

AbstractBackgroundAxonal regeneration following peripheral nerve injury (PNI) depends on the complex interaction between Schwann cells (SCs) and macrophages, but the mechanisms underlying macrophage recruitment and activation in axonal regeneration remain unclear.MethodsRNA sequencing (RNA-seq) was conducted to identify differentially expressed long noncoding RNAs (DElncRNAs) between crushed sciatic nerves and intact contralateral nerves. The putative role of lncRNAs in nerve regeneration was analyzed in vitro and in vivo.ResultsAn lncRNA, called axon regeneration-associated transcript (lncARAT), was upregulated in SCs and SC-derived exosomes (SCs-Exo) after sciatic nerve injury. LncARAT contributed to axonal regeneration and improved motor function recovery. Mechanistically, lncARAT epigenetically activated C–C motif ligand 2 (CCL2) expression by recruiting KMT2A to CCL2 promoter, resulting in increased histone 3 lysine 4 trimethylation (H3K4me3) and CCL2 transcription in SCs. CCL2 facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. LncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p in macrophages, resulting in increased suppressor of cytokine signaling (SOCS) 2 expression, which induced a proregenerative function of macrophages through a signal transducer and activator of transcription (STAT) 1/6-dependent pathway.ConclusionsLncARAT may represent a promising therapeutic avenue for peripheral nerve repair.
DeepPN: a deep parallel neural network based on convolutional neural network and graph convolutional network for predicting RNA-protein binding sites
Authors: Zhang Jidong , Liu Bo , Wang Zhihan , Lehnert Klaus , Gahegan Mark 
Published: June 2022

AbstractBackgroundAddressing the laborious nature of traditional biological experiments by using an efficient computational approach to analyze RNA-binding proteins (RBPs) binding sites has always been a challenging task. RBPs play a vital role in post-transcriptional control. Identification of RBPs binding sites is a key step for the anatomy of the essential mechanism of gene regulation by controlling splicing, stability, localization and translation. Traditional methods for detecting RBPs binding sites are time-consuming and computationally-intensive. Recently, the computational method has been incorporated in researches of RBPs. Nevertheless, lots of them not only rely on the sequence data of RNA but also need additional data, for example the secondary structural data of RNA, to improve the performance of prediction, which needs the pre-work to prepare the learnable representation of structural data.ResultsTo reduce the dependency of those pre-work, in this paper, we introduce DeepPN, a deep parallel neural network that is constructed with a convolutional neural network (CNN) and graph convolutional network (GCN) for detecting RBPs binding sites. It includes a two-layer CNN and GCN in parallel to extract the hidden features, followed by a fully connected layer to make the prediction. DeepPN discriminates the RBP binding sites on learnable representation of RNA sequences, which only uses the sequence data without using other data, for example the secondary or tertiary structure data of RNA. DeepPN is evaluated on 24 datasets of RBPs binding sites with other state-of-the-art methods. The results show that the performance of DeepPN is comparable to the published methods.ConclusionThe experimental results show that DeepPN can effectively capture potential hidden features in RBPs and use these features for effective prediction of binding sites.
Age-related differences of vastus lateralis muscle morphology, contractile properties, upper body grip strength and lower extremity functional capability in healthy adults aged 18 to 70 years
Authors: Jacob Isobel , Johnson Mark I. , Jones Gareth , Jones Ashley , Francis Peter 
Published: June 2022

Abstract
Background
There is a lack of of cross-sectional research that has investigated muscle morphology, function, and functional capability in all age-bands of healthy adults. The primary aim of this study was to evaluate age-related differences in indices of vastus lateralis (VL) muscle morphology, function and functional capability in a sample of healthy males and females aged 18-70yrs. Secondary aims were to evaluate relationships between age and VL muscle morphology and function and functional capability.

Methods
B mode Ultrasonography and Tensiomyography were used to measure VL muscle thickness, pennation angle, fascicle length, and contractile properties in 274 healthy adults aged 18-70yrs. Measurements of grip strength and functional capability (1-min chair rise test) were also taken. Data analysis included descriptive statistics, correlations, one-way ANOVAs, and multiple regressions.

Results
Negative correlations were found between age and muscle thickness (rs = -.56), pennation angle (rs = -.50), fascicle length (rs = -.30), maximal displacement (rs = -.24), grip strength (rs = -.27) and the 1-min chair rise test (rs = -.32). Positive correlations were observed between age and the echo intensity of the muscle (rs = .40) and total contraction time (rs = .20). Differences in the indices of muscle health were noticeable between the 18–29 age band and the 50–59 and 60–70 age bands (p < 0.05). The interaction of age and level of physical activity predicted changes in the variables (r2 = .04—.32).

Conclusion
Age-related differences in muscle health are noticeable at 50 years of age, and age-related differences are larger in females compared to males. It was suggested that the thickness of the VL changed the most with age across the adult lifespan and that physical activity likely acts to abate detrimental change.