bluuebunny/crossref_metadata_2025 huggingface dataset:
Integration of full divertor detachment with improved core confinement for tokamak fusion plasmas
Authors: Wang L. , Wang H. Q. , Ding S. , Garofalo A. M. , Gong X. Z. , Eldon D. , Guo H. Y. , Leonard A. W. , Hyatt A. W. , Qian J. P. , Weisberg D. B. , McClenaghan J. , Fenstermacher M. E. , Lasnier C. J. , Watkins J. G. , Shafer M. W. , Xu G. S. , Huang J. , Ren Q. L. , Buttery R. J. , Humphreys D. A. , Thomas D. M. , Zhang B. , Liu J. B.
Published: March 2021

Divertor detachment offers a promising solution to the challenge of plasma-wall interactions for steady-state operation of fusion reactors. Here, we demonstrate the excellent compatibility of actively controlled full divertor detachment with a high-performance (βN ~ 3, H98 ~ 1.5) core plasma, using high-βp (poloidal beta, βp > 2) scenario characterized by a sustained core internal transport barrier (ITB) and a modest edge transport barrier (ETB) in DIII-D tokamak. The high-βp high-confinement scenario facilitates divertor detachment which, in turn, promotes the development of an even stronger ITB at large radius with a weaker ETB. This self-organized synergy between ITB and ETB, leads to a net gain in energy confinement, in contrast to the net confinement loss caused by divertor detachment in standard H-modes. These results show the potential of integrating excellent core plasma performance with an efficient divertor solution, an essential step towards steady-state operation of reactor-grade plasmas.
Thermochromic aggregation-induced dual phosphorescence via temperature-dependent sp3-linked donor-acceptor electronic coupling
Authors: Wang Tao , Hu Zhubin , Nie Xiancheng , Huang Linkun , Hui Miao , Sun Xiang , Zhang Guoqing
Published: March 2021

Aggregation-induced emission (AIE) has proven to be a viable strategy to achieve highly efficient room temperature phosphorescence (RTP) in bulk by restricting molecular motions. Here, we show that by utilizing triphenylamine (TPA) as an electronic donor that connects to an acceptor via an sp3 linker, six TPA-based AIE-active RTP luminophores were obtained. Distinct dual phosphorescence bands emitting from largely localized donor and acceptor triplet emitting states could be recorded at lowered temperatures; at room temperature, only a merged RTP band is present. Theoretical investigations reveal that the two temperature-dependent phosphorescence bands both originate from local/global minima from the lowest triplet excited state (T1). The reported molecular construct serves as an intermediary case between a fully conjugated donor-acceptor system and a donor/acceptor binary mix, which may provide important clues on the design and control of high-freedom molecular systems with complex excited-state dynamics.
Author Correction: Interstitial boron-doped mesoporous semiconductor oxides for ultratransparent energy storage
Authors: Zhi Jian , Zhou Min , Zhang Zhen , Reiser Oliver , Huang Fuqiang
Published: March 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21705-3
Molecular correlates of muscle spindle and Golgi tendon organ afferents
Authors: Oliver Katherine M. , Florez-Paz Danny M. , Badea Tudor Constantin , Mentis George Z. , Menon Vilas , de Nooij Joriene C.
Published: March 2021

Proprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents and group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates of these three afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and uncovered five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia and skeletal muscle demonstrates that two of these clusters correspond to group Ia MS afferents and group Ib GTO afferent proprioceptors, respectively, and suggest that the remaining clusters could represent group II MS afferents. Lineage analysis between proprioceptor transcriptomes at different developmental stages provides evidence that proprioceptor subtype identities emerge late in development. Together, our data provide comprehensive molecular signatures for groups Ia and II MS afferents and group Ib GTO afferents, enabling genetic interrogation of the role of individual proprioceptor subtypes in regulating motor output.
The calcium binding protein S100β marks hedgehog-responsive resident vascular stem cells within vascular lesions
Authors: Di Luca Mariana , Fitzpatrick Emma , Burtenshaw Denise , Liu Weimin , Helt Jay-Christian , Hakimjavadi Roya , Corcoran Eoin , Gusti Yusof , Sheridan Daniel , Harman Susan , Lally Catriona , Redmond Eileen M. , Cahill Paul A.
Published: March 2021

A hallmark of subclinical atherosclerosis is the accumulation of vascular smooth muscle cell (SMC)-like cells leading to intimal thickening. While medial SMCs contribute, the participation of hedgehog-responsive resident vascular stem cells (vSCs) to lesion formation remains unclear. Using transgenic eGFP mice and genetic lineage tracing of S100β vSCs in vivo, we identified S100β/Sca1 cells derived from a S100β non-SMC parent population within lesions that co-localise with smooth muscle α-actin (SMA) cells following iatrogenic flow restriction, an effect attenuated following hedgehog inhibition with the smoothened inhibitor, cyclopamine. In vitro, S100β/Sca1 cells isolated from atheroprone regions of the mouse aorta expressed hedgehog signalling components, acquired the di-methylation of histone 3 lysine 4 (H3K4me2) stable SMC epigenetic mark at the Myh11 locus and underwent myogenic differentiation in response to recombinant sonic hedgehog (SHh). Both S100β and PTCH1 cells were present in human vessels while S100β cells were enriched in arteriosclerotic lesions. Recombinant SHh promoted myogenic differentiation of human induced pluripotent stem cell-derived S100β neuroectoderm progenitors in vitro. We conclude that hedgehog-responsive S100β vSCs contribute to lesion formation and support targeting hedgehog signalling to treat subclinical arteriosclerosis.
A simple and low-cost approach for irreversible bonding of polymethylmethacrylate and polydimethylsiloxane at room temperature for high-pressure hybrid microfluidics
Authors: Hassanpour-Tamrin Sara , Sanati-Nezhad Amir , Sen Arindom
Published: March 2021

Microfluidic devices have been used progressively in biomedical research due to the advantages they offer, such as relatively low-cost, rapid and precise processing, and an ability to support highly automated analyses. Polydimethylsiloxane (PDMS) and polymethylmethacrylate (PMMA) are both biocompatible materials widely used in microfluidics due to their desirable characteristics. It is recognized that combining these two particular materials in a single microfluidic device would enable the development of an increasingly in-demand array of new applications, including those requiring high flow rates and elevated pressures. Whereas complicated and time-consuming efforts have been reported for bonding these two materials, the robust adhesion of PDMS and PMMA has not yet been accomplished, and remains a challenge. In this study, a new, simple, efficient, and low-cost method has been developed to mediate a strong bond between PMMA and PDMS layers at room temperature in less than 5 min using biocompatible adhesive tape and oxygen plasma treatment. The PDMS–PMMA bond was hydrolytically stable, and could tolerate a high influx of fluid without any leakage. This study addresses the limitations of existing approaches to bond these materials, and will enable the development of highly sought high-pressure and high-throughput biomedical applications.
Mitogenome analyses elucidate the evolutionary relationships of a probable Eocene wet tropics relic in the xerophilic lizard genus Acanthodactylus
Authors: Kirchhof Sebastian , Lyra Mariana L. , Rodríguez Ariel , Ineich Ivan , Müller Johannes , Rödel Mark-Oliver , Trape Jean-François , Vences Miguel , Boissinot Stéphane
Published: March 2021

Climate has a large impact on diversity and evolution of the world’s biota. The Eocene–Oligocene transition from tropical climate to cooler, drier environments was accompanied by global species turnover. A large number of Old World lacertid lizard lineages have diversified after the Eocene–Oligocene boundary. One of the most speciose reptile genera in the arid Palearctic, Acanthodactylus, contains two sub-Saharan species with unresolved phylogenetic relationship and unknown climatic preferences. We here aim to understand how and when adaptation to arid conditions occurred in Acanthodactylus and when tropical habitats where entered. Using whole mitogenomes from fresh and archival DNA and published sequences we recovered a well-supported Acanthodactylus phylogeny and underpinned the timing of diversification with environmental niche analyses of the sub-Saharan species A. guineensis and A. boueti in comparison to all arid Acanthodactylus. We found that A. guineensis represents an old lineage that splits from a basal node in the Western clade, and A. boueti is a derived lineage and probably not its sister. Their long branches characterize them—and especially A. guineensis—as lineages that may have persisted for a long time without further diversification or have undergone multiple extinctions. Environmental niche models verified the occurrence of A. guineensis and A. boueti in hot humid environments different from the other 42 arid Acanthodactylus species. While A. guineensis probably remained in tropical habitat from periods prior to the Eocene–Oligocene boundary, A. boueti entered tropical environments independently at a later period. Our results provide an important baseline for studying adaptation and the transition from humid to arid environments in Lacertidae.
Genomic analysis revealed a novel genotype of methicillin-susceptible Staphylococcus aureus isolated from a fatal sepsis case in dengue patient
Authors: Ngoi Soo Tein , Niek Wen Kiong , Lee Yee Wan , AbuBakar Sazaly , Teh Cindy Shuan Ju
Published: March 2021

Staphylococcus aureus (S. aureus) is an opportunistic pathogen capable of causing serious health implications in susceptible individuals once it invades the host’s protective barriers. Methicillin-susceptible S. aureus (MSSA) often receives lesser attention although it has been frequently associated with serious infections in human. We aim to investigate the genomic features of a highly virulent yet pan susceptible MSSA strain (coded as HS-MSSA) which caused concurrent bacteraemia in a dengue patient, ultimately resulted in sepsis death of the patient. Whole genome sequence analysis was performed. The draft genome of HS-MSSA is approximately 2.78 Mb (GC content = 32.7%) comprising of 2637 predicted coding sequences. In silico genotyping of the HS-MSSA strain revealed a novel combined genotype (t091/ST2990). The HS-MSSA carries a SaPIn1-like pathogenicity island that harbours the staphylococcal enterotoxin and enterotoxin-like genes (sec3 and selL). The strain-specific β-lactamase (blaZ)-bearing plasmid region was identified in HS-MSSA. Core genome phylogeny showed that the HS-MSSA strain shared a common ancestry with the European MRSA clone. We report herein the genomic features of an MSSA lineage with novel genotype previously not reported elsewhere.
Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment
Authors: Sakai Takayuki , Matsuo Yoshiyuki , Okuda Kensuke , Hirota Kiichi , Tsuji Mieko , Hirayama Tasuku , Nagasawa Hideko
Published: March 2021

To develop antitumor drugs capable of targeting energy metabolism in the tumor microenvironment, we produced a series of potent new biguanide derivatives via structural modification of the arylbiguanide scaffold. We then conducted biological screening using hypoxia inducible factor (HIF)-1- and unfolded protein response (UPR)-dependent reporter assays and selective cytotoxicity assay under low glucose conditions. Homologation studies of aryl-(CH2)n-biguanides (n = 0–6) yielded highly potent derivatives with an appropriate alkylene linker length (n = 5, 6). The o-chlorophenyl derivative 7l (n = 5) indicated the most potent inhibitory effects on HIF-1- and UPR-mediated transcriptional activation (IC50; 1.0 ± 0.1 μM, 7.5 ± 0.1 μM, respectively) and exhibited selective cytotoxicity toward HT29 cells under low glucose condition (IC50; 1.9 ± 0.1 μM). Additionally, the protein expression of HIF-1α induced by hypoxia and of GRP78 and GRP94 induced by glucose starvation was markedly suppressed by the biguanides, thereby inhibiting angiogenesis. Metabolic flux and fluorescence-activated cell sorting analyses of tumor cells revealed that the biguanides strongly inhibited oxidative phosphorylation and activated compensative glycolysis in the presence of glucose, whereas both were strongly suppressed in the absence of glucose, resulting in cellular energy depletion and apoptosis. These findings suggest that the pleiotropic effects of these biguanides may contribute to more selective and effective killing of cancer cells due to the suppression of various stress adaptation systems in the tumor microenvironment.
Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology
Authors: Guennewig Boris , Lim Julia , Marshall Lee , McCorkindale Andrew N. , Paasila Patrick J. , Patrick Ellis , Kril Jillian J. , Halliday Glenda M. , Cooper Antony A. , Sutherland Greg T.
Published: March 2021

Tau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.
Machine learning methods to predict amyloid positivity using domain scores from cognitive tests
Authors: Shan Guogen , Bernick Charles , Caldwell Jessica Z. K. , Ritter Aaron
Published: March 2021

Amyloid-$$\beta$$
β
(A$$\beta$$
β
) is the target in many clinical trials for Alzheimer’s disease (AD). Preclinical AD patients are heterogeneous with regards to different backgrounds and diagnosis. Accurately predicting A$$\beta$$
β
status of participants by using machine learning (ML) models based on easily accessible data, could improve the effectiveness of AD clinical trials. We will develop optimal ML models for each subpopulation stratified by sex and disease stages using sub scores from screening neurological tests. Data from the AD Neuroimaging Initiative (ADNI) were used to build the ML models, for three groups: individuals with significant memory concern, early mild cognitive impairment (MCI), and late MCI. Data were further separated into 6 groups by disease stage (3 levels) and sex (2 categories). The outcome was defined as the A$$\beta$$
β
status confirmed by the PET imaging, and the features include demographic data, newly identified risk factors, screening tests, and the domain scores from screening tests. Monte Carlo simulation studies were used together with k-fold cross-validation technique to compute model performance metric. We also develop a new feature selection method based on the stochastic ordering to avoiding searching all possible combinations of features. Accuracy of the identified optimal model for SMC male was over 90% by using domain scores, and accuracy for LMCI female was above 86%. Domain scores can improve the ML model prediction as compared to the total scores. Accurate ML prediction models can identify the proper population for AD clinical trials.
Impact of SARS-CoV-2 infection on the recovery of peripheral blood mononuclear cells by density gradient
Authors: Manunta Maria D. I. , Lamorte Giuseppe , Ferrari Francesca , Trombetta Elena , Tirone Mario , Bianco Cristiana , Cattaneo Alessandra , Santoro Luigi , Baselli Guido , Brasca Manuela , Ostadreza Mahnoosh , Erba Elisa , Gori Andrea , Bandera Alessandra , Porretti Laura , Valenti Luca V. C. , Prati Daniele
Published: March 2021

SARS-CoV-2 virus infection is responsible for coronavirus disease (COVID-19), which is characterised by a hyperinflammatory response that plays a major role in determining the respiratory and immune-mediated complications of this condition. While isolating peripheral blood mononuclear cells (PBMCs) from whole blood of COVID-19 patients by density gradient centrifugation, we noticed some changes in the floating properties and in the sedimentation of the cells on density medium. Investigating this further, we found that in early phase COVID-19 patients, characterised by reduced circulating lymphocytes and monocytes, the PBMC fraction contained surprisingly high levels of neutrophils. Furthermore, the neutrophil population exhibited alterations in the cell size and in the internal complexity, consistent with the presence of low density neutrophils (LDNs) and immature forms, which may explain the shift seen in the floating abilities and that may be predictive of the severity of the disease. The percentage of this subset of neutrophils found in the PBMC band was rather spread (35.4 ± 27.2%, with a median 28.8% and IQR 11.6–56.1, Welch’s t-test early phase COVID-19 versus blood donor healthy controls P < 0.0001). Results confirm the presence of an increased number of LDNs in patients with early stage COVID-19, which correlates with disease severity and may be recovered by centrifugation on a density gradient together with PBMCs.
Comparative performance of PCR using DNA extracted from dried blood spots and whole blood samples for malaria diagnosis: a meta-analysis
Authors: Mahittikorn Aongart , Masangkay Frederick Ramirez , Kotepui Kwuntida Uthaisar , De Jesus Milanez Giovanni , Kotepui Manas
Published: March 2021

Polymerase chain reaction (PCR) using deoxyribonucleic acid (DNA) extracted from dried blood spots (DBS) provides a fast, inexpensive, and convenient method for large-scale epidemiological studies. This study compared the performance of PCR between DNA extracted from DBS and DNA obtained from whole blood for detecting malarial parasites. Primary studies assessing the diagnostic performance of PCR using DNA extracted from DBS and whole blood for detecting malarial parasites were obtained from the ISI Web of Science, Scopus, and PubMed databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were plotted in forest plots using Review Manager version 5.3. Statistical analysis was performed via random-effects meta-analysis. Data heterogeneity was assessed using the I2 statistic. Of the 904 studies retrieved from the databases, seven were included in this study. The pooled meta-analysis demonstrated no significant difference in the comparative performance of PCR for detecting malaria parasites between DNA extracted from DBS and that extracted from whole blood (OR 0.85; 95% CI 0.62–1.16; I2 = 78%). However, subgroup analysis demonstrated that PCR using DNA extracted from DBS was less accurate in detecting Plasmodium vivax than that using DNA extracted from whole blood (OR = 0.85; 95% CI 0.77–0.94). In conclusion, a significant difference in detecting P. vivax was observed between PCR using DNA extracted from DBS and that using DNA extracted from whole blood. Therefore, P. vivax in endemic areas should be identified and detected with care with PCR using DNA obtained from DBS which potentially leads to a negative result. Further studies are required to investigate the performance of PCR using DBS for detecting P. vivax and other malarial parasites to provide data in research and routine surveillance of malaria, especially with renewed efforts towards the eradication of the disease.
The effects of acarbose therapy on reductions of myocardial infarction and all-cause death in T2DM during 10-year multifactorial interventions (The Beijing Community Diabetes Study 24)
Authors: Zhang Xue-Lian , Yuan Shen-Yuan , Wan Gang , Yuan Ming-Xia , Yang Guang-Ran , Fu Han-Jing , Zhu Liang-Xiang , Zhang Jian-Dong , Li Yu-Ling , Gao Da-yong , Cui Xue-Li , Wang Zi-ming , Xie Rong-Rong , Chen Ying-jun
Published: March 2021

To investigate the potential benefits of acarbose therapy on cardiovascular events (CVD) in Type 2 diabetes (T2DM) in an urban community over 10-year follow-up. The study population of Beijing Community Diabetes Study (BCDS) were type 2 diabetes (T2DM) living in 21 communities in Beijing. All patients received comprehensive intervention in accordance with the Chinese guidelines for the prevention and treatment of diabetes. Professors in endocrinology from top tier hospitals regularly visited the communities for consultations, which was a feature of this study. A total of 1797 T2DM in BCDS study had complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose continuous therapy. After 10-year follow-up, the risks of CVD outcomes were assessed according to whether patients had received acarbose therapy or not. All patients were followed-up to assess the long-term effects of the multifactorial interventions. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. From the beginning of 8th year follow-up, the joint target control rate in patients with acarbose therapy was significantly higher than that of acarbose therapy free. During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events. The incidences of myocardial infarction (from the 4th year of follow-up) and all-cause death (from the 2nd year of follow-up) in patients who received acarbose therapy were significantly lower than that of acarbose therapy free respectively. In Cox multivariate analyses, there were significant differences in incidences of myocardial infarction and all-cause death between afore two groups during the 10-year follow-up, and the adjusted HRs were 0.50 and 0.52, respectively. After multifactorial interventions, T2DM with acarbose therapy revealed significant reductions of myocardial infarction and all-cause death. The long-term effects of with acarbose therapy on improving joint target control might be one of the main reasons of myocardial infarction and all-cause death reduction.

Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090.
Disproportionate left atrial myopathy in heart failure with preserved ejection fraction among participants of the PROMIS-HFpEF study
Authors: Patel Ravi B. , Lam Carolyn S. P. , Svedlund Sara , Saraste Antti , Hage Camilla , Tan Ru-San , Beussink-Nelson Lauren , Tromp Jasper , Sanchez Cynthia , Njoroge Joyce , Swat Stanley A. , Faxén Ulrika Ljung , Fermer Maria Lagerstrom , Venkateshvaran Ashwin , Gan Li-Ming , Lund Lars H. , Shah Sanjiv J.
Published: March 2021

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.
A versatile, compartmentalised gut-on-a-chip system for pharmacological and toxicological analyses
Authors: de Haan Pim , Santbergen Milou J. C. , van der Zande Meike , Bouwmeester Hans , Nielen Michel W. F. , Verpoorte Elisabeth
Published: March 2021

A novel, integrated, in vitro gastrointestinal (GI) system is presented to study oral bioavailability parameters of small molecules. Three compartments were combined into one hyphenated, flow-through set-up. In the first compartment, a compound was exposed dynamically to enzymatic digestion in three consecutive microreactors, mimicking the processes of the mouth, stomach, and intestine. The resulting solution (chyme) continued to the second compartment, a flow-through barrier model of the intestinal epithelium allowing absorption of the compound and metabolites thereof. The composition of the effluents from the barrier model were analysed either offline by electrospray-ionisation-mass spectrometry (ESI–MS), or online in the final compartment using chip-based ESI–MS. Two model drugs, omeprazole and verapamil, were used to test the integrated model. Omeprazole was shown to be broken down upon treatment with gastric acid, but reached the cell barrier unharmed when introduced to the system in a manner emulating an enteric-coated formulation. In contrast, verapamil was unaffected by digestion. Finally, a reduced uptake of verapamil was observed when verapamil was introduced to the system dissolved in apple juice, a simple food matrix. It is envisaged that this integrated, compartmentalised GI system has potential for enabling future research in the fields of pharmacology, toxicology, and nutrition.
Development of a poor-prognostic-mutations derived immune prognostic model for acute myeloid leukemia
Authors: Dao Feng-Ting , Wang Jun , Yang Lu , Qin Ya-Zhen
Published: March 2021

Leukemia cell-intrinsic somatic mutations and cytogenetic abnormalities have been used to define risk categories in acute myeloid leukemia (AML). In addition, since the immune microenvironment might influence prognosis and somatic mutations have been demonstrated to modulate the immune microenvironment in AML, there is need for developing and evaluating an immune prognostic model (IPM) derived from mutations associated with poor prognosis. Based on AML cases with intermediate and adverse-cytogenetic risk in the Cancer Genome Atlas (TCGA) database, 64 immune-related differentially expressed genes (DEGs) among patients with RUNX1, TP53, or ASXL1 mutations and patients without these mutations were identified. After Cox proportional hazards analysis, an IPM composed of PYCARD and PEAR1 genes was constructed. IPM defined high-risk (IPM-HR) independently predicted lower 2-year overall survival (OS) rates in both patients with intermediate and adverse-cytogenetic risks and non-M3 patients in the TCGA AML cohort. The poor prognostic impact of IPM-HR on OS was further validated by GSE71014, 37642, and 10358 downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, IPM-HR was remarkably associated with higher proportions of CD8+ T cells and regulatory T cells (Tregs), lower proportions of eosinophils, and higher expression of the checkpoint molecules CTLA-4, PD-1, and LAG3 in the TCGA non-M3 AML cohort. In summary, we developed and validated an IPM derived from mutations related with poor prognosis in AML, which would provide new biomarkers for patient stratification and personalized immunotherapy.
Entangled and correlated photon mixed strategy for social decision making
Authors: Maeda Shion , Chauvet Nicolas , Saigo Hayato , Hori Hirokazu , Bachelier Guillaume , Huant Serge , Naruse Makoto
Published: March 2021

Collective decision making is important for maximizing total benefits while preserving equality among individuals in the competitive multi-armed bandit (CMAB) problem, wherein multiple players try to gain higher rewards from multiple slot machines. The CMAB problem represents an essential aspect of applications such as resource management in social infrastructure. In a previous study, we theoretically and experimentally demonstrated that entangled photons can physically resolve the difficulty of the CMAB problem. This decision-making strategy completely avoids decision conflicts while ensuring equality. However, decision conflicts can sometimes be beneficial if they yield greater rewards than non-conflicting decisions, indicating that greedy actions may provide positive effects depending on the given environment. In this study, we demonstrate a mixed strategy of entangled- and correlated-photon-based decision-making so that total rewards can be enhanced when compared to the entangled-photon-only decision strategy. We show that an optimal mixture of entangled- and correlated-photon-based strategies exists depending on the dynamics of the reward environment as well as the difficulty of the given problem. This study paves the way for utilizing both quantum and classical aspects of photons in a mixed manner for decision making and provides yet another example of the supremacy of mixed strategies known in game theory, especially in evolutionary game theory.
Root characteristics of spring wheat under drip irrigation and their relationship with aboveground biomass and yield
Authors: Chen Rui , Xiong Xing-peng , Cheng Wen-han
Published: March 2021

The objectives of this two-year field experiment were (1) to study the effect of irrigation frequency and irrigation amount on the root characteristics of drip-irrigated spring wheat (Triticum aestivum L.) and (2) to determine the relationship between these root characteristics and aboveground biomass and yield. A split-plot design was used with two wheat cultivars (Xinchun 6 and Xinchun 22). The irrigation treatments consisted of three irrigation intervals (D1, 13 d; D2, 10 d; and D3, 7 d) and three water amounts (W1, 3750 m3/ha; W2, 6000 m3/ha; and W3, 8250 m3/ha). The results showed that root length density (RLD) and root weight density (RWD) were greater at 0–20 cm than at 20–40 cm at flowering. The RLD was greater in D1 and D2 than in D3 in the shallow soil layer and did not differ among the treatments with different irrigation frequencies in deep soil. The RLD at the 0–20 cm depth of W3 was 17.9% greater than that of W2 and 53.8% greater than that of W1, and the RLD trend was opposite at the 20–40 cm depth. The root–shoot ratio was significantly higher in D2 than in the other treatment, whereas the RLD, RWD, leaf Pn and LAI were significantly greater in D3. Leaf Pn and LAI both increased as the irrigation amount increased. Regression analysis showed a natural logarithmic relationship between RWD and aboveground biomass (R2 > 0.60, P < 0.05) and binomial relationships of the RWD at 0–20 cm depth (R2 = 0.43, P < 0.05) and the RLD at 20–40 cm depth (R2 = 0.34, P < 0.05) with grain yield. We found that with the optimum irrigation amount (W2), increasing drip irrigation frequency can increase wheat root length and root weight and aboveground biomass accumulation, thereby improving yield and water use efficiency.
Use of bladder antimuscarinics is associated with an increased risk of dementia: a retrospective population-based case–control study
Authors: Harnod Tomor , Yang Yu-Cih , Chiu Lu-Ting , Wang Jen-Hung , Lin Shinn-Zong , Ding Dah-Ching
Published: March 2021

The association between bladder antimuscarinic use and dementia development is unclear. We used data from the Taiwan National Health Insurance Research Database to determine the association between the exposure dose and duration of bladder antimuscarinics and the subsequent dementia risk. We enrolled participants aged 55 years or more and defined a dementia cohort (International Classification of Diseases, Ninth Revision, Clinical Modification codes 290, 294.1, and 331.0). We used a propensity score matching method, and randomly enrolled two controls without dementia. We evaluated dementia risk with respect to the exposure dose and duration of treatment with seven bladder antimuscarinics (oxybutynin, propiverine, tolterodine, solifenacin, trospium, darifenacin, and fesoterodine) used for at least 1 year before the index date, after adjusting for age, sex, comorbidities, and medications. The dementia risk was 2.46-fold (95% confidence interval: 2.22–2.73) higher in Taiwanese patients who used bladder antimuscarinics for ≥ 1 year than in those who were not exposed to this treatment. The risk proportionally increased with increasing doses of antimuscarinics for less than 4 years. Taiwanese patients aged 55 years or more on bladder antimuscarinics exhibited a higher risk of dementia. Additional studies in other countries are required to determine whether this result is valid worldwide.
Cholesterol loading suppresses the atheroinflammatory gene polarization of human macrophages induced by colony stimulating factors
Authors: Lappalainen Jani , Yeung Nicolas , Nguyen Su D. , Jauhiainen Matti , Kovanen Petri T. , Lee-Rueckert Miriam
Published: March 2021

In atherosclerotic lesions, blood-derived monocytes differentiate into distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines, which also contains macrophage-colony stimulating factor (M-CSF) and granulocyte–macrophage-colony stimulating factor (GM-CSF). Here we generated human macrophages in the presence of either M-CSF or GM-CSF to obtain M-MØ and GM-MØ, respectively. The macrophages were converted into cholesterol-loaded foam cells by incubating them with acetyl-LDL, and their atheroinflammatory gene expression profiles were then assessed. Compared with GM-MØ, the M-MØ expressed higher levels of CD36, SRA1, and ACAT1, and also exhibited a greater ability to take up acetyl-LDL, esterify cholesterol, and become converted to foam cells. M-MØ foam cells expressed higher levels of ABCA1 and ABCG1, and, correspondingly, exhibited higher rates of cholesterol efflux to apoA-I and HDL2. Cholesterol loading of M-MØ strongly suppressed the high baseline expression of CCL2, whereas in GM-MØ the low baseline expression CCL2 remained unchanged during cholesterol loading. The expression of TNFA, IL1B, and CXCL8 were reduced in LPS-activated macrophage foam cells of either subtype. In summary, cholesterol loading converged the CSF-dependent expression of key genes related to intracellular cholesterol balance and inflammation. These findings suggest that transformation of CSF-polarized macrophages into foam cells may reduce their atheroinflammatory potential in atherogenesis.
Endothelin-1 mediated vasoconstriction leads to memory impairment and synaptic dysfunction
Authors: Diwakar Latha , Gowaikar Ruturaj , Chithanathan Keerthana , Gnanabharathi Barathan , Tomar Deepika Singh , Ravindranath Vijayalakshmi
Published: March 2021

Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia. Such vascular insult caused by impairment in blood flow to specific area in brain involving small vessels can gradually worsen the pathology leading to cognitive deficits. In the present study we developed a transient model of vaso-constriction to study the impact of such pathology by bilateral injection of ET-1 (Endothelin-1; a 21 amino acid vasoconstricting peptide) into lateral ventricles of C57 mice. The impediment in cerebral blood flow decreased CD31 expression in endothelial cells lining the blood vessels around the hippocampal region, leading to memory deficits after 7 days. Activity dependent protein translation, critical for synaptic plasticity was absent in synaptoneurosomes prepared from hippocampal tissue. Further, Akt1- mTOR signaling cascade was downregulated indicating the possible cause for loss of activity dependent protein translation. However, these effects were reversed after 30 days indicating the ephemeral nature of deficits following a single vascular insult. Present study demonstrates that vasoconstriction leading to memory deficit and decline in activity dependent protein translation in hippocampus as a potential molecular mechanism impacting synaptic plasticity.
Computational property predictions of Ta–Nb–Hf–Zr high-entropy alloys
Authors: Mishra Shashank , Maiti Soumyadipta , Rai Beena
Published: March 2021

Refractory high entropy alloys (R-HEAs) are becoming prominent in recent years because of their properties and uses as high strength and high hardness materials for ambient and high temperature, aerospace and nuclear radiation tolerance applications, orthopedic applications etc. The mechanical properties like yield strength and ductility of TaNbHfZr R-HEA depend on the local nanostructure and chemical ordering, which in term depend on the annealing treatment. In this study we have computationally obtained various properties of the equimolar TaNbHfZr alloy like the role of configurational entropy in the thermodynamic property, rate of evolution of nanostructure morphology in thermally annealed systems, dislocation simulation based quantitative prediction of yield strength, nature of dislocation movement through short range clustering (SRC) and qualitative prediction of ductile to brittle transition behavior. The simulation starts with hybrid Monte Carlo/Molecular Dynamics (MC/MD) based nanostructure evolution of an initial random solid solution alloy structure with BCC lattice structure created with principal axes along [1 1 1], [− 1 1 0] and [− 1 − 1 2] directions suitable for simulation of ½[1 1 1] edge dislocations. Thermodynamic properties are calculated from the change in enthalpy and configurational entropy, which in term is calculated by next-neighbor bond counting statistics. The MC/MD evolved structures mimic the annealing treatment at 1800 °C and the output structures are replicated in periodic directions to make larger 384,000 atom structures used for dislocation simulations. Edge dislocations were utilized to obtain and explain for the critically resolved shear stress (CRSS) for the structures with various degrees of nanostructure evolution by annealing, where extra strengthening was observed because of the formations of SRCs. Lastly the MC/MD evolved structures containing dislocations are subjected to a high shear stress beyond CRSS to investigate the stability of the dislocations and the lattice structures to explain the experimentally observed transition from ductile to brittle behavior for the TaNbHfZr R-HEA.
The potential risk of exposure to Borrelia garinii, Anaplasma phagocytophilum and Babesia microti in the Wolinski National Park (north-western Poland)
Authors: Asman Marek , Witecka Joanna , Korbecki Jan , Solarz Krzysztof
Published: March 2021

Ixodes ricinus (Acari: Ixodida) is the main vector in Europe of Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum and Babesia microti. Wolinski National Park (WNP) is situated by the Baltic Sea and is frequently visited by tourists. The aim of the study was to determine the potential risk of exposure to tick borne infection with B. burgdorferi s.l., A. phagocytophilum and B. microti on the areas of WNP. In total, 394 I. ricinus were tested. The pathogens in ticks were detected by PCR, nested PCR, RFLP and sequencing. Altogether, pathogens were detected in 12.69% of the studied ticks. B. burgdorferi s.l., was shown in 0.25% of the studied I. ricinus, while A. phagocytophilum and B. microti were detected in 1.01% and 10.65% of studied ticks, respectively. Co-infection by A. phagocytophilum and B. microti was shown in only one I. ricinus nymph. Analysis of B. burgdorferi s.l., genospecies showed that 0.25% of the studied ticks were infected with Borrelia garinii. The obtained results show the potentially high human risk of exposure to tick-borne infection with B. microti, and the low potential risk of infection with B. garinii and A. phagocytophilum on the studied areas of WNP.
Complementary mechanisms stabilize national food production
Authors: Mahaut Lucie , Violle Cyrille , Renard Delphine
Published: March 2021

Ensuring the temporal stability of national food production is crucial for avoiding sharp drops in domestic food availability. The average stability of individual crop yields and asynchrony among crop yield fluctuations are two candidate mechanisms to stabilize national food production. However, the quantification of their respective influence on the stability of national food production is lacking, as is the identification of the factors regulating both mechanisms. Using yield data for 138 crops and 115 countries over a 50-year period, we first show that the stability of total national yield mostly relies on the fluctuations of the yield of crops covering the largest share of cropland. The average yield stability of these crops exert a stabilizing effect on national food production that is twice as important as the one of the asynchronous yield fluctuations among them. Climate variability reduces the stability of national food production by synchronizing yield fluctuations among crops and destabilizing the yield of individual crops. However, our results suggest that increasing crop diversity can counteract the synchronizing effects of climate variability by enhancing asynchronous dynamics among crops. Irrigation can promote the average stability of individual crop yields but cannot compensate for the destabilizing effect of climate variability. Considering both the response of each crop to climatic variations and the dynamics emerging from crop baskets will help agricultural policies to ensure stable food supply at the national level.
Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats
Authors: Medvedev Roman Y. , Sanchez-Alonso Jose L. , Mansfield Catherine A. , Judina Aleksandra , Francis Alice J. , Pagiatakis Christina , Trayanova Natalia , Glukhov Alexey V. , Miragoli Michele , Faggian Giuseppe , Gorelik Julia
Published: March 2021

Right ventricle (RV) dysfunction is an independent predictor of patient survival in heart failure (HF). However, the mechanisms of RV progression towards failing are not well understood. We studied cellular mechanisms of RV remodelling in a rat model of left ventricle myocardial infarction (MI)-caused HF. RV myocytes from HF rats show significant cellular hypertrophy accompanied with a disruption of transverse-axial tubular network and surface flattening. Functionally these cells exhibit higher contractility with lower Ca2+ transients. The structural changes in HF RV myocytes correlate with more frequent spontaneous Ca2+ release activity than in control RV myocytes. This is accompanied by hyperactivated L-type Ca2+ channels (LTCCs) located specifically in the T-tubules of HF RV myocytes. The increased open probability of tubular LTCCs and Ca2+ sparks activation is linked to protein kinase A-mediated channel phosphorylation that occurs locally in T-tubules. Thus, our approach revealed that alterations in RV myocytes in heart failure are specifically localized in microdomains. Our findings may indicate the development of compensatory, though potentially arrhythmogenic, RV remodelling in the setting of LV failure. These data will foster better understanding of mechanisms of heart failure and it could promote an optimized treatment of patients.
Pulmonary blood volume estimation in mice by magnetic particle imaging and magnetic resonance imaging
Authors: Kaul Michael Gerhard , Mummert Tobias , Graeser Matthias , Salamon Johannes , Jung Caroline , Tahir Enver , Ittrich Harald , Adam Gerhard , Peldschus Kersten
Published: March 2021

This methodical work describes the measurement and calculation of pulmonary blood volume in mice based on two imaging techniques namely by using magnetic particle imaging (MPI) and cardiac magnetic resonance imaging (MRI). Besides its feasibility aspects that may influence quantitative analysis are studied. Eight FVB mice underwent cardiac MRI to determine stroke volumes and anatomic MRI as morphological reference for functional MPI data. Arrival time analyses of boli of 1 µl of 1 M superparamagnetic tracer were performed by MPI. Pulmonary transit time of the bolus was determined by measurements in the right and left ventricles. Pulmonary blood volume was calculated out of stroke volume, pulmonary transit time and RR-interval length including a maximal error analysis. Cardiac stroke volume was 31.7 µl ± 2.3 µl with an ejection fraction of 71% ± 6%. A sharp contrast bolus profile was observed by MPI allowing subdividing the first pass into three distinct phases: tracer arrival in the right ventricle, pulmonary vasculature, and left ventricle. The bolus full width at half maximum was 578 ms ± 144 ms in the right ventricle and 1042 ms ± 150 ms in the left ventricle. Analysis of pulmonary transit time revealed 745 ms ± 81 ms. Mean RR-interval length was 133 ms ± 12 ms. Pulmonary blood volume resulted in 177 µl ± 27 µl with a mean maximal error limit of 27 µl. Non-invasive assessment of the pulmonary blood volume in mice was feasible. This technique can be of specific value for evaluation of pulmonary hemodynamics in mouse models of cardiac dysfunction or pulmonary disease. Pulmonary blood volume can complement cardiac functional parameters as a further hemodynamic parameter.
Influenza vaccination reduces incidence of peripheral arterial occlusive disease in elderly patients with chronic kidney disease
Authors: Hu Ping-Jen , Chen Chia-Hsien , Wong Chung-Shun , Chen Tzu-Ting , Wu Mei-Yi , Sung Li-Chin
Published: March 2021

An influenza vaccination might reduce the risk of incident peripheral arterial occlusive disease (PAOD) in patients with chronic kidney disease (CKD), but supporting evidence is limited. This case-crossover study analyzed data from Taiwan’s real-world National Health Insurance Research Database. This study included elderly (≥ 67 years old) patients with CKD having incident PAOD from January 1, 2006, to June 30, 2015. We defined 1 year before PAOD onset as the index date for the self-control group. A conditional logistic regression model was used to investigate exposure to an influenza vaccination for estimating the risk for incident PAOD following vaccination. In total, this study included 46,782 elderly patients with CKD having incident PAOD. The odds ratios for incident PAOD were 0.85 (95% confidence interval 0.77–0.94), 0.85 (0.79–0.92), 0.84 (0.79–0.90), and 0.85 (0.81–0.90) at 1, 2, 3, and 4 months after an influenza vaccination, respectively. We observed consistent results for the subgroups of patients with CKD and concomitant diabetes. However, we did not observe any beneficial effects of influenza vaccination in patients with advanced CKD or end-stage renal disease. This study demonstrated that influenza vaccination may be associated with a reduced risk of incident PAOD among patients with early-stage CKD.