bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional regulation by methyltransferases and their role in the heart: highlighting novel emerging functionality
Authors: Szulik Marta W. , Davis Kathryn , Bakhtina Anna , Azarcon Presley , Bia Ryan , Horiuchi Emilee , Franklin Sarah
Published: August 2020

Methyltransferases are a superfamily of enzymes that transfer methyl groups to proteins, nucleic acids, and small molecules. Traditionally, these enzymes have been shown to carry out a specific modification (mono-, di-, or trimethylation) on a single, or limited number of, amino acid(s). The largest subgroup of this family, protein methyltransferases, target arginine and lysine side chains of histone molecules to regulate gene expression. Although there is a large number of functional studies that have been performed on individual methyltransferases describing their methylation targets and effects on biological processes, no analyses exist describing the spatial distribution across tissues or their differential expression in the diseased heart. For this review, we performed tissue profiling in protein databases of 199 confirmed or putative methyltransferases to demonstrate the unique tissue-specific expression of these individual proteins. In addition, we examined transcript data sets from human heart failure patients and murine models of heart disease to identify 40 methyltransferases in humans and 15 in mice, which are differentially regulated in the heart, although many have never been functionally interrogated. Lastly, we focused our analysis on the largest subgroup, that of protein methyltransferases, and present a newly emerging phenomenon in which 16 of these enzymes have been shown to play dual roles in regulating transcription by maintaining the ability to both activate and repress transcription through methyltransferase-dependent or -independent mechanisms. Overall, this review highlights a novel paradigm shift in our understanding of the function of histone methyltransferases and correlates their expression in heart disease.
More purinergic receptors deserve attention as therapeutic targets for the treatment of cardiovascular disease
Authors: Wernly Bernhard , Zhou (周稚超) Zhichao
Published: August 2020

Cardiovascular disease is a major cause of morbidity and mortality worldwide. Innovative new treatment options for this cardiovascular pandemic are urgently needed. Activation of purinergic receptors (PRs) is critically involved in the development and progression of cardiovascular disease including atherosclerosis, ischemic heart disease, hypertension, and diabetes. PRs have been targeted for the treatment of several cardiovascular diseases in a clinical setting. The P2Y12R antagonists such as clopidogrel, ticagrelor, and others are the most successful class of purinergic drugs targeting platelets for the treatment of acute coronary syndrome. In addition to targeting platelets, ticagrelor may exert P2Y12R-independent effect by targeting erythrocyte-mediated purinergic activation. The partial A1R agonist neladenoson and the A2AR agonist regadenoson have been applied in cardiovascular medicine. In experimental studies, many other PRs have been shown to play a significant role in the development and progression of cardiovascular diseases, and targeting these receptors have resulted in promising outcomes. Therefore, many of these PRs including A2BR, A3R, P2X3R, P2X4R, P2X7R, P2Y1R, P2Y4R, P2Y6R, and P2Y11R can be considered as therapeutic targets. However, the multitude of PR subtypes expressed in different cells of the cardiovascular system may constitute a challenge whether single or multiple receptors should be targeted at the same time for the best efficacy. The present review discusses the promising purinergic drugs used in clinical studies for the treatment of cardiovascular disease. We also update experimental evidence for many other PRs that can be considered as therapeutic targets for future drug development.
Functional coculture of sympathetic neurons and cardiomyocytes derived from human-induced pluripotent stem cells
Authors: Winbo Annika , Ramanan Suganeya , Eugster Emily , Jovinge Stefan , Skinner Jonathan R. , Montgomery Johanna M.
Published: August 2020

We present data on a functional coculture between human-induced pluripotent stem cell-derived sympathetic neurons and cardiomyocytes. Moreover, this study adds significantly to the available data on the electrophysiological function of human-induced pluripotent stem cell-derived sympathetic neurons.
Response of Soybean Root to Phosphorus Deficiency under Sucrose Feeding: Insight from Morphological and Metabolome Characterizations
Authors: Yang Ahui , Kong Lingjian , Wang Hui , Yao Xingdong , Xie Futi , Wang Haiying , Ao Xue
Published: August 2020

Phosphorus (P) is one the least available essential plant macronutrients in soils that is a major constraint on plant growth. Soybean (Glycine max L.) production is often limited due to low P availability. The better management of P deficiency requires improvement of soybean’s P use efficiency. Sugars are implicated in P starvation responses, and a complete understanding of the role of sucrose together with P in coordinating P starvation responses is missing in soybean. This study explored global metabolomic changes in previously screened low‐P‐tolerant (Liaodou, L13) and low‐P‐sensitive (Tiefeng 3, T3) soybean genotypes by liquid chromatography coupled mass spectrometry. We also studied the root morphological response to sucrose application (1%) in P‐starved soybean genotypes against normal P supply. Root morphology in L13 genotype has significantly improved P starvation responses as compared to the T3 genotype. Exogenous sucrose application greatly affected root length, root volume, and root surface area in L13 genotype while low‐P‐sensitive genotype, i.e., T3, only responded by increasing number of lateral roots. Root : shoot ratio increased after sucrose treatment regardless of P conditions, in both genotypes. T3 showed a relatively higher number of differentially accumulated metabolites between P‐starved and normal P conditions as compared to L13 genotype. Common metabolites accumulated under the influence of sucrose were 5‐O‐methylembelin, D‐glucuronic acid, and N‐acetyl‐L‐phenylalanine. We have discussed the possible roles of the pathways associated with these metabolites. The differentially accumulated metabolites between both genotypes under the influence of sucrose are also discussed. These results are important to further explore the role of sucrose in the observed pathways. Especially, our results are relevant to formulate strategies for improving P efficiency of soybean genotypes with different P efficiencies.
Identification of Key Genes and Pathways Associated with Age-Related Macular Degeneration
Authors: Zhang Junyu , Zhou Yu
Published: August 2020

Age-related macular degeneration (AMD) is the leading cause of severe, permanent vision loss among the elderly in the developed world. The cellular and molecular pathogenesis of initiation and development of AMD remain poorly delineated. The limited resources of the human AMD RPE/choroid tissues impeded the extensive study of the disease. To better understand the molecular and pathway changes in human AMD RPE/choroid tissues, we searched the literature and found three independent studies using high-throughput technology to analyze gene expression in 54 human AMD RPE/choroid tissues and 46 age-matched healthy controls. We downloaded these data, pooled them together, and reanalyzed the difference between molecular and pathways by the Ingenuity Pathway Analysis (IPA) database. Totally, 353 differentially expressed genes (DEGs) were identified, among which 181 genes were downregulated and 172 genes were upregulated in RPE/choroid of AMD patients. Furthermore, several significantly enriched biological processes, including cancer, organismal injury and abnormalities, and ophthalmic disease, were identified associated with these DEGs. By analysis of canonical pathway, the phototransduction pathway and atherosclerosis signaling were the top two significant canonical pathways altered in RPE/choroid tissues in human AMD. As expected, several ophthalmic disease-related molecules, including RHO, PDE6A, 3′,5′-cyclic-GMP phosphodiesterase, and G protein alpha, were in the central nodes of disease network. The bioinformatics technology combined with the existing high-throughput data was applied to evaluate the underlying key genes and pathways in human AMD tissues, which may predict downstream and upstream biological processes and identify potential therapeutic intervention targets in human AMD.
The Role of Endogenous Proteins on the Emulsification of Silicone Oils Used in Vitreoretinal Surgery
Authors: Nepita Irene , Repetto Rodolfo , Pralits Jan O. , Romano Mario R. , Ravera Francesca , Santini Eva , Liggieri Libero
Published: August 2020

The present work is aimed at investigating the chemicophysical properties of the interface between silicone oils (SOs) used in vitreoretinal surgery and aqueous solutions, in the presence of surfactant biomolecules. Such molecules are thought to play an important role in the formation of SO emulsions in vitrectomised eyes, in which the natural vitreous body has been replaced with a SO. In particular, we have measured the interfacial tension (IT) and the interfacial dilational viscoelasticity (DV) of the interface between SO (Siluron 1000) and serum proteins (albumin and γ‐globulins) at various concentrations in a Dulbecco alkaline buffer. The equilibrium IT value is relevant for the onset of emulsification, and the DV influences the stability of an emulsion, once formed. The study is complemented by preliminary emulsification tests. The experimental results show that, when proteins are dissolved in the aqueous solution, the rheological properties of the interface change. The IT decreases significantly for physiological protein concentrations, and the DV modulus achieves high values, even for small protein concentrations. The emulsification tests confirm that, in the presence of proteins, emulsions are stable on the time scale of months. We conclude that the measured values of IT in the presence of serum proteins are compatible with the promotion of droplet formation, which, in addition, are expected to be stable against coalescence. Adsorption of biomolecules at the interface with the SO is, therefore, likely to play an important role in the generation of an emulsion in eyes subjected to vitrectomy. These findings are relevant to identify strategies to avoid or control the formation of emulsions in eyes.
Study on the Intelligent Evaluation System of Tunnel Frost Damage in Cold Regions Based on the Fuzzy Comprehensive Evaluation Model
Authors: Wang Dao-yuan , Zhu Yong-quan , Cui Guang-yao , Luan Yong-jun , Cui Hai-long , Sun Liang , Sun Yong-jie , Wang Yue , Yuan Jin-xiu
Published: August 2020

At present, the tunnel design specifications in China do not provide a clear and systematic intelligent evaluation system of tunnel frost damage in cold regions. Based on the research results of 122 seasonal frozen soil tunnels in high-latitude areas of China, four key influencing factors of geohydrology, temperature, surrounding rock, and engineering measures were determined, the intelligent fuzzy comprehensive evaluation model was established, the weights of all factors were considered, and the intelligent evaluation technology system of tunnel frost damage in cold areas had been put forward. Meanwhile, the rationality of the intelligent model was verified by a specific engineering case. The research suggests that the intelligent evaluation model of tunnel frost damage proposed in this paper can accurately describe the relationship of influencing factors of tunnel frost damage in cold areas, the weight of each influencing factor is calculated by using analytic hierarchy process, and the main risk sources of tunnel frost damage in cold areas are found out. The intelligent evaluation model is an efficient and practical method for Intelligent prediction of frost damage. By using the subordinate function method, the improvement from qualitative analysis to quantitative index calculation is realized. The blindness of engineering analogy construction is avoided, and the scientificity and accuracy of renovation measures for frost damage have been improved. At the same time, the research results provide a theoretical basis for the improvement of the intelligent evaluation system of tunnel frost damage in cold regions.
A Comparative Study of High-Dose Colistin Administration for the Management of Multidrug-Resistant Gram-Negative Infections in the ICU
Authors: Ghazaeian Monireh , Mokhtari Majid , Kouchek Mehran , Miri Mir-Mohammad , Goharani Reza , Sistanizad Mohammad
Published: August 2020

The aim of this study was to assess the clinical and microbiological efficacy and toxicity of different high-dose regimens of colistin in the ICU patients with colistin-sensitive MDR Gram-negative infections. In this prospective, open label, randomized clinical trial, patients with clinical features of infection and positive culture for MDR colistin-sensitive Gram-negative bacteria were randomly allocated to receive colistin, 3 or 9 million units every 8 and 24 hours, (groups A and B), respectively. For each dose regimen, clinical and microbiological response, the rates of nephrotoxicity, and its risk factors were analyzed. Forty-three patients were enrolled, and 35 completed the study protocol, of whom 30 (88.2%) had ventilator-associated pneumonia (VAP) and 5 (14%) had bacteremia. Although there were no statistically significant differences in the clinical or microbiological response between the study groups, the microbiological response favored the divided dose group numerically (

p
=
0.40

). Clinical response was achieved in 27 of 35 (77.1%) patients (

p
=
0.999

). Twelve (34.28%) patients developed AKI during colistin treatment, 4 and 8 in groups A and B, respectively (

p

value =0.193). Significant risk factors for nephrotoxicity related to colistin were age, hyperbilirubinemia, and coadministration of other nephrotoxic agents. In multivariate regression analysis, the only independent risk factor for CMS-associated AKI was hyperbilirubinemia (

p

value =0.008). Although the clinical and microbiological responses to colistin administration were not statistically different in two groups, the microbiological response favored the divided dose regimen group numerically. We did not observe any significant safety concerns with high-dose colistin administration in this population.
Nonirritant and Cytocompatible Tinospora cordifolia Nanoparticles for Topical Antioxidant Treatments
Authors: González-Masís Jeimmy , Cubero-Sesin Jorge M. , Corrales-Ureña Yendry Regina , González-Camacho Sara , Mora-Ugalde Nohelia , Vega-Baudrit José Roberto , Rischka Klaus , Verma Virendra , Gonzalez-Paz Rodolfo J.
Published: August 2020

Tinospora cordifolia extract contains antioxidants such as polyphenols, and thus, it has been used as a natural phytochemical antioxidant therapeutic agent. Many of these compounds are insoluble or only partially soluble in water. In this study, we produced a novel aqueous nanoparticle formulation, with an average particle size of 182.9 ± 3.8 nm, to improve the dispersion of the bioactive compounds in water and to increment its bioavailability. The nanoparticles are composed of polyphenols, alkaloids, and glycosides. We studied the effect of this nanoparticle formulation on mouse 3T3 fibroblast cell viability and New Zealand rabbit dermal irritability tests. Concentrations of 2.5, 25, and 250 µg/mL resulted in similar cell viability to cells in culture media. An intermediate concentration of 12.45 mg/ml was used for the acute dermal irritability test. There were no severe alterations that compromised animal health. These results represent a precedent for application of such nanoparticles derived from plant stems, such as Tinospora cordifolia, in biomedicine and in antiaging cosmetic treatments.
A Reinsurance and Investment Game between Two Insurers under the CEV Model
Authors: Zhang Gongliang , Cheng Shuo , Li Ziye , Cao Ming
Published: August 2020

In this paper, the problem of nonzero-sum stochastic differential game between two competing insurance companies is considered, i.e., the relative performance concerns. A certain proportion of reinsurance can be taken out by each insurer to control his own risk. Moreover, each insurer can invest in a risk-free asset and risk asset with the price dramatically following the constant elasticity of variance (CEV) model. Based on the principle of dynamic programming, a general framework regarding Nash equilibrium for nonzero-sum games is established. For the typical case of exponential utilization, we, respectively, give the explicit solutions of the equilibrium strategy as well as the equilibrium function. Some numerical studies are provided at last which assist in obtaining some economic explanations.
Effect of Electroacupuncture at GV20 on Sleep Deprivation‐Induced Depression‐Like Behavior in Mice
Authors: Xu Xiaohong , Zheng Peng , Zhao Hongyan , Song Bailin , Wang Fuchun
Published: August 2020

Accumulating evidence suggests that sleep deprivation (S‐Dep) is a critical risk factor for depression. Electroacupuncture (EA) treatment has been reported to ameliorate posttraumatic stress disorder‐ (PSTD‐) like behavior and enhance hippocampal neurogenesis. However, whether EA treatment has any beneficial effect on S‐Dep‐induced depression‐like behavior is still unknown. In the present study, we focused on whether EA at Baihui (GV20) can ameliorate the deterioration effect of S‐Dep in mice. Mice were randomly divided into normal, S‐Dep, S‐Dep + EA, and S‐Dep + sham EA groups. Cognitive behavior test and in vitro assay were performed separately to avoid the influence of behavior test on synaptic transmission and protein expression. Depression‐like behaviors were determined by forced swimming test (FST), tail suspension test (TST), and Morris water maze (MWM). Neurogenesis was identified by BrdU, DCX, and NeuN immunofluorescence staining. In vitro long‐term potentiation was detected by high frequency stimulation (HFS) at Schaffer collateral‐CA1 synapses in hippocampal slices. Brain‐derived neurotropic factor (BDNF) and tropomyosin receptor kinase B (TrkB) protein expression level were assayed by western blot. Our results indicated that D‐Sep mice demonstrated depression‐like behaviors determined by prolonged immobility duration in FST and TST; D‐Sep mice also manifested spatial memory retention deficit in MWM. Furthermore, EA treatment ameliorated D‐Sep‐induced depression‐like behaviors and spatial memory retention deficit. Mechanically, EA treatment alleviated neuron progenitor cell proliferation and differentiation, ameliorated the field excitatory postsynaptic potentials (fEPSPs) slope impaired by S‐Dep, and elevated BDNF/TrkB protein expression. Taken together, our data suggested that EA treatment has a protective effect on S‐Dep‐induced depression‐like behavior and cognitive impairment, which may be through regulating BDNF/TrkB protein expression.
Circular RNA cir‐ITCH Is a Potential Therapeutic Target for the Treatment of Castration‐Resistant Prostate Cancer
Authors: Li Shoubin , Yu Chunhong , Zhang Yunxia , Liu Junjiang , Jia Yi , Sun Fuzhen , Zhang Panying , Li Jingpo , Guo Liuxiong , Xiao Helong , Gao Fei , Deng Xinna , Cai Ziqi , Cai Jianhui
Published: August 2020

cir‐ITCH, a well‐known tumor‐suppressive circular RNA, plays a critical role in different cancers. However, its expression and functional role in prostate cancer (PCa) are unclear. Herein, we explored the potential mechanism and tumor‐inhibiting role of cir‐ITCH in PCa. Using reverse transcriptase polymerase chain reaction assay, we analyzed the expression of cir‐ITCH in PCa and paired adjacent nontumor tissue samples resected during surgical operation, as well as in two cell lines of human PCa (LNCaP and PC‐3) and the immortalized normal prostate epithelial cell line (RWPE‐1). Cell viability and migration of PCa cell lines were evaluated using CCK‐8 and wound‐healing assays. Expression of key proteins of the Wnt/β‐catenin and PI3K/AKT/mTOR pathways was detected using western blotting. We found that cir‐ITCH expression was typically downregulated in the tissues and cell lines of PCa compared to that in the peritumoral tissue and in RWPE‐1 cells, respectively. The results showed that cir‐ITCH overexpression significantly inhibits the proliferation, migration, and invasion of human PCa cells and that reciprocal inhibition of expression occurred between cir‐ITCH and miR‐17. Proteins in the Wnt/β‐catenin and PI3K/AKT/mTOR pathways were downregulated by overexpression of cir‐ITCH both in androgen receptor‐positive LNCaP cells and androgen receptor‐negative PC‐3 cells. Taken together, these data demonstrated that cir‐ITCH plays a tumor‐suppressive role in human PCa cells, partly through the Wnt/β‐catenin and PI3K/AKT/mTOR pathways. Thus, cir‐ITCH may serve as a novel therapeutic target for the treatment of PCa, especially castration‐resistant prostate cancer.
A Low-Cost Layered Double Hydroxide (LDH) Based Amperometric Sensor for the Detection of Isoproturon in Water Using Carbon Paste Modified Electrode
Authors: Tcheumi Herve Leclerc , Kameni Wendji Aude Peggy , Tonle Ignas Kenfack , Ngameni Emmanuel
Published: August 2020

In this work, a Layered Double Hydroxide (NiAl-LDH) was obtained by coprecipitation method and used to elaborate an electrochemical sensor for the determination of isoproturon, which is a hazardous pollutant, widely used in agriculture, and its residue is distributed into aqueous environment through run-off and leaching from the soil. Various physicochemical techniques such as FT-IR spectroscopy, X-ray diffraction, and thermal analysis were used to characterize this material. The anionic exchange capacity of NiAl-LDH on carbon paste modified electrode was investigated toward [Fe(CN)6]3- using cyclic voltammetry. Used as electrode modifier of carbon paste electrode for isoproturon detection, a remarkable increase in isoproturon signal on modified carbon paste electrode by LDH was observed. The peak current obtained after 3 min of preconcentration in 25 μM ISO on NiAl-LDH/CPE was 2.6 times higher than that exhibited by the same analyte on the unmodified CPE, thereby opening the way to the development of a sensitive method for the detection of ISO. Other parameters that can affect the stripping response (preconcentration time, pH of detection medium, and LDH loading within the paste) were investigated to optimize the proposed sensor. After optimization, a linear calibration curve was obtained in the concentration range from 2 × 10−8 to 1.8 × 10−7 M, leading to a detection limit of 1 × 10−9 M (S/N = 3). The relative standard deviation for 5 identical measurements was 2.7%. The interfering effect of some compounds and ions was examined on the stripping response of ISO. The applicability of the method was verified by the determination of ISO in spiked water sample.
The Predictive Value of Growth Differentiation Factor-15 in Recurrence of Atrial Fibrillation after Catheter Ablation
Authors: Wei Ying , Liu Shuwang , Yu Haiyi , Zhang Yuan , Gao Wei , Cui Ming , Li Lei
Published: August 2020

The mechanisms underlying the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA) are not well concerned. The study sought to explore the association between growth differentiation factor-15 (GDF-15) and the incidence of recurrent events among AF patients after the ablation procedure. We prospectively included 150 consecutive AF patients who underwent RFCA. Clinical information about the patients was collected. Blood samples on the second morning of hospital admission and three months after RFCA were collected, and enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of GDF-15. All participants were followed up at specific times (1st/3rd/6th/12th/18th/24th months) after RFCA to record recurrences events. During a median follow-up of 14.0 months, AF recurrence occurred in 37(24.7%) patients. Baseline serum GDF-15 level in the persistent AF group was significantly higher than the paroxysmal AF group [1140(854~1701)ng/L vs. 1062(651~1374)ng/L, P=0.039]. Baseline serum GDF-15 level in the recurrence group was significantly higher than the nonrecurrence group [1287(889~1768) ng/L vs. 1062(694~1373)ng/L, P=0.022]. Serum GDF-15 level at three months after RFCA was significantly lower than the baseline [870 (579~1270) ng/L vs. 1155 (735~1632)ng/L, P<0.001]. The baseline GDF-15 correlated significantly with LAP (r=0.296, P<0.001) and LAAV(r=−0.235, P=0.003). Kaplan-Meier analysis showed a significantly lower event-free survival time in the high baseline GDF-15 (≥1287.3 ng/L) group than the low baseline GDF-15 (<1287.3 ng/L) group (17.1 months vs. 20.4 months, Log Rank P=0.017). In the multivariate Cox regression, baseline GDF-15(HR 1.053, 95% CI 1.007-1.100, P=0.022) and LAD (HR 1.124, 95% CI 1.011-1.250, P=0.030) were independent predictors of AF recurrence after RFCA. Our study indicated increased preprocedural GDF-15 is associated with left atrial remodeling and acts as a predictor of AF recurrence after ablation.
Atypical Presentation of Post-Kala-Azar Dermal Leishmaniasis in Bhutan
Authors: Pradhan Ambika , Tobgay Tashi , Dorjee Sithar , Wangdi Tenzin , Zhou Guofa , Karunaweera Nadira D.
Published: August 2020

This article describes an atypical case of post-kala-azar dermal leishmaniasis associated with complications due to delayed diagnosis and poor case management. The grave consequences of the prolonged disease process that continued for over 2 decades with eventual healing included facial disfigurement, visual impairment, and mental distress both to the patient and the family. The persistent infection within the skin over a lengthy period with likely increased risk of infection spread in the community highlights its potential negative impact on the ongoing leishmaniasis elimination program in the Indian subcontinent. Bhutan is a member of the leishmaniasis elimination network in Asia, and the government continues to invest in maintenance of the national healthcare system. The case study reveals the gaps in the healthcare system with hardships faced by a patient to access quality healthcare and poor patient outcome used as proxy indicators. It also points to the need to enhance access to healthcare to ensure early diagnosis and effective treatment for leishmaniasis patients including those who live in remote areas, in order to achieve the planned disease elimination targets. It also points towards the key challenges faced by a resource poor nation such as Bhutan in achieving universal health coverage and reaching the set goals for disease elimination. The findings underscore the need for a careful review of the national health care system and to address the deficiencies.
The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies
Authors: Su Angela , Ling Frank , Vaganay Camille , Sodaro Gaetano , Benaksas Chaïma , Dal Bello Reinaldo , Forget Antoine , Pardieu Bryann , Lin Kevin H. , Rutter Justine C. , Bassil Christopher F. , Fortin Gael , Pasanisi Justine , Antony-Debré Iléana , Alexe Gabriela , Benoist Jean-François , Pruvost Alain , Pikman Yana , Qi Jun , Schlageter Marie-Hélène , Micol Jean-Baptiste , Roti Giovanni , Cluzeau Thomas , Dombret Hervé , Preudhomme Claude , Fenouille Nina , Benajiba Lina , Golan Hava M. , Stegmaier Kimberly , Lobry Camille , Wood Kris C. , Itzykson Raphael , Puissant Alexandre
Published: August 2020

Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid–related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies.

Significance:

Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3-THF supplementation thus represents a low-risk intervention to enhance their effects.

See related commentary by Marando and Huntly, p. 1791.

This article is highlighted in the In This Issue feature, p. 1775
Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia
Authors: Berrien-Elliott Melissa M. , Cashen Amanda F. , Cubitt Celia C. , Neal Carly C. , Wong Pamela , Wagner Julia A. , Foster Mark , Schappe Timothy , Desai Sweta , McClain Ethan , Becker-Hapak Michelle , Foltz Jennifer A. , Cooper Matthew L. , Jaeger Natalia , Srivatsan Sridhar Nonavinkere , Gao Feng , Romee Rizwan , Abboud Camille N. , Uy Geoffrey L. , Westervelt Peter , Jacoby Meagan A. , Pusic Iskra , Stockerl-Goldstein Keith E. , Schroeder Mark A. , DiPersio John , Fehniger Todd A.
Published: August 2020

Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes in phenotype that occur after NK-cell transfer that affect patient outcomes remain unclear. Here, we report comprehensive multidimensional correlates from ML NK cell–treated patients with AML using mass cytometry. These data identify a unique in vivo differentiated ML NK–cell phenotype distinct from conventional NK cells. Moreover, the inhibitory receptor NKG2A is a dominant, transcriptionally induced checkpoint important for ML, but not conventional NK-cell responses to cancer. The frequency of CD8α+ donor NK cells is negatively associated with AML patient outcomes after ML NK therapy. Thus, elucidating the multidimensional dynamics of donor ML NK cells in vivo revealed critical factors important for clinical response, and new avenues to enhance NK-cell therapeutics.

Significance:

Mass cytometry reveals an in vivo memory-like NK-cell phenotype, where NKG2A is a dominant checkpoint, and CD8α is associated with treatment failure after ML NK–cell therapy. These findings identify multiple avenues for optimizing ML NK–cell immunotherapy for cancer and define mechanisms important for ML NK–cell function.

This article is highlighted in the In This Issue feature, p. 1775
Prolonged Duration of Erythropoiesis-Stimulating Agents’ Action Delays Disease Progression in Anti-Thy 1 Antibody-Induced Chronic Glomerulonephritis Rats
Authors: Kawasaki Ryohei , Tashiro Yoshihito , Yogo Kenji , Serizawa Kenichi , Aizawa Ken , Endo Koichi , Hirata Michinori
Published: August 2020

Background: Although erythropoiesis-stimulating agents (ESAs) exert renoprotective effects in renal disease models, it has not been revealed whether the prolonged duration of action of ESAs contributes to their renoprotective effects. Objective: We examined whether the prolonged duration of ESAs’ action contributes to their renoprotective effects by comparing a divided administration of a short-acting ESA, epoetin beta (EPO), or a single administration of a long-acting ESA, epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), to a single administration of EPO in chronic glomerulonephritis (GN) rats. Materials and Methods: Chronic GN was induced by intravenous injection of anti-Thy 1.1 antibody (0.6 mg/kg) into uninephrectomized rats (day 0). Chronic GN rats were intravenously injected once with vehicle (disease control; DC), EPO 5,000 IU/kg (single EPO), or C.E.R.A. 25 μg/kg (single C.E.R.A.) on day 1; or 3 times during the first week with EPO 1,667 IU/kg from day 1 (divided EPO; total 5,000 IU/kg). Hemoglobin (Hb) level and urinary total protein (U-TP) level which are the indexes of hematopoiesis and renoprotective effects, respectively, were measured several times over 8 weeks. Results: Divided EPO and single C.E.R.A. increased Hb levels more greatly than did single EPO. In all chronic GN rats, elevated U-TP levels decreased transiently 2 weeks after chronic GN induction and then flared again. Single EPO significantly suppressed this exacerbation of U-TP levels compared to DC. Divided EPO and single C.E.R.A. each significantly suppressed the exacerbation of U-TP levels compared to single EPO. Conclusion: Prolonged duration of ESAs’ action contributed significantly to their renoprotective effects.
Increased CD11b and Decreased CD62L in Blood and Airway Neutrophils from Long-Term Smokers with and without COPD
Authors: Stockfelt Marit , Christenson Karin , Andersson Anders , Björkman Lena , Padra Médea , Brundin Bettina , Ganguly Koustav , Asgeirsdottir Helga , Lindén Sara , Qvarfordt Ingemar , Bylund Johan , Lindén Anders
Published: August 2020

There is incomplete mechanistic understanding of the mobilization of neutrophils in the systemic and local compartment in smokers with chronic obstructive pulmonary disease (COPD). In this pilot study, we characterized how the adhesion molecules CD11b and CD62L, surface markers indicative of priming, are altered as neutrophils extravasate, and whether surface density of CD11b and CD62L differs between long-term tobacco smokers (LTS) with and without COPD compared with healthy never-smokers (HNS). Unstimulated blood neutrophils from LTS with (n = 5) and without (n = 9) COPD displayed lower surface density of CD62L compared with HNS (n = 8). In addition, surface density of CD11b was higher in bronchoalveolar lavage (BAL) neutrophils from LTS without COPD compared with those with COPD and HNS. Moreover, in BAL neutrophils from all study groups, CD62L was lower compared with matched blood neutrophils. In addition, BAL neutrophils responded with a further decrease in CD62L to ex vivo TNF stimulation. Thus, neutrophils in the airway lumen display a higher state of priming than systemic neutrophils and bear the potential to be further primed by local cytokines even with no smoking or the presence of COPD, findings that may represent a universal host defense mechanism against local bacteria. Moreover, systemic neutrophils are primed in LTS regardless of COPD. Further studies in larger materials are warranted to determine whether the priming of neutrophils is protective against COPD or merely preceding it.
Effect of Low-Frequency Therapeutic Ultrasound on Induction of Nitric Oxide in CKD: Potential to Prevent Acute Kidney Injury
Authors: Dae Michael W. , Liu Kathleen D. , Solomon Richard J. , Gao Dong W. , Stillson Carol A.
Published: August 2020

Introduction: Post-contrast acute kidney injury (PC-AKI) develops in a significant proportion of patients with CKD after invasive cardiology procedures and is strongly associated with adverse outcomes. Objective: We sought to determine whether increased intrarenal nitric oxide (NO) would prevent PC-AKI. Methods: To create a large animal model of CKD, we infused 250 micron particles into the renal arteries in 56 ± 8 kg pigs. We used a low-frequency therapeutic ultrasound device (LOTUS – 29 kHz, 0.4 W/cm2) to induce NO release. NO and laser Doppler probes were used to assess changes in NO content and blood flow. Glomerular filtration rate (GFR) was measured by technetium-diethylene-triamine-pentaacetic acid (Tc-99m-DTPA) radionuclide imaging. PC-AKI was induced by intravenous infusion of 7 cm3/kg diatrizoate. In patients with CKD, we measured GFR at baseline and during LOTUS using Tc-99m--DTPA radionuclide imaging. Results: In the pig model, CKD developed over 4 weeks (serum creatinine [Cr], mg/dL, 1.0 ± 0.2–2.6 ± 0.9, p < 0.01, n = 12). NO and renal blood flow (RBF) increased in cortex and medulla during LOTUS. GFR increased 75 ± 24% (p = 0.016, n = 3). PC-AKI developed following diatrizoate i.v. infusion (Cr 2.6 ± 0.7 baseline to 3.4 ± 0.6 at 24 h, p < 0.01, n = 3). LOTUS (starting 15 min prior to contrast and lasting for 90 min) prevented PC-AKI in the same animals 1 week later (Cr 2.5 ± 0.4 baseline to 2.6 ± 0.7 at 24 h, p = ns, n = 3). In patients with CKD (n = 10), there was an overall 25% increase in GFR in response to LOTUS (p < 0.01). Conclusions: LOTUS increased intrarenal NO, RBF, and GFR and prevented PC-AKI in a large animal model of CKD, and significantly increased GFR in patients with CKD. This novel approach may provide a noninvasive nonpharmacological means to prevent PC-AKI in high-risk patients.
Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation
Authors: Weng Lu-Chen , Hall Amelia Weber , Choi Seung Hoan , Jurgens Sean J. , Haessler Jeffrey , Bihlmeyer Nathan A. , Grarup Niels , Lin Honghuang , Teumer Alexander , Li-Gao Ruifang , Yao Jie , Guo Xiuqing , Brody Jennifer A. , Müller-Nurasyid Martina , Schramm Katharina , Verweij Niek , van den Berg Marten E. , van Setten Jessica , Isaacs Aaron , Ramírez Julia , Warren Helen R. , Padmanabhan Sandosh , Kors Jan A. , de Boer Rudolf A. , van der Meer Peter , Sinner Moritz F. , Waldenberger Melanie , Psaty Bruce M. , Taylor Kent D. , Völker Uwe , Kanters Jørgen K. , Li Man , Alonso Alvaro , Perez Marco V. , Vaartjes Ilonca , Bots Michiel L. , Huang Paul L. , Heckbert Susan R. , Lin Henry J. , Kornej Jelena , Munroe Patricia B. , van Duijn Cornelia M. , Asselbergs Folkert W. , Stricker Bruno H. , van der Harst Pim , Kääb Stefan , Peters Annette , Sotoodehnia Nona , Rotter Jerome I. , Mook-Kanamori Dennis O. , Dörr Marcus , Felix Stephan B. , Linneberg Allan , Hansen Torben , Arking Dan E. , Kooperberg Charles , Benjamin Emelia J. , Lunetta Kathryn L. , Ellinor Patrick T. , Lubitz Steven A.
Published: August 2020

Background:

The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.

Methods:

Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.

Results:

We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (
TTN
,
CAND2
,
SCN10A
,
PITX2
,
CAV1
,
SYNPO2L
,
SOX5
,
TBX5, MYH6, RPL3L
). The top variants at known sarcomere genes (
TTN, MYH6
) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg,
PITX2
and
SCN10A
) were associated with longer PWD but lower AF risk.

Conclusions:

Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.
Diabetes Impairs Cellular Cholesterol Efflux From ABCA1 to Small HDL Particles
Authors: He Yi , Ronsein Graziella E. , Tang Chongren , Jarvik Gail P. , Davidson W. Sean , Kothari Vishal , Song Hyun D. , Segrest Jere P. , Bornfeldt Karin E. , Heinecke Jay W.
Published: August 2020

Rationale:

HDL (high-density lipoprotein) may be cardioprotective because it accepts cholesterol from macrophages via the cholesterol transport proteins ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1). The ABCA1-specific cellular cholesterol efflux capacity (ABCA1 CEC) of HDL strongly and negatively associates with cardiovascular disease risk, but how diabetes mellitus impacts that step is unclear.

Objective:

To test the hypothesis that HDL’s cholesterol efflux capacity is impaired in subjects with type 2 diabetes mellitus.

Methods and Results:

We performed a case-control study with 19 subjects with type 2 diabetes mellitus and 20 control subjects. Three sizes of HDL particles, small HDL, medium HDL, and large HDL, were isolated by high-resolution size exclusion chromatography from study subjects. Then we assessed the ABCA1 CEC of equimolar concentrations of particles. Small HDL accounted for almost all of ABCA1 CEC activity of HDL. ABCA1 CEC―but not ABCG1 CEC―of small HDL was lower in the subjects with type 2 diabetes mellitus than the control subjects. Isotope dilution tandem mass spectrometry demonstrated that the concentration of SERPINA1 (serpin family A member 1) in small HDL was also lower in subjects with diabetes mellitus. Enriching small HDL with SERPINA1 enhanced ABCA1 CEC. Structural analysis of SERPINA1 identified 3 amphipathic α-helices clustered in the N-terminal domain of the protein; biochemical analyses demonstrated that SERPINA1 binds phospholipid vesicles.

Conclusions:

The ABCA1 CEC of small HDL is selectively impaired in type 2 diabetes mellitus, likely because of lower levels of SERPINA1. SERPINA1 contains a cluster of amphipathic α-helices that enable apolipoproteins to bind phospholipid and promote ABCA1 activity. Thus, impaired ABCA1 activity of small HDL particles deficient in SERPINA1 could increase cardiovascular disease risk in subjects with diabetes mellitus.
Creative destruction: Sparse activity emerges on the mammal connectome under a simulated communication strategy with collisions and redundancy
Authors: Hao Yan , Graham Daniel
Published: August 2020

Signal interactions in brain network communication have been little studied. We describe how nonlinear collision rules on simulated mammal brain networks can result in sparse activity dynamics characteristic of mammalian neural systems. We tested the effects of collisions in “information spreading” (IS) routing models and in standard random walk (RW) routing models. Simulations employed synchronous agents on tracer-based mesoscale mammal connectomes at a range of signal loads. We find that RW models have high average activity that increases with load. Activity in RW models is also densely distributed over nodes: a substantial fraction is highly active in a given time window, and this fraction increases with load. Surprisingly, while IS models make many more attempts to pass signals, they show lower net activity due to collisions compared to RW, and activity in IS increases little as function of load. Activity in IS also shows greater sparseness than RW, and sparseness decreases slowly with load. Results hold on two networks of the monkey cortex and one of the mouse whole-brain. We also find evidence that activity is lower and more sparse for empirical networks compared to degree-matched randomized networks under IS, suggesting that brain network topology supports IS-like routing strategies.
Revisiting correlation-based functional connectivity and its relationship with structural connectivity
Authors: Liégeois Raphael , Santos Augusto , Matta Vincenzo , Van De Ville Dimitri , Sayed Ali H.
Published: August 2020

Patterns of brain structural connectivity (SC) and functional connectivity (FC) are known to be related. In SC-FC comparisons, FC has classically been evaluated from correlations between functional time series, and more recently from partial correlations or their unnormalized version encoded in the precision matrix. The latter FC metrics yield more meaningful comparisons to SC because they capture ‘direct’ statistical dependencies, that is, discarding the effects of mediators, but their use has been limited because of estimation issues. With the rise of high-quality and large neuroimaging datasets, we revisit the relevance of different FC metrics in the context of SC-FC comparisons. Using data from 100 unrelated Human Connectome Project subjects, we first explore the amount of functional data required to reliably estimate various FC metrics. We find that precision-based FC yields a better match to SC than correlation-based FC when using 5 minutes of functional data or more. Finally, using a linear model linking SC and FC, we show that the SC-FC match can be used to further interrogate various aspects of brain structure and function such as the timescales of functional dynamics in different resting-state networks or the intensity of anatomical self-connections.
The Neural Basis of Metaphor Comprehension: Evidence from Left Hemisphere Degeneration
Authors: Klooster Nathaniel , McQuire Marguerite , Grossman Murray , McMillan Corey , Chatterjee Anjan , Cardillo Eileen
Published: August 2020

Despite the ubiquity of metaphor in cognition and communication, it is absent from standard clinical assessments of language, and the neural systems that support metaphor processing are debated. Previous research shows that patients with focal brain lesions can display selective impairments in processing metaphor, suggesting that figurative language abilities may be disproportionately vulnerable to brain injury. We hypothesized that metaphor processing is especially vulnerable to neurodegenerative disease, and that the left hemisphere is critical for normal metaphor processing. To evaluate these hypotheses, we tested metaphor comprehension in patients with left-hemisphere neurodegeneration, and in demographically matched healthy comparison participants. Stimuli consisted of moderately familiar metaphors and closely matched literal sentences sharing the same source term (e.g., The interview was a painful crawl / The infant’s motion was a crawl). Written sentences were presented, followed by four modifier-noun answer choices (one target and three foils). Healthy controls, though reliably better at literal than metaphor trials, comprehended both sentence conditions well. By contrast, participants with left-hemisphere neurodegeneration performed disproportionately poorly on metaphor comprehension. Anatomical analyses show relationships between metaphor accuracy and patient atrophy in the left middle and superior temporal gyri, and the left inferior frontal gyrus, areas that have been implicated in supporting metaphor comprehension in previous imaging research. The behavioral results also suggest deficits of metaphor comprehension may be a sensitive measure of cognitive dysfunction in some forms of neurodegenerative disease.