bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of Pharmaceutically Relevant 2‐Aminotetralin and 3‐Aminochroman Derivatives via Enzymatic Reductive Amination
Authors: Citoler Joan , Harawa Vanessa , Marshall James R. , Bevinakatti Han , Finnigan James D. , Charnock Simon J. , Turner Nicholas J.
Published: September 2021

2‐Aminotetralin and 3‐aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2‐tetralones and 3‐chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for >15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5‐OH‐DPAT. We also present a convergent chemo‐enzymatic total synthesis of the Parkinson's disease therapy Rotigotine in 63 % overall yield and 92 % ee.
Visualization of Vaccine Dynamics with Quantum Dots for Immunotherapy
Authors: Sun Junlin , Liu Feng , Yu Wenqian , Fu Dandan , Jiang Qunying , Mo Fengye , Wang Xiuyuan , Shi Tianhui , Wang Fuan , Pang Dai‐Wen , Liu Xiaoqing
Published: September 2021

The direct visualization of vaccine fate is important to investigate its immunoactivation process to elucidate the detailed molecular reaction process at single‐molecular level. Yet, visualization of the spatiotemporal trafficking of vaccines remains poorly explored. Here, we show that quantum dot (QD) nanomaterials allow for monitoring vaccine dynamics and for amplified immune response. Synthetic QDs enable efficient conjugation of antigen and adjuvants to target tissues and cells, and non‐invasive imaging the trafficking dynamics to lymph nodes and cellular compartments. The nanoparticle vaccine elicits potent immune responses and anti‐tumor efficacy alone or in combination with programmed cell death protein 1 blockade. The synthetic QDs showed high fluorescence quantum yield and superior photostability, and the reliable and long‐term spatiotemporal tracking of vaccine dynamics was realized for the first time by using the synthetic QDs, providing a powerful strategy for studying immune response and evaluating vaccine efficacy.
Effect of Surfactants on the Molecular Structure of the Buried Oil/Water Interface
Authors: Hosseinpour Saman , Götz Vanessa , Peukert Wolfgang
Published: September 2021

The oil/water interface, for instance in emulsions, is often stabilized by surfactants. Hence, the co‐existence of oil, water, and surfactant molecules at the buried oil/water interface determines macroscopic properties such as surface tension or emulsion stability. Utilizing an inherently surface sensitive spectroscopic method, sum frequency generation (SFG) spectroscopy, we show that adsorption of an anionic surfactant to the buried oil/water interface increases the magnitude of the interfacial electric field. Meanwhile, the degree of ordering of the interfacial oil molecules increases with the surfactant concentration owing to the intercalation of aliphatic chains of interfacial oil and surfactant molecules. At sufficiently high surfactant concentrations, the interfacial charge reaches a maximum value and the interfacial oil molecules arrange in a fully ordered conformation, a state which coincides with the significant decrease in interfacial tension and increased emulsion stability.
Synthesis of α‐Amino Tertiary Alkylperoxides by Lewis Acid‐Catalyzed Peroxidation of 1,3,5‐Triazines
Authors: Liu Lijuan , Shi Zhichao , Zhang Xun , Zhan Feng , Lin Jin‐Shun , Jiang Yuyang
Published: September 2021

α‐Substituted peroxides have been found in natural products and are widely used as anti‐malarial agents. Zn(OTf)2‐catalyzed peroxidation of 1,3,5‐triazines has been developed, accessing diversely substituted α‐amino tertiary alkylperoxides with high efficiency. Mechanistic investigations and useful synthetic application of the products have also been presented.
An integrated biomimetic array chip for establishment of collagen‐based 3D primary human hepatocyte model for prediction of clinical drug‐induced liver injury
Authors: Xiao Rong‐Rong , Lv Tian , Tu Xia , Li Peiwen , Wang Tiantian , Dong Haiheng , Tu Pengfei , Ai Xiaoni
Published: September 2021

Drug‐induced liver injury (DILI) is a leading cause of therapy failure in the clinic and also contributes much to acute liver failure cases. Investigations of predictive sensitivity in animal models have limitations due to interspecies differences. Previously reported in vitro models of liver injury based on primary human hepatocytes (PHHs) cannot meet the requirements of high physiological fidelity, low cost, simple operation, and high throughput with improved sensitivity. Herein, we developed an integrated biomimetic array chip (iBAC) for establishing extracellular matrix (ECM)‐based models. A collagen‐based 3D PHH model was constructed on the iBAC as a case for the prediction of clinical DILI at throughput. The iBAC has a three‐layer structure with a core component of 3D implanting holes. At an initial cell seeding numbers of 5000–10,000, the collagen‐based 3D PHH model was optimized with improved and stabilized liver functionality, including cell viability, albumin, and urea production. Moreover, basal activities of most metabolic enzymes on the iBAC were maintained for at least 12 days. Next, a small‐scale hepatotoxicity screening indicated that the 3D PHH model on the iBAC was more sensitive for predicting hepatotoxicity than the 2D PHH model on the plate. Finally, a large‐scale screening of liver toxicity using 122 clinical drugs further demonstrated that the collagen‐based 3D PHH model on the iBAC had superior predictive sensitivity compared to all previously reported in vitro models. These results indicated the importance of 3D collagen for liver physiological functionality and hepatotoxicity prediction. We anticipant it being a promising tool for risk assessment of drug‐induced hepatotoxicity with a widespread acceptance in drug industry.
Electrochemically induced deposition of hydroxyl‐terminated poly(amidoamine) dendrimers encapsulating Pt nanoparticles on indium tin oxide for enhanced electrochemiluminescence
Authors: Kim Jiwoo , Kim Joohoon
Published: September 2021

We reported the electrochemically induced deposition of hydroxyl‐terminated poly(amidoamine) dendrimers encapsulating Pt nanoparticles on the surface of indium tin oxide (ITO). The electrochemical deposition led to significantly high surface coverage of Pt nanoparticles encapsulated inside the dendrimers on ITO surfaces, which allowed enhanced (i.e., ca. 212‐fold) electrochemiluminescence of Ru(bpy)32+/tripropylamine on the modified ITOs compared to unmodified ITO.
Maternal and fetal metabolomic alterations in maternal lipopolysaccharide exposure‐induced male offspring glucose metabolism disorders
Authors: Qing Qiting , Huang Lili , Sun Wanxiao , Chen Jing , Yu Ningning , Chen Yuanhua , Xu Dexiang , Zhao Mei
Published: September 2021

Maternal lipopolysaccharide (LPS) exposure during pregnancy induces metabolic abnormalities in male offspring, but the underlying mechanisms remain unclear. The purpose of this study was to investigate the effects of maternal LPS exposure during pregnancy on metabolic profiling of maternal serum and male fetal liver using Liquid Chromatograph Mass Spectrometer techniques. From day 15 to day 17 of gestation, pregnant mice were administered intraperitoneal LPS (experimental group) (50 μg/kg/d) or saline (control group). On day 18 of gestation, maternal serum and male fetal liver were collected. After LPS exposure, levels of 38 and 75 metabolites, mainly glycerophospholipid and fatty acid metabolites, were altered in maternal serum and male fetal liver, respectively. It was found that in maternal serum and male fetal livers, the glycerophospholipids containing saturated fatty acids (SFAs) and the SFAs were upregulated, while the glycerophospholipids containing polyunsaturated fatty acids (PUFAs) and the PUFAs were downregulated. This concordance between maternal and fetal alterations in glycerophospholipid and fatty acid metabolites may be a metabolomic signature of the early intrauterine period and may provide insight into the mechanisms by which maternal LPS exposure induces disorders of glucose metabolism in male offspring.
Expression of telomerase reverse transcriptase in peripheral T‐cell lymphoma
Authors: Arakawa Fumiko , Miyoshi Hiroaki , Yoshida Noriaki , Nakashima Kazutaka , Watatani Yosaku , Furuta Takuya , Yamada Kyohei , Moritsubo Mayuko , Takeuchi Mai , Yanagida Eriko , Shimasaki Yasumasa , Kohno Kei , Kataoka Keisuke , Ohshima Koichi
Published: September 2021

Telomere length is maintained by the activation of telomerase, which causes continuous cell division and proliferation in many carcinomas. A catalytic reverse transcriptase protein (TERT) encoded by the TERT gene plays a critical role in the activation of telomerase. We performed a molecular and pathological analysis of the TERT against three different peripheral T‐cell lymphoma (PTCL) subtypes: PTCL, not otherwise specified (PTCL‐NOS), angioimmunoblastic T‐cell lymphoma (AITL), and adult T‐cell leukemia/lymphoma (ATLL). Immunohistochemical analysis demonstrated TERT expression in 31% of AITL, 11% of PTCL‐NOS, and 5% of ATLL. Among them, AITL frequently showed high TERT expression with statistical significance. TERT promoter mutation analysis and genomic copy number evaluation were performed. TERT promoter mutation was observed in two cases of PTCL‐NOS (2/40) and not in other PTCLs. Genome copy number amplification was detected in 33% of PTCL‐NOS, 33% of AITL, and 50% of ATLL cases. We evaluated the relationship between the analyzed TERT genomic abnormalities and protein expression; however, no apparent relationship was observed. Furthermore, immunostaining showed TERT expression in the PTCL cytoplasm, suggesting the existence of mechanisms other than the maintenance of telomere length. Statistical analysis of the effect of TERT expression on the prognosis in PTCL cases revealed that TERT expression tended to have a poor prognosis in PTCL‐NOS. Since TERT expression was not an independent factor in multivariate analysis, further research will be needed to clarify the poor prognosis of PTCL‐NOS in TERT expression.
Menstrual blood CD146+ mesenchymal stem cells reduced fibrosis rate in the rat model of premature ovarian failure
Authors: Yamchi Nahideh Nazdikbin , Rahbarghazi Reza , Bedate Alberto Miranda , Mahdipour Mahdi , Nouri Mohammad , Khanbabaee Ramazan
Published: September 2021

Here, the regenerative potential of menstrual blood–derived mesenchymal stem cells (MenSCs) was examined on restoration of premature ovarian failure (POF) ovaries in rats' POF model. Freshly isolated CD146+ MenSCs using magnetic‐activated cell storing method were immediately injected into ovaries of POF rats. Four and eight weeks after cell administration, both ovarian tissues were sampled for histological examination and the expression of fibrosis‐related genes. Serum samples were also prepared for hormonal analysis. At the endpoint, mating trials were performed to assess the fertility of POF rats following MenSC transplantation. Histopathological examination revealed the induction of POF after Ceftriaxone injection by increasing atretic follicles and abnormal morphologies. MenSCs transplantation increased the number of normal follicles and coincided with the reduction of follicular atresia. Biochemical analyses exhibited the reduction and increase of systemic follicle‐stimulating hormone (FSH) and E2 respectively after MenSCs transplantation compared to the POF rats (P < .05). No significant differences in anti‐mullerian hormone (AMH) blood levels were detected in this study between POF controls and MenSCs‐treated rats. We noted moreover the transcriptional up‐regulation of Smad 2, 4, and TGF‐β1 in POF rats, and these values were decreased after MenSCs transplantation (P < .01). By contrast, the RNA expression of Smad 6 remained increased in both pre‐ and post‐treatment with MenSCs groups (P < .05). Finally, we found an increase in neonate births in POF rats treated with MenSCs, and that this feature was associated with ovarian rejuvenation through amelioration of fibrosis. These data showed that MenSCs are promising cell lineage for the alleviation of POF in the rat model by controlling the fibrosis rate.
Predictors of asthma‐related quality of life in a large cohort of asthmatics: A cross‐sectional study in a secondary care center
Authors: Louis Gilles , Pétré Benoit , Schleich Florence , Zahraei Halehsadat Nekoee , Donneau Anne‐Françoise , Silvestre Aude , Henket Monique , Paulus Virginie , Guissard Françoise , Guillaume Michèle , Louis Renaud
Published: September 2021

Background

In recent decades, asthma‐related quality of life questionnaires have joined objective clinical indicators as important outcome measures. In this study, we sought to investigate the predictors of asthma‐related quality of life in a large cohort of patients recruited from a secondary care center.

Methods

We conducted a cross‐sectional study on asthmatics (N = 1301) recruited from the Liège University Hospital asthma clinic (Belgium). After performing a descriptive analysis highlighting the distribution of scores from the Mini Asthma Quality of Life Questionnaire (Mini AQLQ) and its four dimensions (symptoms, activity limitation, emotional function, and environmental stimuli), we did multiple regression analysis to identify the independent predictors of AQLQ.

Results

Multiple regression beta analysis showed that AQLQ and its four dimensions were primarily associated with asthma control (p < 0.0001 in all instances). Female gender was associated with a lower score for the AQLQ's activity and environmental dimensions (p < 0.05 for both), while current smokers had a higher score on the AQLQ's environmental dimension (p < 0.0001). The burden of asthma treatment was associated with a lower score for the AQLQ's emotional (p < 0.05) and environmental (p < 0.05) dimensions. BMI was associated with a lower score in the AQLQ's activity dimension (p < 0.0001), while the opposite was true for the FeNO test (p < 0.0001). Sputum neutrophils were inversely related to the score for the AQLQ's symptom dimension (p < 0.05), whereas post‐bronchodilator FEV1 showed a positive relationship for that same dimension (p < 0.05).

Conclusion

Asthma control is the main predictor of AQLQ score and impacts all its dimensions, but demographic, functional, and airway inflammatory parameters may also influence some dimensions of the AQLQ.
Social determinants of health and cancer mortality in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study
Authors: Pinheiro Laura C. , Reshetnyak Evgeniya , Akinyemiju Tomi , Phillips Erica , Safford Monika M.
Published: September 2021

Background

Social determinants of health (SDOHs) cluster together and can have deleterious impacts on health outcomes. Individually, SDOHs increase the risk of cancer mortality, but their cumulative burden is not well understood. The authors sought to determine the combined effect of SDOH on cancer mortality.

Methods

Using the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, the authors studied 29,766 participants aged 45+ years and followed them 10+ years. Eight potential SDOHs were considered, and retained SDOHs that were associated with cancer mortality (P < .10) were retained to create a count (0, 1, 2, 3+). Cox proportional hazard models estimated associations between the SDOH count and cancer mortality through December 31, 2017, adjusting for confounders. Models were age‐stratified (45‐64 vs 65+ years).

Results

Participants were followed for a median of 10.6 years (interquartile range [IQR], 6.5, 12.7 years). Low education, low income, zip code poverty, poor public health infrastructure, lack of health insurance, and social isolation were significantly associated with cancer mortality. In adjusted models, among those <65 years, compared to no SDOHs, having 1 SDOH (adjusted hazard ratio [aHR], 1.39; 95% CI, 1.11‐1.75), 2 SDOHs (aHR, 1.61; 95% CI, 1.26‐2.07), and 3+ SDOHs (aHR, 2.09; 95% CI, 1.58‐2.75) were associated with cancer mortality (P for trend <.0001). Among individuals 65+ years, compared to no SDOH, having 1 SDOH (aHR, 1.16; 95% CI, 1.00‐1.35) and 3+ SDOHs (aHR, 1.26; 95% CI, 1.04‐1.52) was associated with cancer mortality (P for trend = .032).

Conclusions

A greater number of SDOHs were significantly associated with an increased risk of cancer mortality, which persisted after adjustment for confounders.
The role of self‐compassion on the relationship between trauma and hearing voices
Authors: Maisey Sarah , Correia Helen , Paulik Georgie
Published: September 2021

Traumatic life events are associated with increased risk of hearing voices and posttraumatic stress (PTS) symptoms have been implicated in this relationship. Studies indicate that increased self‐compassion is associated with reduced PTS symptoms and voice‐distress. The present study sought to examine whether self‐compassion moderated the relationship between PTS symptoms and voice‐distress. Self‐report and clinician‐administered questionnaires were used to measure self‐compassion, PTS symptom severity, voice‐frequency, and voice‐distress in 62 trauma‐affected voice‐hearers who presented to a community voice‐hearing clinic. Correlation analyses revealed that PTS symptom severity was positively correlated with voice‐distress, but not voice‐frequency, and that self‐compassion was negatively correlated with voice‐distress and PTS symptom severity. While self‐compassion did not moderate the relationship between PTS symptom severity and voice‐distress, it was associated with a significant reduction in voice‐distress, at all levels of PTS symptom severity. Preliminary findings suggest self‐compassion may play an important role in reducing voice‐distress and thus warrant further consideration of self‐compassion as a target in treatment for help‐seeking voice‐hearers.
Thinking Beyond the Border: Edge‐of‐Field Practices to Improve the Environment
Authors: Young Kelly Murray , Thomson Allison
Published: September 2021

This article is brought to you by the SPARC Initiative created in partnership between the American Society for Agronomy, the Agricultural Retailers Association, Environmental Defense Fund, and Field to Market: The Alliance for Sustainable Agriculture to empower trusted advisers to deliver services that drive continuous improvement in the productivity, profitability, and environmental outcomes of farmers’ operations. Learn more about the SPARC Initiative and access additional resources, including the six‐module series on sustainability, at www.fieldtomarket.org/SPARC. Earn 0.5 CEUs in Sustainability by reading this article and taking the quiz at https://web.sciencesocieties.org/Learning‐Center/Courses.
BASE: A novel workflow to integrate nonubiquitous genes in comparative genomics analyses for selection
Authors: Forni Giobbe , Ruggieri Angelo Alberto , Piccinini Giovanni , Luchetti Andrea
Published: September 2021

Inferring the selective forces that orthologous genes underwent across different lineages can help us understand the evolutionary processes that have shaped their extant diversity and the phenotypes they underlie. The most widespread metric to estimate the selection regimes of coding genes—across sites and phylogenies—is the ratio of nonsynonymous to synonymous substitutions (dN/dS, also known as ω). Nowadays, modern sequencing technologies and the large amount of already available sequence data allow the retrieval of thousands of orthologous genes across large numbers of species. Nonetheless, the tools available to explore selection regimes are not designed to automatically process all genes, and their practical usage is often restricted to the single‐copy ones which are found across all species considered (i.e., ubiquitous genes). This approach limits the scale of the analysis to a fraction of single‐copy genes, which can be as low as an order of magnitude in respect to those which are not consistently found in all species considered (i.e., nonubiquitous genes). Here, we present a workflow named BASE that—leveraging the CodeML framework—eases the inference and interpretation of gene selection regimes in the context of comparative genomics. Although a number of bioinformatics tools have already been developed to facilitate this kind of analyses, BASE is the first to be specifically designed to allow the integration of nonubiquitous genes in a straightforward and reproducible manner. The workflow—along with all relevant documentation—is available at github.com/for‐giobbe/BASE.
Bimodal activity of diurnal flower visitation at high elevation
Authors: Xu Xin , Ren Zong‐Xin , Trunschke Judith , Kuppler Jonas , Zhao Yan‐Hui , Knop Eva , Wang Hong
Published: September 2021

Successful pollination in animal‐pollinated plants depends on the temporal overlap between flower presentation and pollinator foraging activity. Variation in the temporal dimension of plant–pollinator networks has been investigated intensely across flowering seasons. However, over the course of a day, the dynamics of plant–pollinator interactions may vary strongly due environmental fluctuations. It is usually assumed there is a unimodal, diurnal, activity pattern, while alternative multimodal types of activity patterns are often neglected and deserve greater investigation. Here, we quantified the daily activity pattern of flower visitors in two different habitats contrasting high elevation meadows versus forests in Southwest China to investigate the role of abiotic conditions in the temporal dynamics of plant–pollinator interactions. We examined diurnal activity patterns for the entire pollinator community. Pollinator groups may differ in their ability to adapt to habitats and abiotic conditions, which might be displayed in their patterns of activity. We hypothesized that (a) pollinator communities show multimodal activity patterns, (b) patterns differ between pollinator groups and habitat types, and (c) abiotic conditions explain observed activity patterns. In total, we collected 4,988 flower visitors belonging to six functional groups. There was a bimodal activity pattern when looking at the entire pollinator community and in five out of six flower visitor groups (exempting solitary bees) regardless of habitat types. Bumblebees, honeybees, dipterans, lepidopterans, and other insects showed activity peaks in the morning and afternoon, whereas solitary bees were most active at midday. Activity of all six pollinator groups increased as solar radiation increased and then decreased after reaching a certain threshold. Our findings suggest that in habitats at higher elevations, a bimodal activity pattern of flower visitation is commonly employed across most pollinator groups that are diurnal foragers. This pattern may be caused by insects avoiding overheating due to elevated temperatures when exposed to high solar radiation at midday.
Automated audio recording as a means of surveying tinamous (Tinamidae) in the Peruvian Amazon
Authors: Rumelt Reid B. , Basto Arianna , Mere Roncal Carla
Published: September 2021

The use of machine learning technologies to process large quantities of remotely collected audio data is a powerful emerging research tool in ecology and conservation.

We applied these methods to a field study of tinamou (Tinamidae) biology in Madre de Dios, Peru, a region expected to have high levels of interspecies competition and niche partitioning as a result of high tinamou alpha diversity. We used autonomous recording units to gather environmental audio over a period of several months at lowland rainforest sites in the Los Amigos Conservation Concession and developed a Convolutional Neural Network‐based data processing pipeline to detect tinamou vocalizations in the dataset.

The classified acoustic event data are comparable to similar metrics derived from an ongoing camera trapping survey at the same site, and it should be possible to combine the two datasets for future explorations of the target species' niche space parameters.

Here, we provide an overview of the methodology used in the data collection and processing pipeline, offer general suggestions for processing large amounts of environmental audio data, and demonstrate how data collected in this manner can be used to answer questions about bird biology.
Policy coherence for sustainable development and environmental security: A case study of European Union policies on renewable energy
Authors: Häbel Sandra , Hakala Emma
Published: September 2021

Policy coherence for sustainable development (PCSD) and environmental security are crucial for achieving sustainable development, yet their intersections remain largely unexplored. In this article, we combine these two approaches to examine renewable energy policies of the European Union (EU). The EU is a key actor championing sustainable development, often considered to be a ground breaker particularly in environmental policies. At the same time, the EU aims to be a significant global security actor, and it has also recognised the role of environmental change as a factor for security. In this article, we explore whether the EU coherently integrates the sustainable development dimensions (society, environment, economy) in its renewable energy policies through inductive and deductive content analysis of key policy documents. Our analysis shows that the EU's renewable energy policies are not fully coherent with all dimensions of sustainability, particularly with respects to societal considerations and impacts on third countries.
Right ventricular and cyclic guanosine monophosphate signalling abnormalities in stages B and C of heart failure with preserved ejection fraction
Authors: Petit Thibault , Claessen Guido , Claeys Mathias , La Gerche Andre , Claus Piet , Ghysels Stefan , Delcroix Marion , Ciarka Agnieszka , Droogne Walter , Van Cleemput Johan , Willems Rik , Voigt Jens‐Uwe , Bogaert Jan , Janssens Stefan
Published: September 2021

Aims

Identifying early right ventricular (RV) dysfunction and impaired vasodilator reserve is challenging in heart failure with preserved ejection fraction (HFpEF). We hypothesized that cardiac magnetic resonance (CMR)‐based exercise imaging and serial cyclic guanosine monophosphate (cGMP) measurements can identify dynamic RV‐arterial uncoupling and responsiveness to pulmonary vasodilators at early stages of the HFpEF syndrome.

Methods and results

Patients with HFpEF (n = 16), impaired left ventricular relaxation due to concentric remodelling (LVCR, n = 7), and healthy controls (n = 8) underwent CMR at rest and during supine bicycle exercise with simultaneous measurements of central haemodynamics and circulating cGMP levels, before and after oral administration of 50 mg sildenafil. At rest, mean pulmonary artery pressures (mPAP) were higher in HFpEF, compared with LVCR and controls (27 ± 2, 18 ± 1, and 11 ± 1, respectively; P = 0.01), whereas biventricular volumes, heart rate, and stroke volume were similar. During exercise, LVCR and HFpEF had a greater increase in the ratio of mPAP over cardiac output than controls (5.50 ± 0.77 and 6.34 ± 0.86 vs. 2.24 ± 0.55 in controls, P = 0.005). The ratio of peak exercise to rest RV end‐systolic pressure‐volume, a surrogate of RV contractility, was significantly reduced in LVCR and HFpEF (2.32 ± 0.17 and 1.56 ± 0.08 vs. 3.49 ± 0.35 in controls, P < 0.001) and correlated with peak exercise VO2 (R2 = 0.648, P < 0.001). cGMP levels increased with exercise across the HFpEF spectrum (P < 0.05 vs. baseline), except when postcapillary pulmonary hypertension was present at rest (P = 0.73 vs. baseline). A single sildenafil administration failed to increase circulating cGMP levels and did not improve RV performance.

Conclusion

Exercise CMR identifies impaired RV‐arterial coupling at an early stage of HFpEF. Circulating cGMP levels phenocopy the haemodynamic spectrum in HFpEF but fail to increase after phosphodiesterase type 5 inhibition, endorsing the need for alternative interventions to increase cGMP signalling in HFpEF.
The prediction of right atrial pressure using electrocardiogram: a novel approach
Authors: Mirtajaddini Marzieh , Naderi Nasim , Chenaghlou Maryam , Taghavi Sepideh , Amin Ahmad
Published: September 2021

Aims

Pulmonary hypertension (PH) is a serious disorder that can complicate pulmonary and cardiovascular diseases. Right atrial (RA) pressure is a robust predictor of the pulmonary hypertension severity, which is measured via right heart catheterization. Limited studies have been carried out to assess the association between electrocardiogram data and the RA pressure as a prognostic factor of PH. In this study, the relation between P wave and PR segment changes with RA pressure was evaluated.

Methods and results

In this study, 94 patients in PH groups of 1, 3, and 4, based on the World Health Organization classification, were entered. RA pressure was measured using the right heart catheterization. PR segment and P wave morphology in leads II and V1 were evaluated in patient's electrocardiogram. The median age of the patients was 35.5 years old in which 64.9% of them were female. The distribution of patients in groups 1, 3, and 4 PH were 77.7%, 5.3%, and 17%, respectively. Among the studied P wave and PR segment changes, PR segment depression in lead II and pulmonary P wave in lead V1 had significant relation with the RA pressure (P‐value <0.001). The sensitivity, specificity, and negative predictive values of PR segment depression for detection of patients with high RA pressure (RA pressure > 14 mmHg) were 80%, 84%, and 94%. The specificity and negative predictive values of pulmonary P wave in lead V1 were determined 89% and 88%.

Conclusions

It was found that the PR segment depression in lead II and pulmonary P wave in lead V1 associate with the RA pressure in patients with precapillary PH. PR segment depression had useful sensitivity, specificity, and negative predictive values, and the pulmonary P wave in lead V1 had acceptable specificity and negative predictive values for detection of patients with high RA pressure. Therefore, the electrocardiogram can be used as a screening tool for determination of pulmonary hypertension severity.
On the Synthesis and Reduction of Trigonal Halido Bis(silylamido) Metalates of Chromium to Cobalt
Authors: Weller Ruth , Völlinger Lena , Werncke C. Gunnar
Published: September 2021

A series of halido bis(silylamido) metalates of chromium to cobalt is reported. Reaction of [NBu4]Br with linear metal silylamides ML2 (M=Mn−Co, L=−N(SiMe3)2, −N(Dipp)SiMe3; Dipp=2,6‐iPr−C6H3) leads to NBu4[M(Br)L2] whereas for chromium either intramolecular deprotonation (L=−N(SiMe3)2) or ligand exchange (L=−N(Dipp)SiMe3) is observed. Attempts for their reduction with KC8 showed in part the formation of linear metal(I) silylamide complexes but also degradation. In contrast, analogous compounds bearing a [K{18c6}]+ counter ion of cobalt and iron, obtained from reaction of anionic linear metal(I) complexes [M{N(SiMe3)2}2]− with allyl bromide – can be cleanly reduced. The adduct formation studies are also extended to benzyl potassium yielding [KM(Bn)L2] (M=Mn, Co) and subsequently the salt separated [K{18c6}][M(Bn)L2] using 18‐crown‐6 as sequestrating agent.
Spatial Recruitment of Cardiolipins in Inguinal White Adipose Tissue after Cold Stimulation is Independent of UCP1
Authors: Dieckmann Sebastian , Maurer Stefanie , Kleigrewe Karin , Klingenspor Martin
Published: September 2021

Brown and brite adipocytes are unique for uncoupling protein 1 (UCP1) dependent non‐shivering thermogenesis (NST) induced by cold exposure. Several lipid species are associated with NST in brown and white adipose tissues (WAT). Studies investigating this association rely on the analysis of whole organ homogenates, or pre‐adipocytes differentiated in vitro. These approaches do not account for the regional heterogeneity of WAT. The authors aimed to characterize the spatial lipid composition of WAT in an in vivo context to identify and validate lipids colocalized with UCP1. Therefore, matrix‐assisted laser desorption ionization mass spectrometry imaging (MALDI‐MSI), high‐resolution mass spectrometry, and immunohistochemistry are applied on sections of inguinal WAT from UCP1 knockout and wildtype mice acclimatized to cold. The authors identified spatial overlap of cardiolipins and diacylglycerols in UCP1 positive regions, and triacylglycerols as the main lipid class characteristic for UCP1 negative regions within inguinal WAT. Investigation of UCP1 knockout and wildtype mice housed at room temperature or acclimatized to cold demonstrated that cardiolipins content in WAT is increased upon cold stimulation, independent of UCP1. In summary, a MALDI‐MSI‐based approach is introduced to identify lipids associated with thermogenic adipocytes in adipose tissues and demonstrate a regional cold‐dependent upregulation of cardiolipins independent of UCP1.

Practical application: It is demonstrated that MALDI‐MSI is a valuable tool to investigate the spatial distribution of lipids in WAT. Consequently, it is an important complement to LC‐MS/MS analysis of whole tissue homogenates. In combination with immunohistochemistry, it allows the straightforward examination of potential interactions between structural and metabolic traits, as demonstrated by spatial colocalization of UCP1 expression with specific lipid species in the current study. As a major advantage, this enables analyses on subsets of the same sample combining different analytic approaches, thereby potentially reducing the number of experimental animals.
A Highly Sensitive Amperometric Galactose Biosensor Based on Graphene‐doped Sol‐gel‐derived Titania‐Nafion Composite Films
Authors: Lee Sumin , Jeong Daeho , Lee Sangjung , Nam Sungju , Lee Won‐Yong
Published: September 2021

A highly sensitive amperometric galactose biosensor was developed by encapsulating galactose oxidase within the graphene‐doped sol‐gel titania‐Nafion composite film on platinized glassy carbon electrode. Due to the combined electrocatalytic activity of graphene and Pt NPs on the electrode towards hydrogen peroxide as well as the mesoporous nature of the titania‐Nafion composite, the present galactose biosensor exhibited relatively fast response time under 2 s, high sensitivity of 40.6 mAM−1cm−2, and wide dynamic range over three orders of magnitude with a detection limit of 3.78×10−6 M (S/N=3). In addition, the biocompatible composite in the biosensor secures excellent long‐term stability.
Seismic evidence on the complex rupture system of the 23 January 2018 MW 7.9 offshore Kodiak event
Authors: Hui Gege , Wang Pengcheng , Sun Chuang , Zhang Yipeng , Hu Litian
Published: September 2021

In this study, we probe the formation mechanisms of the 23 January 2018 Mw7.9 Kodiak earthquake in the Gulf of Alaska region from detailed structural analysis, combined with the regional crustal stress status evaluation via seismology methods measured by the b‐value imaging. The large earthquake not only aroused heated debate due to its intraplate deformation and complex rupture system approaching to the Aleutian subduction zone, but also the complex rupture system. Aftershocks of this event propagated along the ENE‐striking and NNW‐striking fractures in planar view, whereas it shows double‐layer seismicity zones at depth. The b‐value image indicates the highly fractured crustal stress status above 12 km and above 25 km, respectively, while the faulting was locked at a depth between 12 and 20 km. We suggest that mantle peridotite serpentinization induced the aseismic zone gap. Besides, the bathymetric map, the multichannel profiles, and the sub‐bottom seismic evidence across the study area have shown the sinistral seismogenic strike‐slip faults may have been reactivated from the deep‐seated oceanic fracture zones involving the subduction front. In addition, all these faults conjunction has formed the topographic uplift or fault blocks and contribute to the complex earthquake ruptures.
Intracontinental deformation of the western Ordos Basin in North China and sandstone‐type uranium mineralization: Constraints from AFT chronology of the Helan Mountain
Authors: Nie Fengjun , Yan Zhaobin , Wang Yannan , Zhang Jin , Xia Fei , Yang Dongguang , Wang Sili , Chen Mengya , Peng Yunbiao , Miao Aisheng
Published: September 2021

Apatite fission track (AFT) sampled from Helan Mountain, of the western Ordos Basin, North China shows that the study area located in the western part of the North China Craton (NCC) has undergone four‐stage exhumation since Mesozoic time, that is, Late Jurassic to Early Cretaceous, Late Cretaceous, Early Cenozoic, and post‐late Miocene. Helan Mountain had slowly uplifted and eroded from the Late Jurassic to the beginning of the Cenozoic. The intensive deformation within NCC is attributable dynamically to the gently angular subduction of the Pacific Plate under the Eurasian Plate (EP). Helan Mountain has undergone sinistral strike‐slipping with a 60‐km maximum displacement caused by the collision of the southeast margin of EP during the Late Cretaceous. The Early Cenozoic tectonic event in the study area is respondent to collision between the Indian Plate and Eurasian Plate, whereas, the post‐late Miocene event is likely related to the eastward extension of Tibet Plateau. Based on the available AFT ages, the partial annealing zone for the palaeo‐Helan Mountain is ascertained to elevation ~1,200 m to ~2,100 m. The tectonic events occurring from Mesozoic to Cenozoic in Helan Mountain is directly related to the plate margin tectonism and representative for the intracontinental deformation of Eurasian Plate convergence. The sandstone‐type uranium deposits in the western margin thrust belt of Ordos Basin are related to the Late Jurassic to Early Cretaceous and Late Cretaceous exhumation events. Immediately after the host rock, the Zhiluo Formation sedimentation during the Middle Jurassic, the Late Jurassic ~ Late Cretaceous exhumations resulted in north–south‐trending anticlines, synclines, and thrust faults; meanwhile, the Zhiluo Formation was uplifted to the surface and infiltrated by uranium‐bearing oxidized fluids originated from the Helan Mountain. Uranium deposits were formed in both east and west limbs of folds. Finally, uranium mineralization ceased since the Cenozoic because the Yinchuan and Hetao faulted grabens have separated the Helan Mountain provenance from the western margin thrust belt.
Platinum‐group element and Au geochemistry of an ultramafic intrusion from the Sonakhan greenstone belt, Bastar craton, Central India: Tectono‐magmatic implications
Authors: Manu Prasanth M. P. , Shellnutt J. Gregory , Hari K. R. , Chalapathi Rao N. V. , Hou Guiting
Published: September 2021

The Sonakhan greenstone belt (SGB), located in the north‐eastern Bastar craton of the Indian shield, comprises mafic‐ultramafic and volcanic‐intrusive sequences in the lower stratigraphic units. We investigate the Platinum‐group element (PGE) relations of Boradih intrusion of the SGB to evaluate its tectono‐magmatic evolution. The chondrite‐normalized PGE patterns of boninitic cumulate rocks exhibit higher abundance of Palladium group PGEs (∑PPGE = 292–496 ppb) relative to the Iridium group PGEs (∑IPGE = 32–52 ppb) along with variable Au concentrations (51.34–718.05 ppb). The PGE concentrations are attributed to a boninitic parental melt, where the IPGEs in the source possibly partitioned into a monosulphide solid solution. The Cu (22–80 ppm), elevated Pt (22–238 ppb), and Pd (31–377 ppb) concentrations indicate Pt and Pd have partitioned into a semi‐metal rich melt during the later stages of crystallization. The geochemical characteristics of the basalts and ultramafic cumulates of the SGB indicate a supra‐subduction zone tectonic setting for its formation. Similar geochemical and litho‐tectonic correlations are also noticed between the SGB of Bastar craton and greenstone belts of the Eastern Dharwar craton of south India. The SGB (V/Yb =146 ± 25) and greenstone belts of Eastern Dharwar craton (V/Yb = 134 ± 52) record similar oxidation conditions of Phanerozoic subduction zones. Accordingly, we propose magmatic as well as tectonic correlations are possible for the Archean‐Palaeoproterozoic Bastar and Eastern Dharwar cratons.
The nature of the self: Neural analyses and heritability estimates of self‐evaluations in middle childhood
Authors: van Drunen Lina , Dobbelaar Simone , van der Cruijsen Renske , van der Meulen Mara , Achterberg Michelle , Wierenga Lara M. , Crone Eveline A.
Published: September 2021

How neural correlates of self‐concept are influenced by environmental versus genetic factors is currently not fully understood. We investigated heritability estimates of behavioral and neural correlates of self‐concept in middle childhood since this phase is an important time window for taking on new social roles in academic and social contexts. To do so, a validated self‐concept fMRI task was applied in a twin sample of 345 participants aged between 7 and 9 years. In the self‐concept condition, participants were asked to indicate whether academic and social traits applied to them whereas the control condition required trait categorization. The self‐processing activation analyses (n = 234) revealed stronger medial prefrontal cortex (mPFC) activation for self than for control conditions. This effect was more pronounced for social‐self than academic self‐traits, whereas stronger dorsolateral prefrontal cortex (DLPFC) activation was observed for academic versus social self‐evaluations. Behavioral genetic modeling (166 complete twin pairs) revealed that 25–52% of the variation in academic self‐evaluations was explained by genetic factors, whereas 16–49% of the variation in social self‐evaluations was explained by shared environmental factors. Neural genetic modeling (91 complete twin pairs) for variation in mPFC and anterior prefrontal cortex (PFC) activation for academic self‐evaluations confirmed genetic and unique environmental influences, whereas anterior PFC activation for social self‐evaluations was additionally influenced by shared environmental influences. This indicates that environmental context possibly has a larger impact on the behavioral and neural correlates of social self‐concept at a young age. This is the first study demonstrating in a young twin sample that self‐concept depends on both genetic and environmental factors, depending on the specific domain.
Comprehensive characterization of viral integrations and genomic aberrations in HBV‐infected intrahepatic cholangiocarcinomas
Authors: An Jihyun , Kim Deokhoon , Oh Bora , Oh Yoo‐Jin , Song Jihyun , Park Naomi , Kim Ha Il , Kang Hyo Jeong , Oh Ji‐Hye , Kim Wonkyung , Lee Eunjung , Sung Chang Ohk , Song Gi‐Won , Kim Dae‐Ghon , Yu Eunsil , Letouzé Eric , Zucman‐Rossi Jessica , Lee Han Chu , Shim Ju Hyun
Published: September 2021

Background and Aims

Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV‐infected iCCA (HBV‐iCCA) tumors.

Approach and Results

We profiled a cohort of 108 HBV‐iCCAs using whole‐genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV‐infected HCC (HBV‐HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV‐cHCC/CCA; n = 59), and conventional (n = 154) and fluke‐related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial–mesenchymal transition–related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non‐protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV‐iCCA was closer to that of nonviral conventional iCCA, than to HBV‐HCC and HBV‐cHCC/CCA.

Conclusions

Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.
ACGME Milestones in global health: Need for standardized assessment of global health training in obstetrics/gynecology residency
Authors: Monestime Gianina M. , Baird Isabelle , Rebarber Andrei , Shirazian Taraneh
Published: September 2021

Collective interest in global health training during US obstetrics/gynecology (Ob/Gyn) residency has grown over the past decade. The benefits of participation in global health electives have been well described. This review seeks to determine what literature exists regarding the use of Accreditation Council for Graduate Medical Education (ACGME) Milestones in Ob/Gyn residency as an assessment tool to evaluate global health programs. The PubMed database was searched from July 14, 2020 to August 20, 2021, using six search phrases: “global health curriculum(s) and ACGME”; “international health and ACGME”; “global health and Ob/Gyn residency”; “international health and Ob/Gyn residency”; “global health and Ob/Gyn residents”; and “global health curriculum(s) and Ob/Gyn residency.” Publications that described global health programming outside of residency, within other medical specialties, and/or at non‐US institutions were excluded from this review. In total, 259 publications resulted from the preliminary search. Five articles described US global health residency training in Ob/Gyn in some capacity. Only one publication described a specific global health elective and its evaluation with respect to ACGME Milestones. Despite growing popularity of global health electives among residency programs, few are assessing the educational value of these offerings using ACGME Milestones or describing these efforts in the literature.
Pevonedistat attenuates cisplatin‐induced nephrotoxicity in mice by downregulating the release of inflammatory mediators
Authors: El‐Far Yousra M. , El‐Mesery Mohamed
Published: September 2021

Pevonedistat (MLN4924) is a specific NEDD8‐activating enzyme inhibitor that inactivates cullin–RING ligases involved in ubiquitylation and turnover of different signaling molecules. In the current study, we evaluated the effect of pevonedistat on cisplatin (CIS)‐induced nephrotoxicity in mice. Serum creatinine and urea levels were analyzed in different groups. Histopathological examination of renal tissue was done using hematoxylin and eosin staining. In addition, renal IL‐6 and TNF‐α expressions were analyzed using the enzyme‐linked immunosorbent assay technique, and IL‐1β and NF‐κB expressions were analyzed by immunohistochemical staining of renal tissue. Caspase‐3, A20, β‐catenin, and Nrf2 gene expressions in renal tissue were analyzed using the reverse‐transcription polymerase chain reaction technique. Western blot analysis was adopted to assess cleaved caspase‐3 and β‐catenin expressions in renal tissue. Pevonedistat coadministration with CIS improved kidney functions and attenuated CIS‐induced nephrotoxicity as indicated by the significant decrease in serum creatinine and urea levels. In addition, pevonedistat coadministration with CIS showed a significant decrease in caspase‐3 and a significant increase in A20, β‐catenin, and Nrf2 gene expressions. Also, pevonedistat decreased caspase‐3 cleavage to p19 in mice treated with CIS. Moreover, pevonedistat decreased CIS‐induced upregulation of IL‐6, TNF‐α, IL‐1β, and NF‐κB protein expressions in renal tissue. Thus, pevonedistat alleviated CIS‐induced nephrotoxicity that might be attributed to suppression of the inflammation induced in renal tissue.