bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal Seismic Velocity Changes During the 2020 Rapid Inflation at Mt. Þorbjörn‐Svartsengi, Iceland, Using Seismic Ambient Noise
Authors: Cubuk‐Sabuncu Yesim , Jónsdóttir Kristín , Caudron Corentin , Lecocq Thomas , Parks Michelle Maree , Geirsson Halldór , Mordret Aurélien
Published: June 2021

Repeated periods of inflation‐deflation in the vicinity of Mt. Þorbjörn‐Svartsengi, SW‐Iceland, were detected in January–July, 2020. We used seismic ambient noise and interferometry to characterize temporal variations of seismic velocities (dv/v, %). This is the first time in Iceland that dv/v variations are monitored in near real‐time during volcanic unrest. The seismic station closest to the inflation source center (∼1 km) showed the largest velocity drop (∼1%). Different frequency range measurements, from 0.1 to 2 Hz, show dv/v variations, which we interpret in terms of varying depth sensitivity. The dv/v correlates with deformation measurements (GPS, InSAR), over the unrest period, indicating sensitivity to similar crustal processes. We interpret the velocity drop to be caused by crack opening triggered by intrusive magmatic activity. We conclude that single‐station cross‐component analyses provide the most robust solutions for early detection of magmatic activity.
Integrating Community Science Research and Space‐Time Mapping to Determine Depth to Groundwater in a Remote Rural Region
Authors: Gómez A. M. , Serre M. , Wise E. , Pavelsky T.
Published: June 2021

Continuous depth to groundwater (DTG) data collection is challenging in remote regions. Community participation offers a way to both increase data collection and involves the local community in scientific projects. Local knowledge, which is often descriptive, can be difficult to include in quantitative analysis; however, it can increase scientists' ability to formulate hypotheses or identify relevant environmental processes. We show how Community Science Research can add useful descriptive information for a study based in rural Colombia. To estimate the spatiotemporal distribution of DTG, the community collected water level measurements during a wet (La Niña) year and an average year. We built one spatial and two spatiotemporal models (with and without probabilistic data) using Bayesian Maximum Entropy. Due to the inclusion of local knowledge, the spatiotemporal model with probabilistic data reduced its mean square error by a factor of 15 compared to the spatial model. Using this model, we found that 13% of the study area has a high probability of very shallow DTG (<0.1 m) during an average year, whereas during La Niña, this area increases to 56%. The difference in shallow DTG between the average and wet year implies that after reaching a precipitation threshold, the study region may lose its flow regulation capacity, contributing to flooding during extreme precipitation events. Our approach presents a method to incorporate local knowledge in data‐driven models by combining qualitative and quantitative information.
Nepal’s Communities Brace for Multihazard Risks
Authors: Rakhal Biplob , Sharma Sanjib , Ghimire Ganesh , Adhikari Tirtha , Shrestha Ramesh
Published: June 2021

From its high mountains to its low plains, Nepal faces growing risks from natural hazards. Preparing for these risks requires accurate, locally relevant risk assessments and effective communications.
Fifteen Years of Radar Reveal Venus’s Most Basic Facts
Authors: Cartier Kimberly
Published: June 2021

Venus’s heavy atmosphere tugs the planet’s surface enough to change the length of its day by up to 21 minutes.
Seismic Slip‐Pulse Experiments Simulate Induced Earthquake Rupture in the Groningen Gas Field
Authors: Hunfeld Luuk B. , Chen Jianye , Niemeijer André R. , Ma Shengli , Spiers Christopher J.
Published: June 2021

Rock materials show dramatic dynamic weakening in large‐displacement (m), high‐velocity (∼1 m/s) friction experiments, providing a mechanism for the generation of large, natural earthquakes. However, whether such weakening occurs during induced M3‐4 earthquakes (dm displacements) is unknown. We performed rotary‐shear experiments on simulated fault gouges prepared from the source‐, reservoir‐ and caprock formations present in the seismogenic Groningen gas field (Netherlands). Water‐saturated gouges were subjected to a slip pulse reaching a peak circumferential velocity of 1.2–1.7 m/s and total displacements of 13–20 cm, at 2.5–20 MPa normal stress. The results show 22%–81% dynamic weakening within 5–12 cm of slip, depending on normal stress and gouge composition. At 20 MPa normal stress, dynamic weakening from peak friction coefficients of 0.4–0.9 to 0.19–0.27 was observed, probably through thermal pressurization. We infer that similar effects play a key role during induced seismic slip on faults in the Groningen and other reservoir systems.
Combined Effects of Global Warming and Ozone Depletion/Recovery on Southern Hemisphere Atmospheric Circulation and Regional Precipitation
Authors: Mindlin Julia , Shepherd Theodore G. , Vera Carolina , Osman Marisol
Published: June 2021

Ozone depletion led to a positive trend in the summertime Southern Annular Mode (SAM) during the last decades of the 20th century. During the present century, global warming (GW) is expected to contribute to a positive SAM trend while ozone recovery is expected to act in the opposite direction. Here, Southern Hemisphere (SH) circulation and regional precipitation change are studied with a methodology that separates the effects from GW and ozone depletion/recovery. Our results show that a “tug‐of‐war” between ozone and GW occurs in the summertime stratosphere, propagating to the troposphere where it is manifest in the SAM. However, at the regional scale this “tug‐of‐war” is not as relevant as the combined effects of other remote drivers of circulation change, which force different kinds of precipitation changes in the SH. For regional precipitation changes, the uncertainty in future circulation change is as important as the uncertainty in the GW level.
Reexamining the Indian Summer Monsoon Rainfall–ENSO Relationship From Its Recovery in the 21st Century: Role of the Indian Ocean SST Anomaly Associated With Types of ENSO Evolution
Authors: Yu Shi‐Yun , Fan Lei , Zhang Yu , Zheng Xiao‐Tong , Li Ziguang
Published: June 2021

This study found that the relationship between the Indian Summer Monsoon Rainfall (ISMR) and El Niño‐Southern Oscillation (ENSO) has recovered since 2001, and the relationship strength is closely related to the summer tropical Indian Ocean (TIO) sea surface temperature (SST) anomaly, with the TIO warming (cooling) indicating a stronger (weaker) relationship. Under the same El Niño/La Niña scenario, different signs of the TIO anomaly indicate distinct atmospheric circulation anomalies over the Indian Ocean, thus affecting the ISMR–ENSO relationship. The TIO anomaly is principally associated with different types of ENSO temporal evolution. Strong El Niño events with an early onset, and the transition of El Niño to La Niña, tend to have a warmer TIO and a stronger ISMR–ENSO relationship, in contrast to most of the cases of a decaying La Niña or a La Niña that persists throughout the year. The result brings a prospect for improving the ISMR prediction.
Fossil Versus Nonfossil CO Sources in the US: New Airborne Constraints From ACT‐America and GEM
Authors: Gonzalez Andres , Millet Dylan B. , Yu Xueying , Wells Kelley C. , Griffis Timothy J. , Baier Bianca C. , Campbell Patrick C. , Choi Yonghoon , DiGangi Joshua P. , Gvakharia Alexander , Halliday Hannah S. , Kort Eric A. , McKain Kathryn , Nowak John B. , Plant Genevieve
Published: June 2021

Carbon monoxide (CO) is an ozone precursor, oxidant sink, and widely used pollution tracer. The importance of anthropogenic versus other CO sources in the US is uncertain. Here, we interpret extensive airborne measurements with an atmospheric model to constrain US fossil and nonfossil CO sources. Measurements reveal a low bias in the simulated CO background and a 30% overestimate of US fossil CO emissions in the 2016 National Emissions Inventory. After optimization we apply the model for source partitioning. During summer, regional fossil sources account for just 9%–16% of the sampled boundary layer CO, and 32%–38% of the North American enhancement—complicating use of CO as a fossil fuel tracer. The remainder predominantly reflects biogenic hydrocarbon oxidation plus fires. Fossil sources account for less domain‐wide spatial variability at this time than nonfossil and background contributions. The regional fossil contribution rises in other seasons, and drives ambient variability downwind of urban areas.
Oct4 confers stemness and radioresistance to head and neck squamous cell carcinoma by regulating the homologous recombination factors PSMC3IP and RAD54L
Authors: Nathansen Jacqueline , Lukiyanchuk Vasyl , Hein Linda , Stolte Maya-Isabel , Borgmann Kerstin , Löck Steffen , Kurth Ina , Baumann Michael , Krause Mechthild , Linge Annett , Dubrovska Anna
Published: June 2021

Head and neck squamous cell carcinoma (HNSCC) is often being diagnosed at an advanced stage, conferring a poor prognosis. The probability of local tumor control after radiotherapy depends on the eradication of cancer stem cells (CSCs) with activated DNA repair. This study provides evidence that the CSC-related transcription factor Oct4 contributes to HNSCC radioresistance by regulating DNA damage response and the CSC phenotype. Knockdown of Oct4 A isoform reduced self-renewal capacity in HNSCC and led to partial tumor cell radiosensitization caused by transcriptional downregulation of the cell cycle checkpoint kinases CHK1 and WEE1 and homologous recombination (HR) repair genes PSMC3IP and RAD54L. Besides, PARP inhibition with Olaparib selectively radiosensitized Oct4 A knockout, but not wild-type HNSCC cells. This finding links Oct4 A to the HR-mediated DNA repair mechanisms. In turn, knockdown of PSMC3IP and RAD54L reduced the HNSCC self-renewal capacity and clonogenic cell survival after irradiation, suggesting the interplay between DNA repair and the CSC phenotype. Similar to the effect of Oct4 knockdown, overexpression of Oct4 also resulted in significant HNSCC radiosensitization and increased DNA damage, suggesting that Oct4-dependent regulation of DNA repair depends on its fine-tuned expression. In line with this observation, HNSCC patients with high and low nuclear Oct4 expression at the invasive tumor front exhibited better loco-regional tumor control after postoperative radio(chemo)therapy compared to the intermediate expression subgroup. Thus, we found that the Oct4-driven transcriptional program plays a critical role in regulating HNSCC radioresistance, and a combination of radiotherapy with PARP inhibitors may induce synthetic lethality in Oct4-deregulated tumors.
Compositional and genetic alterations in Graves’ disease gut microbiome reveal specific diagnostic biomarkers
Authors: Zhu Qiyun , Hou Qiangchuan , Huang Shi , Ou Qianying , Huo Dongxue , Vázquez-Baeza Yoshiki , Cen Chaoping , Cantu Victor , Estaki Mehrbod , Chang Haibo , Belda-Ferre Pedro , Kim Ho-Cheol , Chen Kaining , Knight Rob , Zhang Jiachao
Published: June 2021

Graves’ Disease is the most common organ-specific autoimmune disease and has been linked in small pilot studies to taxonomic markers within the gut microbiome. Important limitations of this work include small sample sizes and low-resolution taxonomic markers. Accordingly, we studied 162 gut microbiomes of mild and severe Graves’ disease (GD) patients and healthy controls. Taxonomic and functional analyses based on metagenome-assembled genomes (MAGs) and MAG-annotated genes, together with predicted metabolic functions and metabolite profiles, revealed a well-defined network of MAGs, genes and clinical indexes separating healthy from GD subjects. A supervised classification model identified a combination of biomarkers including microbial species, MAGs, genes and SNPs, with predictive power superior to models from any single biomarker type (AUC = 0.98). Global, cross-disease multi-cohort analysis of gut microbiomes revealed high specificity of these GD biomarkers, notably discriminating against Parkinson’s Disease, and suggesting that non-invasive stool-based diagnostics will be useful for these diseases.
Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours
Authors: Middleton Mark R. , Dean Emma , Evans Thomas R. J. , Shapiro Geoffrey I. , Pollard John , Hendriks Bart S. , Falk Martin , Diaz-Padilla Ivan , Plummer Ruth
Published: June 2021

Background

Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours.

Methods

We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2.

Results

Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease.

Conclusions

Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs.

Clinical trial identifier

NCT02157792.
Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours
Authors: Shapiro Geoffrey I. , Wesolowski Robert , Devoe Craig , Lord Simon , Pollard John , Hendriks Bart S. , Falk Martin , Diaz-Padilla Ivan , Plummer Ruth , Yap Timothy A.
Published: June 2021

Background

Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin.

Methods

Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W).

Results

Thirty-one patients received berzosertib (90–210 mg/m2) and cisplatin (40–75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2(days 2 and 9) and cisplatin 75 mg/m2(day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy.

Conclusions

Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting.

Clinical Trials Identifier

NCT02157792.
MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF
Authors: Wang Xin , Ros Uris , Agrawal Deepti , Keller Eva C. , Slotta-Huspenina Julia , Dill Veronika , Shen Bo , Shi Run , Herold Tobias , Belka Claus , Mishra Ritu , Bassermann Florian , Garcia-Saez Ana J. , Jost Philipp J.
Published: June 2021

The blockade of cellular differentiation represents a hallmark of acute myeloid leukemia (AML), which is largely attributed to the dysfunction of lineage-specific transcription factors controlling cellular differentiation. However, alternative mechanisms of cellular differentiation programs in AML remain largely unexplored. Here we report that mixed lineage kinase domain-like protein (MLKL) contributes to the cellular differentiation of transformed hematopoietic progenitor cells in AML. Using gene-targeted mice, we show that MLKL facilitates the release of granulocyte colony-stimulating factor (G-CSF) by controlling membrane permeabilization in leukemic cells. Mlkl−/− hematopoietic stem and progenitor cells released reduced amounts of G-CSF while retaining their capacity for CSF3 (G-CSF) mRNA expression, G-CSF protein translation, and G-CSF receptor signaling. MLKL associates with early endosomes and controls G-CSF release from intracellular storage by plasma membrane pore formation, whereas cell death remained unaffected by loss of MLKL. Of note, MLKL expression was significantly reduced in AML patients, specifically in those with a poor-risk AML subtype. Our data provide evidence that MLKL controls myeloid differentiation in AML by controlling the release of G-CSF from leukemic progenitor cells.
RNA atlas of human bacterial pathogens uncovers stress dynamics linked to infection
Authors: Avican Kemal , Aldahdooh Jehad , Togninalli Matteo , Mahmud A. K. M. Firoj , Tang Jing , Borgwardt Karsten M. , Rhen Mikael , Fällman Maria
Published: June 2021

Bacterial processes necessary for adaption to stressful host environments are potential targets for new antimicrobials. Here, we report large-scale transcriptomic analyses of 32 human bacterial pathogens grown under 11 stress conditions mimicking human host environments. The potential relevance of the in vitro stress conditions and responses is supported by comparisons with available in vivo transcriptomes of clinically important pathogens. Calculation of a probability score enables comparative cross-microbial analyses of the stress responses, revealing common and unique regulatory responses to different stresses, as well as overlapping processes participating in different stress responses. We identify conserved and species-specific ‘universal stress responders’, that is, genes showing altered expression in multiple stress conditions. Non-coding RNAs are involved in a substantial proportion of the responses. The data are collected in a freely available, interactive online resource (PATHOgenex).
Through bonds or contacts? Mapping protein vibrational energy transfer using non-canonical amino acids
Authors: Deniz Erhan , Valiño-Borau Luis , Löffler Jan G. , Eberl Katharina B. , Gulzar Adnan , Wolf Steffen , Durkin Patrick M. , Kaml Robert , Budisa Nediljko , Stock Gerhard , Bredenbeck Jens
Published: June 2021

Vibrational energy transfer (VET) is essential for protein function. It is responsible for efficient energy dissipation in reaction sites, and has been linked to pathways of allosteric communication. While it is understood that VET occurs via backbone as well as via non-covalent contacts, little is known about the competition of these two transport channels, which determines the VET pathways. To tackle this problem, we equipped the β-hairpin fold of a tryptophan zipper with pairs of non-canonical amino acids, one serving as a VET injector and one as a VET sensor in a femtosecond pump probe experiment. Accompanying extensive non-equilibrium molecular dynamics simulations combined with a master equation analysis unravel the VET pathways. Our joint experimental/computational endeavor reveals the efficiency of backbone vs. contact transport, showing that even if cutting short backbone stretches of only 3 to 4 amino acids in a protein, hydrogen bonds are the dominant VET pathway.
UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation
Authors: Subramanian Manivannan , Hyeon Seung Jae , Das Tanuza , Suh Yoon Seok , Kim Yun Kyung , Lee Jeong-Soo , Song Eun Joo , Ryu Hoon , Yu Kweon
Published: June 2021

The formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer’s disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD.
Analysis of the Coptis chinensis genome reveals the diversification of protoberberine-type alkaloids
Authors: Liu Yifei , Wang Bo , Shu Shaohua , Li Zheng , Song Chi , Liu Di , Niu Yan , Liu Jinxin , Zhang Jingjing , Liu Heping , Hu Zhigang , Huang Bisheng , Liu Xiuyu , Liu Wei , Jiang Liping , Alami Mohammad Murtaza , Zhou Yuxin , Ma Yutao , He Xiangxiang , Yang Yicheng , Zhang Tianyuan , Hu Hui , Barker Michael S. , Chen Shilin , Wang Xuekui , Nie Jing
Published: June 2021

Chinese goldthread (Coptis chinensis Franch.), a member of the Ranunculales, represents an important early-diverging eudicot lineage with diverse medicinal applications. Here, we present a high-quality chromosome-scale genome assembly and annotation of C. chinensis. Phylogenetic and comparative genomic analyses reveal the phylogenetic placement of this species and identify a single round of ancient whole-genome duplication (WGD) shared by the Ranunculaceae. We characterize genes involved in the biosynthesis of protoberberine-type alkaloids in C. chinensis. In particular, local genomic tandem duplications contribute to member amplification of a Ranunculales clade-specific gene family of the cytochrome P450 (CYP) 719. The functional versatility of a key CYP719 gene that encodes the (S)-canadine synthase enzyme involved in the berberine biosynthesis pathway may play critical roles in the diversification of other berberine-related alkaloids in C. chinensis. Our study provides insights into the genomic landscape of early-diverging eudicots and provides a valuable model genome for genetic and applied studies of Ranunculales.
Inactivation and sensitization of Pseudomonas aeruginosa by microplasma jet array for treating otitis media
Authors: Sun Peter P. , Won Jungeun , Choo-Kang Gabrielle , Li Shouyan , Chen Wenyuan , Monroy Guillermo L. , Chaney Eric J. , Boppart Stephen A. , Eden J. Gary , Nguyen Thanh H.
Published: June 2021

Otitis media (OM), known as a middle ear infection, is the leading cause of antibiotic prescriptions for children. With wide-spread use of antibiotics in OM, resistance to antibiotics continues to decrease the efficacy of the treatment. Furthermore, as the presence of a middle ear biofilm has contributed to this reduced susceptibility to antimicrobials, effective interventions are necessary. A miniaturized 3D-printed microplasma jet array has been developed to inactivate Pseudomonas aeruginosa, a common bacterial strain associated with OM. The experiments demonstrate the disruption of planktonic and biofilm P. aeruginosa by long-lived molecular species generated by microplasma, as well as the synergy of combining microplasma treatment with antibiotic therapy. In addition, a middle ear phantom model was developed with an excised rat eardrum to investigate the antimicrobial effects of microplasma on bacteria located behind the eardrum, as in a patient-relevant setup. These results suggest the potential for microplasma as a new treatment paradigm for OM.
Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes
Authors: Bassenden Angelia V. , Dumalo Linda , Park Jaeok , Blanchet Jonathan , Maiti Krishnagopal , Arya Dev P. , Berghuis Albert M.
Published: June 2021

Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2′)-Ia from Providencia stuartii. As the clinical use of plazomicin begins to increase, the spread of resistance factors will undoubtedly accelerate, rendering this aminoglycoside increasingly obsolete. Understanding resistance to plazomicin is an important step to ensure this aminoglycoside remains a viable treatment option for the foreseeable future. Here, we present three crystal structures of AAC(2′)-Ia from P. stuartii, two in complex with acetylated aminoglycosides tobramycin and netilmicin, and one in complex with a non-substrate aminoglycoside, amikacin. Together, with our previously reported AAC(2′)-Ia-acetylated plazomicin complex, these structures outline AAC(2′)-Ia’s specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2′)-I homologues highlights the conservation of residues predicted to be involved in aminoglycoside binding, and identifies the presence of plasmid-encoded enzymes in environmental strains that confer resistance to the latest next-generation aminoglycoside. These results forecast the likely spread of plazomicin resistance and highlight the urgency for advancements in next-generation aminoglycoside design.
Mitochondria in epithelial ovarian carcinoma exhibit abnormal phenotypes and blunted associations with biobehavioral factors
Authors: Bindra Snehal , McGill Marlon A. , Triplett Marina K. , Tyagi Anisha , Thaker Premal H. , Dahmoush Laila , Goodheart Michael J. , Ogden R. Todd , Owusu-Ansah Edward , R Karan Kalpita , Cole Steve , Sood Anil K. , Lutgendorf Susan K. , Picard Martin
Published: June 2021

Malignant tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and mitochondria in malignant tumors remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign tissue and in high-grade epithelial ovarian carcinoma (EOC) in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n = 1435) showed that gene expression of specific mitochondrial proteins in EOC is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in tissue from 51 patients with benign ovarian masses and 128 patients with high-grade EOC revealed that compared to benign tissue, EOCs exhibit 3.3–8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P < 0.001) but similar mitochondrial DNA (mtDNA) levels (− 3.1%), documenting abnormal mitochondrial phenotypes in EOC. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r = − 0.43 to 0.47). In contrast, serous EOCs showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in EOC and warrant further research on the link between biobehavioral factors and mitochondria in cancer.
Subsoil-potassium depletion accounts for the nutrient budget in high-potassium agricultural soils
Authors: Correndo Adrian A. , Rubio Gerardo , García Fernando O. , Ciampitti Ignacio A.
Published: June 2021

Continuous potassium (K) removal without replenishment is progressively mining Argentinean soils. Our goals were to evaluate the sensitivity of soil-K to K budgets, quantify soil-K changes over time along the soil profile, and identify soil variables that regulate soil-K depletion. Four on-farm trials under two crop rotations including maize, wheat and soybean were evaluated. Three treatments were compared: (1) control (no fertilizer applied); (2) application of nitrogen, phosphorus, and sulfur fertilizers -NPS-; and (3) pristine condition. After nine years, crops removed from 258 to 556 kg K ha−1. Only two sites showed a decline in the exchangeable-K levels at 0–20 cm but unrelated to K budget. Topsoil exchangeable-K levels under agriculture resulted 48% lower than their pristine conditions, although still above response levels. Both soil exchangeable-K and slowly-exchangeable K vertical distribution patterns (0–100 cm) displayed substantial depletion relative to pristine conditions, mainly concentrated at subsoil (20–100 cm), with 55–83% for exchangeable-K, and 74–95% for slowly-exchangeable-K. Higher pristine levels of exchangeable-K and slowly-exchangeable-K and lower clay and silt contents resulted in higher soil-K depletion. Soil K management guidelines should consider both topsoil and subsoil nutrient status and variables related to soil K buffer capacity.
Good prediction of treatment responses to neoadjuvant chemoradiotherapy for esophageal cancer based on preoperative inflammatory status and tumor glucose metabolism
Authors: Li Chuan , Lin Jing-Wei , Yeh Hui-Ling , Chuang Cheng-Yen , Chen Chien-Chih
Published: June 2021

To develop a tool for predicting pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (neoCRT) in patients with esophageal cancer by combining inflammatory status and tumor glucose metabolic activity. This study included 127 patients with locally advanced esophageal cancer who had received neoCRT followed by esophagectomy from 2007 to 2016. We collected their neutrophil–lymphocyte ratio (NLR) and standardized uptake value (SUV) obtained from fluorodeoxyglucose positron emission tomography (PET/CT) before and after neoCRT. Univariate and multivariate logistic regression analyses were performed to identify potential predictive factors for pCR. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of predictors were calculated. Between pCR and non-pCR groups, there were no statistically significant differences in patient characteristics, such as sex, age, site, and clinical T/N stage. Multivariate analyses identified four independent predictors for pCR, including pre-OP NLR < 5.4 [OR 11.179; 95% CI 8.385–13.495; p = 0.003], NLR change (ΔNLR) < 3 [OR 4.891; 95% CI 2.274–9.180; p = 0.005], changes in SUV (ΔSUV) > 7.2 [OR 3.033; 95% CI 1.354–6.791; p = 0.007], and SUV changes ratio (ΔSUV ratio) > 58% [OR 3.585; 95% CI 1.576–8.152; p = 0.002]. ΔNLR had the highest accuracy and NPV (84.3% and 90.3%, respectively). Combined factors of ΔNLR < 3 and ΔSUV ratio > 58% had the best PPV for pCR (84.8%). Inflammatory status (ΔNLR) and tumor glucose metabolic activity (ΔSUV ratio), when considered together, constitute a promising low-invasive tool with high efficacy for prediction of treatment response before surgery.
Covid-19 diagnosis by combining RT-PCR and pseudo-convolutional machines to characterize virus sequences
Authors: Gomes Juliana Carneiro , Masood Aras Ismael , Silva Leandro Honorato de S. , da Cruz Ferreira Janderson Romário B. , Freire Júnior Agostinho Antônio , Rocha Allana Laís dos Santos , de Oliveira Letícia Castro Portela , da Silva Nathália Regina Cauás , Fernandes Bruno José Torres , dos Santos Wellington Pinheiro
Published: June 2021

The Covid-19 pandemic, a disease transmitted by the SARS-CoV-2 virus, has already caused the infection of more than 120 million people, of which 70 million have been recovered, while 3 million people have died. The high speed of infection has led to the rapid depletion of public health resources in most countries. RT-PCR is Covid-19’s reference diagnostic method. In this work we propose a new technique for representing DNA sequences: they are divided into smaller sequences with overlap in a pseudo-convolutional approach and represented by co-occurrence matrices. This technique eliminates multiple sequence alignment. Through the proposed method, it is possible to identify virus sequences from a large database: 347,363 virus DNA sequences from 24 virus families and SARS-CoV-2. When comparing SARS-CoV-2 with virus families with similar symptoms, we obtained$$0.97 \pm 0.03$$0.97±0.03for sensitivity and$$0.9919 \pm 0.0005$$0.9919±0.0005for specificity with MLP classifier and 30% overlap. When SARS-CoV-2 is compared to other coronaviruses and healthy human DNA sequences, we obtained$$0.99 \pm 0.01$$0.99±0.01for sensitivity and$$0.9986 \pm 0.0002$$0.9986±0.0002for specificity with MLP and 50% overlap. Therefore, the molecular diagnosis of Covid-19 can be optimized by combining RT-PCR and our pseudo-convolutional method to identify DNA sequences for SARS-CoV-2 with greater specificity and sensitivity.
Influence of InP coupling cavity on Fano resonance of sub wavelength MIM waveguide
Authors: Ban Shihao , Liu Huangqing , Xiao Shifang , Mao Jingjing , Luo Jie
Published: June 2021

In this paper, influence of InP coupling cavity on Fano resonance of sub wavelength MIM waveguide was studied by FDTD. It was observed that the resonant wavelengths of mode mj (j = 1, 2, 3) were closely related with the height H2 of InP coupling cavity. In addition, before and after the addition of air cavity, the relative farfield intensities I was a function of height H2. Therefore, InP as discrete state could be used as the filling dielectrics of Fano resonance in the MIM waveguide.
Contingency and determinism in the evolution of bird song sound frequency
Authors: Friis Jakob I. , Dabelsteen Torben , Cardoso Gonçalo C.
Published: June 2021

Sexual signals are archetypes of contingent evolution: hyper-diverse across species, often evolving fast and in unpredictable directions. It is unclear to which extent their evolutionary unpredictability weakens deterministic evolution, or takes place bounded by deterministic patterns of trait evolution. We compared the evolution of sound frequency in sexual signals (advertisement songs) and non-sexual social signals (calls) across > 500 genera of the crown songbird families. Contrary to the acoustic adaptation hypothesis, we found no evidence that forest species used lower sound frequencies in songs or calls. Consistent with contingent evolution in song, we found lower phylogenetic signal for the sound frequency of songs than calls, which suggests faster and less predictable evolution, and found unpredictable direction of evolution in lineages with longer songs, which presumably experience stronger sexual selection on song. Nonetheless, the most important deterministic pattern of sound frequency evolution—its negative association with body size—was stronger in songs than calls. This can be explained by songs being longer-range signals than most calls, and thus using sound frequencies that animals of a given size produce best at high amplitude. Results indicate that sexual selection can increase aspects of evolutionary contingency while strengthening, rather than weakening, deterministic patterns of evolution.
Tarsal morphology of ischyromyid rodents from the middle Eocene of China gives an insight into the group’s diversity in Central Asia
Authors: Fostowicz-Frelik Łucja , López-Torres Sergi , Li Qian
Published: June 2021

Ischyromyids are a group of large rodents with the earliest fossil record known from the late Paleocene (Clarkforkian) of North America; they are considered the earliest fossil representatives of Rodentia of modern aspect. Ischyromyids dominated early Paleogene small-mammal assemblages of North America and in the latest Paleocene migrated to western Europe and to Asia; in the latter they survived only to the beginning of the late Eocene, but were never abundant. Here we describe for the first time the calcanei of ischyromyids from the early middle Eocene of the Erlian Basin in Nei Mongol, northern China. These calcanei document the existence of three species. The morphology of the studied tarsal bones overall suggests ambulatory locomotion for these animals (‘slow cursors’), similar to that of the coypu and porcupines, but one form shows more marked cursorial capabilities. These differences show that Chinese ischyromyids, although rare, had attained greater taxonomic diversity by the middle Eocene in Nei Mongol than estimated from dental remains. We also address the question of the morphological and ecological divergence of these ischyromyids in relation to their North American counterparts, as well as the issue of a direct dispersal route from North America to Asia in the early Eocene.
Learning from crowds in digital pathology using scalable variational Gaussian processes
Authors: López-Pérez Miguel , Amgad Mohamed , Morales-Álvarez Pablo , Ruiz Pablo , Cooper Lee A. D. , Molina Rafael , Katsaggelos Aggelos K.
Published: June 2021

The volume of labeled data is often the primary determinant of success in developing machine learning algorithms. This has increased interest in methods for leveraging crowds to scale data labeling efforts, and methods to learn from noisy crowd-sourced labels. The need to scale labeling is acute but particularly challenging in medical applications like pathology, due to the expertise required to generate quality labels and the limited availability of qualified experts. In this paper we investigate the application of Scalable Variational Gaussian Processes for Crowdsourcing (SVGPCR) in digital pathology. We compare SVGPCR with other crowdsourcing methods using a large multi-rater dataset where pathologists, pathology residents, and medical students annotated tissue regions breast cancer. Our study shows that SVGPCR is competitive with equivalent methods trained using gold-standard pathologist generated labels, and that SVGPCR meets or exceeds the performance of other crowdsourcing methods based on deep learning. We also show how SVGPCR can effectively learn the class-conditional reliabilities of individual annotators and demonstrate that Gaussian-process classifiers have comparable performance to similar deep learning methods. These results suggest that SVGPCR can meaningfully engage non-experts in pathology labeling tasks, and that the class-conditional reliabilities estimated by SVGPCR may assist in matching annotators to tasks where they perform well.
Metabolic syndrome in women with previous gestational diabetes
Authors: Kaiser Karsten , Nielsen Michael Festersen , Kallfa Ervin , Dubietyte Greta , Lauszus Finn Friis
Published: June 2021

To evaluate the incidence and timing of the diagnosis of metabolic syndrome in a cohort of Danish women after a pregnancy with gestational diabetes (GDM) to estimate the optimum time for preventative actions in relation to metabolic syndrome (MetS). In this follow-up study, 435 women were included from a consecutive cohort with prior history of GDM. Data on dyslipidemia, hypertension and other cardiovascular disorders (CVD) were extracted from the electronic patient journal. Any antidiabetic, cardiovascular and cholesterol-lowering medicine was ascertained in the national prescription database. Similarly, any blood test taken was evaluated. We defined a patient having MetS if the criteria of the WHO based definition of diabetes or impaired glucose regulation were met. Further, we added as alternative for glucose intolerance, a glycosylated hemoglobin (HbA1c) > 44 mmol/mol or the former level ≥ 6.5%. Further, dyslipidemia, lipid lowering medications, BMI > 30 kg/m2 or antihypertensive treatment were used. For MetS outcome, diagnosis or medication for CVD was registered. All women were followed for median 5.7 years (range 0; 9). The incidence of MetS was 28%. Thirteen percent of these qualified already within one year after pregnancy for the diagnosis of MetS. Postpartum MetS was detected after a median of 3 years (range 0; 7 years); further, 36 (8%) had been diagnosed with manifest diabetes after pregnancy. The diagnosis of postpartum MetS was strongly associated with the prevalence of manifest diabetes. Six years after pregnancy the rate of metabolic syndrome was more than tripled (25 vs. 89%, no DM vs manifest DM, RR: 6.7; 95% CI 2.7–17, p < 0.001). At 40 years the MetS rate nearly tripled if manifest DM was diagnosed (26 vs. 78%, no DM vs. manifest DM, RR: 3.3, 95% CI 1.8–6, p < 0.001). We found that GDM and later on manifest DM in women increase the risk of metabolic syndrome. There seems to be a window of opportunity before the early thirties where it would be especially beneficial to begin preventive efforts in women with GDM.
Three novel quantum-inspired swarm optimization algorithms using different bounded potential fields
Authors: Alvarez-Alvarado Manuel S. , Alban-Chacón Francisco E. , Lamilla-Rubio Erick A. , Rodríguez-Gallegos Carlos D. , Velásquez Washington
Published: June 2021

Based on the behavior of the quantum particles, it is possible to formulate mathematical expressions to develop metaheuristic search optimization algorithms. This paper presents three novel quantum-inspired algorithms, which scenario is a particle swarm that is excited by a Lorentz, Rosen–Morse, and Coulomb-like square root potential fields, respectively. To show the computational efficacy of the proposed optimization techniques, the paper presents a comparative study with the classical particle swarm optimization (PSO), genetic algorithm (GA), and firefly algorithm (FFA). The algorithms are used to solve 24 benchmark functions that are categorized by unimodal, multimodal, and fixed-dimension multimodal. As a finding, the algorithm inspired in the Lorentz potential field presents the most balanced computational performance in terms of exploitation (accuracy and precision), exploration (convergence speed and acceleration), and simulation time compared to the algorithms previously mentioned. A deeper analysis reveals that a strong potential field inside a well with weak asymptotic behavior leads to better exploitation and exploration attributes for unimodal, multimodal, and fixed-multimodal functions.
Mortality and microbial diversity after allogeneic hematopoietic stem cell transplantation: secondary analysis of a randomized nutritional intervention trial
Authors: Skaarud Kristin J. , Hov Johannes R. , Hansen Simen H. , Kummen Martin , Valeur Jørgen , Seljeflot Ingebjørg , Bye Asta , Paulsen Vemund , Lundin Knut E. A. , Trøseid Marius , Tjønnfjord Geir E. , Iversen Per Ole
Published: June 2021

Gut mucosal barrier injury is common following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and associated with poor clinical outcomes. Diet is critical for microbial diversity, but whether nutritional support affects microbiota and outcome after allo-HSCT is unknown. We present a secondary analysis of a randomized controlled nutritional intervention trial during allo-HSCT. We investigated if the intervention influenced gut microbiota, short-chain fatty acids (SCFAs), and markers of gut barrier functions, and if these parameters were associated with clinical outcomes. Fecal specimens were available from 47 recipients, and subjected to 16S rRNA gene sequencing. We found no significant differences between the intervention group and controls in investigated parameters. We observed a major depletion of microbiota, SCFAs, and altered markers of gut barrier function from baseline to 3 weeks post-transplant. One-year mortality was significantly higher in patients with lower diversity at 3 weeks post-HSCT, but not related to diversity at baseline. The relative abundance of Blautia genus at 3 weeks was higher in survivors. Fecal propionic acid was associated with survival. Markers of gut barrier functions were less strongly associated with clinical outcomes. Possibly, other strategies than dietary intervention are needed to prevent negative effects of gut microbiota and clinical outcomes after allo-HSCT.

ClinicalTrials.gov (NCT01181076).
Reproducibility of CT-based radiomic features against image resampling and perturbations for tumour and healthy kidney in renal cancer patients
Authors: Mottola Margherita , Ursprung Stephan , Rundo Leonardo , Sanchez Lorena Escudero , Klatte Tobias , Mendichovszky Iosif , Stewart Grant D , Sala Evis , Bevilacqua Alessandro
Published: June 2021

Computed Tomography (CT) is widely used in oncology for morphological evaluation and diagnosis, commonly through visual assessments, often exploiting semi-automatic tools as well. Well-established automatic methods for quantitative imaging offer the opportunity to enrich the radiologist interpretation with a large number of radiomic features, which need to be highly reproducible to be used reliably in clinical practice. This study investigates feature reproducibility against noise, varying resolutions and segmentations (achieved by perturbing the regions of interest), in a CT dataset with heterogeneous voxel size of 98 renal cell carcinomas (RCCs) and 93 contralateral normal kidneys (CK). In particular, first order (FO) and second order texture features based on both 2D and 3D grey level co-occurrence matrices (GLCMs) were considered. Moreover, this study carries out a comparative analysis of three of the most commonly used interpolation methods, which need to be selected before any resampling procedure. Results showed that the Lanczos interpolation is the most effective at preserving original information in resampling, where the median slice resolution coupled with the native slice spacing allows the best reproducibility, with 94.6% and 87.7% of features, in RCC and CK, respectively. GLCMs show their maximum reproducibility when used at short distances.
Working memory load reduces corticospinal suppression to former go and trained no-go cues
Authors: Tran Dominic M. D. , Nicholson William G. , Harris Justin A. , Harris Irina M. , Livesey Evan J.
Published: June 2021

Environmental cues associated with an action can prime the motor system, decreasing response times and activating motor regions of the brain. However, when task goals change, the same responses to former go-associated cues are no longer required and motor priming needs to be inhibited to avoid unwanted behavioural errors. The present study tested whether the inhibition of motor system activity to presentations of former go cues is reliant on top-down, goal-directed cognitive control processes using a working memory (WM) load manipulation. Applying transcranial magnetic stimulation over the primary motor cortex to measure motor system activity during a Go/No-go task, we found that under low WM, corticospinal excitability was suppressed to former go and trained no-go cues relative to control cues. Under high WM, the cortical suppression to former go cues was reduced, suggesting that the underlying mechanism required executive control. Unexpectedly, we found a similar result for trained no-go cues and showed in a second experiment that the corticospinal suppression and WM effects were unrelated to local inhibitory function as indexed by short-interval intracortical inhibition. Our findings reveal that the interaction between former response cues and WM is complex and we discuss possible explanations of our findings in relation to models of response inhibition.