bluuebunny/crossref_metadata_2025 huggingface dataset:
Constraints on Early Paleozoic Deep‐Ocean Oxygen Concentrations From the Iron Geochemistry of the Bay of Islands Ophiolite
Authors: Stolper Daniel A. , Pu Xiaofei , Lloyd Max K. , Christensen Nikolas I. , Bucholz Claire E. , Lange Rebecca A.
Published: June 2022

The deep ocean is generally considered to have changed from anoxic in the Precambrian to oxygenated by the Late Paleozoic (∼420–400 Ma) due to changes in atmospheric oxygen concentrations. When the transition occurred, that is, in the Early Paleozoic or not until the Late Paleozoic, is less well constrained. To address this, we measured Fe3+/ΣFe of volcanic rocks, sheeted dykes, gabbros, and ultramafic rocks from the Early Paleozoic (∼485 Ma) Bay of Islands (BOI) ophiolite as a proxy for hydrothermal alteration in the presence or absence of O2derived from deep marine fluids. Combining this data with previously published data from the BOI indicates that volcanic rocks are oxidized relative to intrusive crustal rocks (0.35 ± 0.02 vs. 0.19 ± 0.01, 1 standard error), which we interpret to indicate that the volcanic section was altered by marine‐derived fluids that contained some dissolved O2. We compare our results directly to the Macquarie Island and Troodos ophiolites, drilled oceanic crust, previously compiled data for ophiolitic volcanic rocks, and newly compiled data for ophiolitic intrusive rocks. These comparisons show that the BOI volcanic (but not intrusive) rocks are oxidized relative to Precambrian equivalents, but are less oxidized relative to Late Paleozoic to modern equivalents. We interpret these results to indicate that the Early Paleozoic ocean contained dissolved O2, but at concentrations ∼2.4× lower than for the Late Paleozoic to today.
Seismic Imaging of Crust Beneath the Western Tibet‐Pamir and Western Himalaya Using Ambient Noise and Earthquake Data
Authors: Kumar Vivek , Rai Shyam S. , Hawkins Rhys , Bodin Thomas
Published: June 2022

We present a new high‐resolution image of the crust beneath the western Himalaya‐Asia convergence zone encompassing the geographical domain of western Himalaya‐western Tibet‐Ladakh‐Karakoram‐Pamir‐Hindu Kush, using ambient noise cross‐correlations from 530 seismological stations along with surface wave observations from 1,261 earthquakes recorded over the network. The 3‐D shear wave velocity image is created using 22,726 inter‐station Rayleigh wave dispersion measurements from 5 to 60 s period at a horizontal resolution of less than 0.5° × 0.5° following the Bayesian Trans‐dimensional Tree tomography approach. The Moho beneath the Himalayas and south Tibet correlates with a velocity transition of 4.4–4.6 km/s and a reduced velocity transition of 4.0–4.2 km/s in northern Tibet and the Pamir. We used the Moho depth and the nature of high‐velocity lower crust (Vs > 4.0 km/s) to map the northern limit of the Indian crust that extends beyond the Qiangtang block in western Tibet (77–82°E) from its previously assumed boundary in the Lhasa block and till the central Pamir farther west. The velocity image reveals discontinuous low‐velocity zones (LVZs; Vs < 3.4 km/s) in the mid‐crust of western Tibet and the Pamir that do not support the existence of the channel flow model. The LVZs in the Pamir correlate with the surface distribution of gneiss domes. The lowest velocities (Vs < 3.2 km/s) are observed over the Ladakh‐Karakoram batholith and the Nanga Parbat region. The study suggests a continuation of LVZs across the Karakoram Fault at a depth below 20 km, indicating the fault's upper crustal depth extent.
Subpolar Southern Ocean Seasonal Variability of the Geostrophic Circulation From Multi‐Mission Satellite Altimetry
Authors: Auger Matthis , Sallée Jean‐Baptiste , Prandi Pierre , Naveira Garabato Alberto C.
Published: June 2022

A novel multi‐satellite product is used to shed light on the sea surface height seasonal cycle and associated geostrophic circulation in the subpolar Southern Ocean. We find three main modes of variability governing the Sea Level Anomaly seasonal cycle, all of them primarily governed by wind forcing. The main mode of seasonal variability is associated with the seasonality of the main subpolar gyres governed by large‐scale wind stress curl, qualitatively consistent with Sverdrup dynamics. The second seasonal mode is related to the Antarctic Slope Current (ASC), governed by the coastal easterlies, with a rapid circumpolar propagation of anomalous sea‐level along the continental slope that is dynamically consistent with the so‐called Southern Mode. The first two modes induce an acceleration of the gyres and the ASC in winter. The third seasonal mode appears to be driven by sea ice‐modulated surface stress and induces an offshore extension of the ASC from autumn to winter.
Indoor Air Pollution in the Time of Coronavirus
Authors: Sima Richard
Published: June 2022

How aerosol scientists spread the word on the airborne transmission of COVID-19–and what it means for cleaning our indoor air.
Planting Wetlands Could Help Stave Off Climate Catastrophe
Authors: Schmidt Jennifer
Published: June 2022

A shift in priority and approach to wetland restoration could reduce atmospheric carbon.
Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations
Authors: Toksvang Linea N. , Lee Shawn H. R. , Yang Jun J. , Schmiegelow Kjeld
Published: June 2022

Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy—the addition of low-dose (2.5–12.5 mg/m2/day) 6-thioguanine to the 6-MP/MTX backbone—that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.
Accelerated epigenetic aging in suicide attempters uninfluenced by high intent-to-die and choice of lethal methods
Authors: Jokinen Jussi , Andersson Peter , Chatzittofis Andreas , Savard Josephine , Rask-Andersen Mathias , Åsberg Marie , Boström Adrian Desai E.
Published: June 2022

Suicide attempts (SA) are associated with excess non-suicidal mortality, putatively mediated in part by premature cellular senescence. Epigenetic age (EA) estimators of biological age have been previously demonstrated to strongly predict physiological dysregulation and mortality risk. Herein, we investigate if violent SA with high intent-to-die is predictive of epigenetics-derived estimates of biological aging. The genome-wide methylation pattern was measured using the Illumina Infinium Methylation EPIC BeadChip in whole blood of 88 suicide attempters. Subjects were stratified into two groups based on the putative risk of later committed suicide (low- [n = 58] and high-risk [n = 30]) in dependency of SA method (violent or non-violent) and/or intent-to-die (high/low). Estimators of intrinsic and extrinsic EA acceleration, one marker optimized to predict physiological dysregulation (DNAmPhenoAge/AgeAccelPheno) and one optimized to predict lifespan (DNAmGrimAge/AgeAccelGrim) were investigated for associations to severity of SA, by univariate and multivariate analyses. The study was adequately powered to detect differences of 2.2 years in AgeAccelGrim in relation to SA severity. Baseline DNAmGrimAge exceeded chronological age by 7.3 years on average across all samples, conferring a mean 24.6% increase in relation to actual age. No individual EA acceleration marker was differentiated by suicidal risk group (p > 0.1). Thus, SA per se but not severity of SA is related to EA, implicating that excess non-suicidal mortality in SA is unrelated to risk of committed suicide. Preventative healthcare efforts aimed at curtailing excess mortality after SA may benefit from acting equally powerful to recognize somatic comorbidities irrespective of the severity inherent in the act itself.
Transcription factor SNAI2 exerts pro-tumorigenic effects on glioma stem cells via PHLPP2-mediated Akt pathway
Authors: Peng Lilei , Fu Jie , Chen Yitian , Ming Yang , He Haiping , Zeng Shan , Zhong Chuanhong , Chen Ligang
Published: June 2022

The current study aimed to investigate the effects associated with SNAI2 on the proliferation of glioma stem cells (GSCs) to elucidate its underlying molecular mechanism in the development of glioma. The expression of Snail family transcriptional repressor 2 (SNAI2) in glioma tissues was initially predicted via bioinformatics analysis and subsequently confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), which revealed that SNAI2 was highly expressed in glioma tissues as well as GSCs, with an inverse correlation with overall glioma patient survival detected. Loss- and gain- of-function assays were performed to determine the roles of SNAI2 and pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) on GSC viability, proliferation and apoptosis. Data were obtained indicating that SNAI2 promoted the proliferation of GSCs, while overexpressed PHLPP2 brought about a contrasting trend. As detected by chromatin immunoprecipitation, RT-qPCR and agarose gel electrophoresis, SNAI2 bound to the promoter region of PHLPP2 and repressed the transcription of PHLPP2 while SNAI2 was found to inhibit PHLPP2 resulting in activation of the Akt pathway. Finally, the roles of SNAI2 and PHLPP2 were verified in glioma growth in nude mice xenografted with tumor. Taken together, the key findings of the present study suggest that SNAI2 may promote the proliferation of GSCs through activation of the Akt pathway by downregulating PHLPP2.
Essential role of Rnd1 in innate immunity during viral and bacterial infections
Authors: Kumar Akhilesh , Mishra Shalabh , Kumar Ashish , Raut Ashwin Ashok , Sato Seiichi , Takaoka Akinori , Kumar Himanshu
Published: June 2022

Intracellular and cell surface pattern-recognition receptors (PRRs) are an essential part of innate immune recognition and host defense. Here, we have compared the innate immune responses between humans and bats to identify a novel membrane-associated protein, Rnd1, which defends against viral and bacterial infection in an interferon-independent manner. Rnd1 belongs to the Rho GTPase family, but unlike other small GTPase members, it is constitutively active. We show that Rnd1 is induced by pro-inflammatory cytokines during viral and bacterial infections and provides protection against these pathogens through two distinct mechanisms. Rnd1 counteracts intracellular calcium fluctuations by inhibiting RhoA activation, thereby inhibiting virus internalisation. On the other hand, Rnd1 also facilitates pro-inflammatory cytokines IL-6 and TNF-α through Plxnb1, which are highly effective against intracellular bacterial infections. These data provide a novel Rnd1-mediated innate defense against viral and bacterial infections.
Induction of autophagy-dependent ferroptosis to eliminate drug-tolerant human retinoblastoma cells
Authors: Liu Ke , Huang Jun , Liu Jiao , Klionsky Daniel J. , Kang Rui , Tang Daolin
Published: June 2022

Carboplatin is the most used first-line drug for the treatment of human retinoblastoma (RB), a rare form of cancer in infancy and childhood. However, the clinical application of carboplatin is restricted due to the emergence of acquired multi-drug resistance (MDR) after long-term treatment. Here, we report a new strategy to eliminate MDR RB cells by inducing autophagy-dependent ferroptosis. Compared with parent cells, carboplatin-resistant human RB cells have higher autophagy activity, which drives the formation of MDR to other chemotherapeutic drugs (e.g., etoposide and vincristine). In addition to confirming the traditional strategy of inhibiting autophagy to overcome MDR, we also establish an approach of inducing selective ferritinophagy to eliminate drug-resistant cells. We evaluate the effectiveness and safety of 4-octyl itaconate, a cell-permeable derivative of the metabolite itaconate, in inducing ferritinophagy-dependent ferroptosis in the treatment of MDR RB cells in vitro and in xenograft mouse models. These findings may provide essential clues for initiating clinical trials that target autophagy-dependent ferroptosis to kill drug-tolerant persistent cells during RB therapy.
A role for microfluidic systems in precision medicine
Authors: Ayuso Jose M. , Virumbrales-Muñoz María , Lang Joshua M. , Beebe David J.
Published: June 2022

Precision oncology continues to challenge the “one-size-fits-all” dogma. Under the precision oncology banner, cancer patients are screened for molecular tumor alterations that predict treatment response, ideally leading to optimal treatments. Functional assays that directly evaluate treatment efficacy on the patient’s cells offer an alternative and complementary tool to improve the accuracy of precision oncology. Unfortunately, traditional Petri dish-based assays overlook much tumor complexity, limiting their potential as predictive functional biomarkers. Here, we review past applications of microfluidic systems for precision medicine and discuss the present and potential future role of functional microfluidic assays as treatment predictors.
Mistargeting of aggregation prone mitochondrial proteins activates a nucleus-mediated posttranscriptional quality control pathway in trypanosomes
Authors: Dewar Caroline E. , Oeljeklaus Silke , Mani Jan , Mühlhäuser Wignand W. D. , von Känel Corinne , Zimmermann Johannes , Ochsenreiter Torsten , Warscheid Bettina , Schneider André
Published: June 2022

Mitochondrial protein import in the parasitic protozoanTrypanosoma bruceiis mediated by the atypical outer membrane translocase, ATOM. It consists of seven subunits including ATOM69, the import receptor for hydrophobic proteins. Ablation of ATOM69, but not of any other subunit, triggers a unique quality control pathway resulting in the proteasomal degradation of non-imported mitochondrial proteins. The process requires a protein of unknown function, an E3 ubiquitin ligase and the ubiquitin-like protein (TbUbL1), which all are recruited to the mitochondrion upon ATOM69 depletion. TbUbL1 is a nuclear protein, a fraction of which is released to the cytosol upon triggering of the pathway. Nuclear release is essential as cytosolic TbUbL1 can bind mislocalised mitochondrial proteins and likely transfers them to the proteasome. Mitochondrial quality control has previously been studied in yeast and metazoans. Finding such a pathway in the highly diverged trypanosomes suggests such pathways are an obligate feature of all eukaryotes.
Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate
Authors: Carrettiero Daniel C. , Almeida Maria C. , Longhini Andrew P. , Rauch Jennifer N. , Han Dasol , Zhang Xuemei , Najafi Saeed , Gestwicki Jason E. , Kosik Kenneth S.
Published: June 2022

The formation of membraneless organelles can be a proteotoxic stress control mechanism that locally condenses a set of components capable of mediating protein degradation decisions. The breadth of mechanisms by which cells respond to stressors and form specific functional types of membraneless organelles, is incompletely understood. We found that Bcl2-associated athanogene 2 (BAG2) marks a distinct phase-separated membraneless organelle, triggered by several forms of stress, particularly hyper-osmotic stress. Distinct from well-known condensates such as stress granules and processing bodies, BAG2-containing granules lack RNA, lack ubiquitin and promote client degradation in a ubiquitin-independent manner via the 20S proteasome. These organelles protect the viability of cells from stress and can traffic to the client protein, in the case of Tau protein, on the microtubule. Components of these ubiquitin-independent degradation organelles include the chaperone HSP-70 and the 20S proteasome activated by members of the PA28 (PMSE) family. BAG2 condensates did not co-localize with LAMP-1 or p62/SQSTM1. When the proteasome is inhibited, BAG2 condensates and the autophagy markers traffic to an aggresome-like structure.
Estimating tumor mutational burden from RNA-sequencing without a matched-normal sample
Authors: Katzir Rotem , Rudberg Noam , Yizhak Keren
Published: June 2022

Detection of somatic mutations using patients sequencing data has many clinical applications, including the identification of cancer driver genes, detection of mutational signatures, and estimation of tumor mutational burden (TMB). We have previously developed a tool for detection of somatic mutations using tumor RNA and a matched-normal DNA. Here, we further extend it to detect somatic mutations from RNA sequencing data without a matched-normal sample. This is accomplished via a machine-learning approach that classifies mutations as either somatic or germline based on various features. When applied to RNA-sequencing of >450 melanoma samples high precision and recall are achieved, and both mutational signatures and driver genes are correctly identified. Finally, we show that RNA-based TMB is significantly associated with patient survival, showing similar or higher significance level as compared to DNA-based TMB. Our pipeline can be utilized in many future applications, analyzing novel and existing datasets where only RNA is available.
Evidence for pressure induced unconventional quantum criticality in the coupled spin ladder antiferromagnet C9H18N2CuBr4
Authors: Hong Tao , Ying Tao , Huang Qing , Dissanayake Sachith E. , Qiu Yiming , Turnbull Mark M. , Podlesnyak Andrey A. , Wu Yan , Cao Huibo , Liu Yaohua , Umehara Izuru , Gouchi Jun , Uwatoko Yoshiya , Matsuda Masaaki , Tennant David A. , Chern Gia-Wei , Schmidt Kai P. , Wessel Stefan
Published: June 2022

Quantum phase transitions in quantum matter occur at zero temperature between distinct ground states by tuning a nonthermal control parameter. Often, they can be accurately described within the Landau theory of phase transitions, similarly to conventional thermal phase transitions. However, this picture can break down under certain circumstances. Here, we present a comprehensive study of the effect of hydrostatic pressure on the magnetic structure and spin dynamics of the spin-1/2 ladder compound C9H18N2CuBr4. Single-crystal heat capacity and neutron diffraction measurements reveal that the Néel-ordered phase breaks down beyond a critical pressure of Pc ∼ 1.0 GPa through a continuous quantum phase transition. Estimates of the critical exponents suggest that this transition may fall outside the traditional Landau paradigm. The inelastic neutron scattering spectra at 1.3 GPa are characterized by two well-separated gapped modes, including one continuum-like and another resolution-limited excitation in distinct scattering channels, which further indicates an exotic quantum-disordered phase above Pc.
The microbiome of cryospheric ecosystems
Authors: Bourquin Massimo , Busi Susheel Bhanu , Fodelianakis Stilianos , Peter Hannes , Washburne Alex , Kohler Tyler J. , Ezzat Leïla , Michoud Grégoire , Wilmes Paul , Battin Tom J.
Published: June 2022

The melting of the cryosphere is among the most conspicuous consequences of climate change, with impacts on microbial life and related biogeochemistry. However, we are missing a systematic understanding of microbiome structure and function across cryospheric ecosystems. Here, we present a global inventory of the microbiome from snow, ice, permafrost soils, and both coastal and freshwater ecosystems under glacier influence. Combining phylogenetic and taxonomic approaches, we find that these cryospheric ecosystems, despite their particularities, share a microbiome with representatives across the bacterial tree of life and apparent signatures of early and constrained radiation. In addition, we use metagenomic analyses to define the genetic repertoire of cryospheric bacteria. Our work provides a reference resource for future studies on climate change microbiology.
Parental inflammatory bowel disease and autism in children
Authors: Sadik Aws , Dardani Christina , Pagoni Panagiota , Havdahl Alexandra , Stergiakouli Evie ,   The iPSYCH Autism Spectrum Disorder Working Group, Grove Jakob , Khandaker Golam M. , Sullivan Sarah A. , Zammit Stan , Jones Hannah J. , Davey Smith George , Dalman Christina , Karlsson Håkan , Gardner Renee M. , Rai Dheeraj
Published: June 2022

Evidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated.
Noninvasive proteomic biomarkers for alcohol-related liver disease
Authors: Niu Lili , Thiele Maja , Geyer Philipp E. , Rasmussen Ditlev Nytoft , Webel Henry Emanuel , Santos Alberto , Gupta Rajat , Meier Florian , Strauss Maximilian , Kjaergaard Maria , Lindvig Katrine , Jacobsen Suganya , Rasmussen Simon , Hansen Torben , Krag Aleksander , Mann Matthias
Published: June 2022

Alcohol-related liver disease (ALD) is a major cause of liver-related death worldwide, yet understanding of the three key pathological features of the disease—fibrosis, inflammation and steatosis—remains incomplete. Here, we present a paired liver–plasma proteomics approach to infer molecular pathophysiology and to explore the diagnostic and prognostic capability of plasma proteomics in 596 individuals (137 controls and 459 individuals with ALD), 360 of whom had biopsy-based histological assessment. We analyzed all plasma samples and 79 liver biopsies using a mass spectrometry (MS)-based proteomics workflow with short gradient times and an enhanced, data-independent acquisition scheme in only 3 weeks of measurement time. In plasma and liver biopsy tissues, metabolic functions were downregulated whereas fibrosis-associated signaling and immune responses were upregulated. Machine learning models identified proteomics biomarker panels that detected significant fibrosis (receiver operating characteristic–area under the curve (ROC–AUC), 0.92, accuracy, 0.82) and mild inflammation (ROC–AUC, 0.87, accuracy, 0.79) more accurately than existing clinical assays (DeLong’s test, P < 0.05). These biomarker panels were found to be accurate in prediction of future liver-related events and all-cause mortality, with a Harrell’s C-index of 0.90 and 0.79, respectively. An independent validation cohort reproduced the diagnostic model performance, laying the foundation for routine MS-based liver disease testing.
Age and sex influence the response in lipid metabolism of dehydrated Wistar rats
Authors: Quirós Cognuck S. , Reis W. L. , Silva M. S. , Zorro S. V. , Almeida-Pereira G. , Debarba L. K. , Elias L. L. K. , Antunes-Rodrigues J.
Published: June 2022

Aging is associated a decrease in thirst sensation, which makes old people more susceptible to dehydration. Dehydration produces energy metabolism alterations. Our objective was to determinate the effect of water deprivation (WD) in the lipid metabolism of old male and female rats. Here we show that in the state of WD, aging and sex alters retroperitoneal white adipose tissue (R-WAT) weight of rats, WD old female rats had more lipolysis products than old male rats, a sexual dimorphism in the hormonal response related with metabolism of the adipose tissue of old rats during WD, the expression of P-para mRNA in R-WAT did not present any alteration in animals submitted to WD, the expression of Aqp7 mRNA in R-WAT is altered by WD, age, and sex. Also, WD stimulated an increase in the plasma concentration of oxytocin and the expression of mRNA of the oxytocin receptors in R-WAT.
Trends and effect of marginalization on diabetes mellitus-related mortality in Mexico from 1990 to 2019
Authors: Gutiérrez-León Eduardo , Escamilla-Santiago Ricardo Antonio , Martínez-Amezcua Pablo , Bilal Usama , Lazo Mariana , Ogaz-González Rafael , López-Cervantes Malaquías
Published: June 2022

Diabetes mellitus (DM) is currently one of the leading causes of mortality worldwide. However, the disease evolves differently across countries. This study intends to characterize the trends and assess the potential effects of marginalization on DM mortality between 1990 and 2019 in Mexico. We analyzed death certificates that listed DM as the underlying cause of death (N = 1,907,173), as well as the extent to which DM mortality changes were associated with marginalization through an age-period-cohort analysis. DM mortality increased in Mexico between 1990 and 2019; the change was faster in the first half and slowed down after 2004. The highest marginalization quintiles drove the changes in DM mortality trends during the study period, with a higher risk of dying in these quintiles as age increased. In recent cohorts, the highest marginalization quintiles doubled the risk of dying from DM as compared to the lowest. Renal complications was the main death driver among persons with DM, with a marked increase between 1999 and 2001. In conclusion, Mexico continues to have a substantially high DM mortality, but its pace slowed over time. Moreover, subnational differences in marginalization can partially explain such a trend.
High-speed optical resolution photoacoustic microscopy with MEMS scanner using a novel and simple distortion correction method
Authors: Shintate Ryo , Ishii Takuro , Ahn Joongho , Kim Jin Young , Kim Chulhong , Saijo Yoshifumi
Published: June 2022

Optical resolution photoacoustic microscopy (OR-PAM) is a remarkable biomedical imaging technique that can selectively visualize microtissues with optical-dependent high resolution. However, traditional OR-PAM using mechanical stages provides slow imaging speed, making it difficult to biologically interpret in vivo tissue. In this study, we developed a high-speed OR-PAM using a recently commercialized MEMS mirror. This system (MEMS-OR-PAM) consists of a 1-axis MEMS mirror and a mechanical stage. Furthermore, this study proposes a novel calibration method that quickly removes the spatial distortion caused by fast MEMS scanning. The proposed calibration method can easily correct distortions caused by both the scan geometry of the MEMS mirror and its nonlinear motion by running an image sequence only once using a ruler target. The combination of MEMS-OR-PAM and distortion correction method was verified using three experiments: (1) leaf skeleton phantom imaging to test the distortion correction efficacy; (2) spatial resolution and depth of field (DOF) measurement for system performance; (3) in-vivo finger capillary imaging to verify their biomedical use. The results showed that the combination could achieve a high-speed (32 s in 2 × 4 mm) and high lateral resolution (~ 6 µm) imaging capability and precisely visualize the circulating structure of the finger capillaries.
Interparticle and Brownian forces controlling particle aggregation and rheology of silicate melts containing platinum-group element particles
Authors: Pereira Luiz , Vasseur Jérémie , Wadsworth Fabian B. , Trixler Frank , Dingwell Donald B.
Published: June 2022

We study the rheology of silicate melts containing platinum-group element (PGE) particles. They exhibit a shear-thinning behaviour, an intense aggregation tendency, and an anomalously high apparent viscosity in the low shear rate limit, even at very low particle volume fraction. Using a compilation of published experimental data, we analyse these effects in three steps. Firstly, we observe that the viscosities of these suspensions are much higher than those of natural silicate crystal-bearing melts for low shear rate regimes. Secondly, we demonstrate that the viscosities at low shear rate limit cannot be estimated by classical rheological models but rather may be understood as the result of particle aggregation, trapping dead fluid, and thereby increasing the effective particle volume fraction. Finally, we scale the critical shear rates for shear-thinning using a Peclet number analysis—invoking a competition between random thermal particle motion and hydrodynamic shearing motion—and, using an empirical extension, we additionally account for the particle–particle interaction energetics. We propose a framework in which the rheology of this family of particle-bearing melts can be predicted, and demonstrate that at low Peclet numbers, PGE-bearing particle aggregation is driven by interparticle forces and Brownian motion.
Plasma metabolites associated with functional and clinical outcomes in heart failure with reduced ejection fraction with and without type 2 diabetes
Authors: Lerman Joseph B. , Giamberardino Stephanie N. , Hernandez Adrian F. , Felker G. Michael , Shah Svati H. , McGarrah Robert W.
Published: June 2022

Heart failure with reduced ejection fraction (HFrEF) is increasingly treated with medications for type 2 diabetes mellitus (T2DM). Whether metabolic derangements in HFrEF and T2DM are associated with differential outcomes remains unclear. Therefore, understanding molecular pathways in HFrEF and T2DM and their effects on clinical endpoints is important. The FIGHT trial randomized 300 individuals with HFrEF and a recent HF hospitalization to liraglutide (a GLP-1 receptor agonist) versus placebo to assess effects on mortality, HF rehospitalization, and 6-month change in NT-ProBNP. Although the trial showed no clinical benefit of liraglutide, the trial population was highly enriched for individuals with T2DM. Sixty metabolites were quantified via mass spectrometry in plasma from 254 FIGHT participants (N = 147 (57.9%) with T2DM). Principal components analysis reduced the high number of correlated metabolites into uncorrelated factors. The association of factor levels with 90-day changes in 6-min walk distance (6MWD) and NT-proBNP, and with time to mortality or HF hospitalization were evaluated. There were no changes in metabolite factors according to treatment assignment. However, in analyses stratified by T2DM status, changes in five plasma metabolite factors correlated with changes in functional outcomes beyond adjustment: factor 2 (branched-chain amino acids [BCAA]) correlated with changes in NT-proBNP (ρ = − 0.291, p = 4 × 10–4) and 6MWD (ρ= 0.265, p = 0.011); factor 1 (medium-chain acylcarnitines;  ρ = 0.220, p = 0.008), factor 4 (long-chain dicarboxylacylcarnitines; ρ = 0.191, p = 0.019), factor 5 (long-chain acylcarnitines; ρ = 0.198, p = 0.017), and factor 8 (urea cycle metabolites; ρ = − 0.239, p = 4 × 10–3), correlated with change in NT-proBNP. Factor 4 was associated with time-to-event (HR = 1.513 [95% CI 1.208–1.896], p = 3 × 10–4) with a trend towards stronger prognostic effect in T2DM (T2DM: p = 1 × 10–3, non-T2DM: p = 0.1). We identified metabolites of BCAA, urea cycle and fatty acid metabolism as biomarkers of HFrEF outcomes, with observed differences in HFrEF patients with T2DM. Such biomarkers might enable future diagnostic or therapeutic interventions in individuals with HFrEF and T2DM.

Trial Registration: Clinicaltrials.gov. Identifier: NCT01800968. First posted: February 28, 2013.
The Minichromosome Maintenance Complex Component 2 (MjMCM2) of Meloidogyne javanica is a potential effector regulating the cell cycle in nematode-induced galls
Authors: Fitoussi Nathalia , de Almeida Engler Janice , Sichov Natalia , Bucki Patricia , Sela Noa , Harel Arye , Belausuv Eduard , Kumar Anil , Brown Miyara Sigal
Published: June 2022

Root-knot nematodes Meloidogyne spp. induce enlarged multinucleate feeding cells—galls—in host plant roots. Although core cell-cycle components in galls follow a conserved track, they can also be usurped and manipulated by nematodes. We identified a candidate effector in Meloidogyne javanica that is directly involved in cell-cycle manipulation—Minichromosome Maintenance Complex Component 2 (MCM2), part of MCM complex licensing factor involved in DNA replication. MjMCM2, which is induced by plant oxilipin 9-HOT, was expressed in nematode esophageal glands, upregulated during parasitic stages, and was localized to plant cell nucleus and plasma membrane. Infected tomato hairy roots overexpressing MjMCM2 showed significantly more galls and egg-mass-producing females than wild-type roots, and feeding cells showed more nuclei. Phylogenetic analysis suggested seven homologues of MjMCM2 with unknown association to parasitism. Sequence mining revealed two RxLR-like motifs followed by SEED domains in all Meloidogyne spp. MCM2 protein sequences. The unique second RxLR-like motif was absent in other Tylenchida species. Molecular homology modeling of MjMCM2 suggested that second RxLR2-like domain is positioned on a surface loop structure, supporting its function in polar interactions. Our findings reveal a first candidate cell-cycle gene effector in M. javanica—MjMCM2—that is likely secreted into plant host to mimic function of endogenous MCM2.
A systematic review: normative reference values of the median nerve cross-sectional area using ultrasonography in healthy individuals
Authors: Ng Audrey Jing Ting , Chandrasekaran Ramya , Prakash Ashutosh , Mogali Sreenivasulu Reddy
Published: June 2022

Median nerve cross-sectional area (CSA) was used for screening and diagnosis of neuropathy, but few studies have suggested reference range. Hence, this systematic review was performed to evaluate a normative values of median nerve CSA at various landmarks of upper limb based on ultrasonography. PubMed and Web of science were used to search relevant articles from 2000 to 2020. Forty-one eligible articles (2504 nerves) were included to access median nerve CSA at different landmarks (mid-arm, elbow, mid-forearm, carpal tunnel (CT) inlet and CT outlet). Data was also stratified based on age, sex, ethnicity, geographical location, and method of measurement. Random effects model was used to calculate pooled weighted mean (95% confidence interval (CI), [upper bound, lower bound]) at mid-arm, elbow, mid-forearm, CT inlet and outlet which found to be 8.81 mm2, CI [8.10, 9.52]; 8.57 mm2 [8.00, 9.14]; 7.07 mm2 [6.41, 7.73]; 8.74 mm2 [8.45, 9.03] and 9.02 mm2 [8.08, 9.95] respectively. Median nerve CSA varies with age, geographical location, and sex at all landmarks. A low (I2 < 25%) to considerable heterogeneity (I2 > 75%) was observed, indicating the variation among the included studies. These findings show that median nerve CSA is varying not only along its course but also in other sub-variables.
Effects of colchicine use on ischemic and hemorrhagic stroke risk in diabetic patients with and without gout
Authors: Yeh Jun-Jun , Kuo I-Ling , Yip Hei-Tung , Hsueh Min-Yuan , Hsu Chung-Y. , Kao Chia-Hung
Published: June 2022

This study aimed to determine the effect of colchicine use on the risk of stroke among patients with diabetes mellitus (DM). We retrospectively enrolled patients with DM between 2000 and 2013 from the Longitudinal Health Insurance Database and divided them into a colchicine cohort (n = 8761) and noncolchicine cohort (n = 8761) by using propensity score matching (PSM). The event of interest was a stroke, including ischemic stroke and hemorrhagic stroke. The incidence of stroke was analyzed using multivariate Cox proportional hazards models between the colchicine cohort and the comparison cohort after adjustment for several confounding factors. The subdistribution hazard model was also performed for examination of the competing risk. The colchicine cohort had a significantly lower incidence of stroke [adjusted hazard ratios (aHR), 95% confidence intervals (95%CI)] (aHR = 0.61, 95%CI = 0.55–0.67), ischemic stroke (aHR = 0.59, 95%CI = 0.53–0.66), and hemorrhagic stroke (aHR = 0.66, 95%CI = 0.53–0.82) compared with the noncolchicine cohort. Drug analysis indicated that patients in the colchicine cohort who received colchicine of cumulative daily defined dose (cDDD) > 14 and duration > 28 days had a lower risk of stroke and ischemic stroke compared with nonusers. The colchicine cohort (cDDD > 150, duration > 360 days) also had a lower risk of stroke, ischemic stroke, and hemorrhagic stroke. The cumulative incidence of stroke, ischemic stroke, and hemorrhagic stroke in the colchicine cohort was significantly lower than that in the noncolchicine cohort (log-rank P < 0.001). However, the subdistribution hazard model reveal the colchicine was not associated with the hemorrhagic stroke in DM patients without gout (aHR = 0.69, 95%CI = 0.47–1.00). Colchicine use with cDDD > 14 and duration > 28 days was associated with lower risk of stroke and ischemic stroke, and colchicine use with cDDD > 150 and duration > 360 days played an auxiliary role in the prevention of stroke, ischemic stroke, and hemorrhagic stroke in patients with DM. The colchicine for the hemorrhagic stroke in DM patients without gout seem to be null effect.
A synergistic bacterial pool decomposes tebuthiuron in soil
Authors: de Lima Edivaldo Wilson , Brunaldi Bruno Pinheiro , Frias Yanca Araujo , de Almeida Moreira Bruno Rafael , da Silva Alves Lucas , Lopes Paulo Renato Matos
Published: June 2022

This study aimed to propose an eco-compatible strategy to mitigate the possible environmental contamination caused by tebuthiuron. Therefore, we screened potential tebuthiuron-degrading microorganisms from conventional (CS) and no-till (NTS) systems producing sugarcane. Then, they were bioprospected for their ability of decomposing the target-molecule at 2.48 mmol g−1 and 4.96 mmol g−1 into CO2 via respirometry. Integrating microbiota from CS and NTS into an advantageously synergistic bacterial pool produced the highest specific-growth rate of CO2 of 89.60 mg day−1, so outstripped the other inoculum. The bacterial CN-NTS framework notably stabilized the sigmoidal Gompertz curve on microbial degradation earliest and enabled the seeds of Lactucasativa to germinate healthiest throughout ecotoxicological bioassay for cross-validation. Our study is preliminary, but timely to provide knowledge of particular relevance to progress in the field's prominence in remediating terrestrial ecosystems where residual tebuthiuron can persist and contaminate. The analytical insights will act as an opening of solutions to develop high-throughput biotechnological strategies for environmental decontamination.
Molecular evidence of the amelioration of toluene induced encephalopathy by human breast milk mesenchymal stem cells
Authors: Hamid Omaima I. Abdel , Domouky Ayat M. , El-fakharany Yara M.
Published: June 2022

Toluene was widely used volatile organic compound that accumulates in tissues with high lipid content. Stem cells have been proposed as an increasingly attractive approach for repair of damaged nervous system, we aimed to evaluate the ability of breast milk mesenchymal stem cells (MSc) to ameliorate toluene-induced encephalopathy. Sixty adult male albino rats were assigned to 3 groups, control, toluene, and toluene/breast milk-MSc. Neurological assessment was evaluated as well as serum levels of glial fibrillary acidic protein (GFAP), tumor necrosis factor-alpha (TNF-α), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), tissue dopamine and oxidative markers. Gene expression of peroxisome Proliferator-Activated Receptor-Gamma (PPAR-ɣ), nuclear factor-kappaB (NF-kB), and interleukin-6 (IL-6) were evaluated. Moreover, histological and immunohistochemical investigation were done. Results revealed that toluene caused cerebral injury, as evidenced by a significant increase in serum GFAP, TNF-α, malondialdehyde (MDA) and nitric oxide (NO), a significant decrease in serum NGF, tissue dopamine and oxidative markers, besides, a non-significant change in VEGF. Toluene also caused changes in normal cerebral structure and cellular degeneration, including a significant decrease in the total number of neurons and thickness of frontal cortex. Meninges showing signs of inflammation with inflammatory cell infiltration and exudation, a significant decrease in MBP immunoreactivity, and increase in the percent of high motility group box protein-1 (HMGB1) positive cells. PPAR- ɣ, NF-kB, and IL-6 gene expression were all considerably elevated by toluene. These changes were greatly improved by breast milk MSc. Therefore, we conclude that breast milk MSc can attenuate toluene-induced encephalopathy.
Pyroptosis is related to immune infiltration and predictive for survival of colon adenocarcinoma patients
Authors: Lu Huiwen , Sun Yimeng , Zhu Zirui , Yao Junqiao , Xu Huimian , Huang Rui , Huang Baojun
Published: June 2022

Pyroptosis is a novel type of programmed cell death, initiated by inflammasome. Pyroptosis inhibits the development and metastasis of colon cancer and is associated with patients’ prognosis. However, how the pyroptosis-related genes predict the survival of patients is still unclear. In the study, colon adenocarcinoma (COAD) patients were divided into two groups according to the expression of pyroptosis-related regulators through consensus clustering. DEGs between two clusters were analyzed by using COX and Lasso regression. Then, regression coefficients in Lasso were used to calculate the risk score for every patient. Patients were classified into two types: low- and high-risk group according to their risk score. The difference of immune microenvironment infiltration and clinicopathological characteristics between subgroups was performed. Moreover, the nomogram model was built on the bases of risk model and clinicopathological factors. The TCGA-COAD cohort and GEO cohort were used as training and validating set respectively. 398 COAD patients in TCGA training set were identified as two regulation patterns via unsupervised clustering method. Patients in cluster 2 showed better prognosis (P = 0.002). Through differentiated expression analysis, COX and Lasso regression, a 5-gene prognostic risk model was constructed. This risk model was significantly associated with OS (HR: 2.088, 95% CI: 1.183–3.688, P = 0.011), validated in GEO set (HR:1.344, 95%CI: 1.061–1.704, P = 0.014), and patients with low risk had better prognosis (P < 0.001 in TCGA; P = 0.038 in GEO). Through ROC analysis, it can be found that this model presented better predictive accuracy for long-term survival. Clinical analyses demonstrated that high-risk group had more advanced N stage, higher risk of metastasis and later pathological stage. Immune-related analysis illustrated that low-risk group had more immune cell infiltration and more activated immune pathways. The pyroptosis-related risk model can be predictive for the survival of COAD patients. That patients with higher risk had poorer prognosis was associated with more advanced tumor stage and higher risk of metastasis, and resulted from highly activated pro-tumor pathways and inhibited immune system and poorer integrity of intestinal epithelial. This study proved the relationship between pyroptosis and immune, which offered basis for future studies.
Prevalence of SARS-CoV-2 antibodies and risk factors in the pandemic epicentre of Catalonia
Authors: Moreno Sandra , Miró Queralt , Soler Ainhoa , Gallego Mireia , Homs Maria , Garcia Maria José
Published: June 2022

To define the seroprevalence of antibodies against SARS-CoV-2 in the municipality of Vilanova del Camí (in the region of Conca d'Ódena, Barcelona, Spain) and to know the risk factors associated with positive seroprevalence. Cross-sectional descriptive study. The population of Vilanova del Camí had the opportunity to voluntarily attend two screenings (October and December 2020) for antibodies against the nucleocapsid protein of SARS-CoV-2 using a Rapid Diagnostic Test (RDT) (Salocor (Salofa Oy). Participants in the screening signed an informed consent form. From the 3,610 attendees at the screening, 2,170 patients were randomly selected. The relationship between antibody test results and other demographic (sex, age, morbidity index) and clinical (diagnoses, smoking and drugs) variables was analysed. The prevalence of antibodies against SARS-CoV-2 was 9.6% (95% CI of 8.4% to 10.9%) and was similar for men and women but increased with age. Among complex chronic patients, 14.3% had antibodies against SARS-CoV-2, and among patients with advanced chronic disease, 25% had antibodies against SARS-CoV-2. Age, AMG (Adjusted Morbidity Groups) index, COVID-19 diagnosis and contact with a COVID-19 case were risk factors for positive seroprevalence. A higher seroprevalence was detected in the October screening (12.16%) than in the December screening (8.38%). In the December screening, obesity was a risk factor for positive seroprevalence. This study demonstrates the high seroprevalence of antibodies against SARS-CoV-2 in the pandemic epicentre of Catalonia.