bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel Fabry–Pérot (FP) antenna with high gain, low radar-cross-section (RCS), and wideband circular polarization
Authors: Chen Qiang , He Changhui , Zhang Di , Hong Liang , Huang Siyu , Hu Jiabei , Cui Zhulin
Published: July 2021

We propose a novel Fabry–Pérot (FP) antenna consisting of a checkered polarization-conversion metasurface (PCM), corner-cut square patch antennas, and sandwiched compounds. The proposed antenna achieves low radar-cross-section (RCS), high gain, and wideband circular polarization (CP). The corner-cut square patch antennas facilitate high reflectivity, satisfactory transmission magnitude, and the desired phase difference. An embedded metal between two rings of substrate contributes to reducing cross-polarization, improving transmission efficiency, enhancing bandwidth, and reducing RCS. Following simulations, we fabricated a prototype of the proposed antenna and tested its performance. Measurements from the simulation and prototype tests were similar within a reasonable margin of error. Compared with alternative antennas, our proposed FP antenna offers high gain, wideband CP, low cost, a low RCS, and a lower profile.
Genome-wide association study of stimulant dependence
Authors: Cox Jiayi , Sherva Richard , Wetherill Leah , Foroud Tatiana , Edenberg Howard J. , Kranzler Henry R. , Gelernter Joel , Farrer Lindsay A.
Published: July 2021

Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls). An independent cohort from the family-based Collaborative Study on the Genetics of Alcoholism (532 EA cases, 7635 EA controls; 53 AA cases, AA 3352 controls) was used for replication. One variant in SLC25A16 (rs2394476, p = 3.42 × 10−10, odds ratio [OR] = 3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p = 2.99 × 10−7, OR = 2.31) which encodes one of the potassium voltage-gated channel protein that has been linked to several other substance use disorders, and CPVL in the combined population groups (rs1176440, p = 3.05 × 10−7, OR = 1.35), whose expression was previously shown to be upregulated in the prefrontal cortex from users of cocaine, cannabis, and phencyclidine. Analysis of the top GWAS signals revealed a significant enrichment with nicotinic acetylcholine receptor genes (adjusted p = 0.04) and significant pleiotropy between stimulant dependence and alcohol dependence in EAs (padj = 3.6 × 10−3), an anxiety disorder in EAs (padj = 2.1 × 10−4), and ADHD in both AAs (padj = 3.0 × 10−33) and EAs (padj = 6.7 × 10−35). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.
Shared genetic architecture between neuroticism, coronary artery disease and cardiovascular risk factors
Authors: Torgersen Kristin , Bahrami Shahram , Frei Oleksandr , Shadrin Alexey , Connell Kevin S. O’ , Smeland Olav B. , Munkhaugen John , Djurovic Srdjan , Dammen Toril , Andreassen Ole A.
Published: July 2021

Neuroticism is associated with poor health, cardiovascular disease (CVD) risk factors and coronary artery disease (CAD). The conditional/conjunctional false discovery rate method (cond/conjFDR) was applied to genome wide association study (GWAS) summary statistics on neuroticism (n = 432,109), CAD (n = 184,305) and 12 CVD risk factors (n = 188,577–339,224) to investigate genetic overlap between neuroticism and CAD and CVD risk factors. CondFDR analyses identified 729 genomic loci associated with neuroticism after conditioning on CAD and CVD risk factors. The conjFDR analyses revealed 345 loci jointly associated with neuroticism and CAD (n = 30), body mass index (BMI) (n = 96) or another CVD risk factor (n = 1–60). Several loci were jointly associated with neuroticism and multiple CVD risk factors. Seventeen of the shared loci with CAD and 61 of the shared loci with BMI are novel for neuroticism. 21 of 30 (70%) neuroticism risk alleles were associated with higher CAD risk. Functional analyses of the genes mapped to the shared loci implicated cell division, nuclear receptor, elastic fiber formation as well as starch and sucrose metabolism pathways. Our results indicate polygenic overlap between neuroticism and CAD and CVD risk factors, suggesting that genetic factors may partly cause the comorbidity. This gives new insight into the shared molecular genetic basis of these conditions.
Brain glutamate concentration in men with early psychosis: a magnetic resonance spectroscopy case–control study at 7 T
Authors: Godlewska Beata R. , Minichino Amedeo , Emir Uzay , Angelescu Ilinca , Lennox Belinda , Micunovic Masa , Howes Oliver , Cowen Philip J.
Published: July 2021

Abnormalities in glutamate neurotransmission are linked to psychotic symptoms and cognitive dysfunction in schizophrenia. magnetic resonance spectroscopy (MRS) provides an acceptable means of measuring glutamate in the human brain but findings from patient studies at conventional magnetic field strength show considerable heterogeneity. Ultra-high-field MRS offers greater precision in glutamate measurement, particularly in delineation of glutamate from its precursor and metabolite, glutamine. This study aimed to use high-field (7 T) MRS to measure concentrations of glutamate and glutamine in three brain regions, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and putamen (PUT), in young men with early psychosis. MRS was performed in 17 male participants with early psychosis and 18 healthy age-matched controls. Neurometabolite levels were calculated with unsuppressed water signal as the reference and corrected for individual grey matter, white matter and cerebrospinal fluid concentration. Cognitive function was measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Compared to controls, patients with early psychosis had lower concentrations of glutamate and glutamine in ACC. No differences were apparent in the DLPFC and PUT. In patients with early psychosis, there was a highly significant correlation between glutamate concentration in ACC and performance on the BACS, though the numbers available for this analysis were small. Our finding of lower glutamate levels in ACC in patients with schizophrenia is consistent with a recent meta-analysis of 7 T studies and suggests that this abnormality is present in both patients with early psychosis and those with longer-established illness. The possible link between ACC glutamate and cognitive performance requires replication in larger studies.
Toll-like receptor 4 methylation grade is linked to depressive symptom severity
Authors: Rasmusson Annica J. , Gallwitz Maike , Soltanabadi Bardia , Ciuculete Diana M. , Mengel-From Jonas , Christensen Kaare , Nygaard Marianne , Soerensen Mette , Boström Adrian E. , Fredriksson Robert , Freyhult Eva , Mwinyi Jessica , Czamara Darina , Binder Elisabeth B. , Schiöth Helgi B. , Cunningham Janet L.
Published: July 2021

This study explores potential associations between the methylation of promoter-associated CpG sites of the toll-like receptor (TLR)-family, plasma levels of pro-inflammatory proteins and depressive symptoms in young female psychiatric patients. Ratings of depressive symptoms and blood samples were obtained from 92 young women seeking psychiatric care. Methylation of 32 promoter-associated CpG sites in TLR1 to TLR10 was analysed using the Illumina Infinium Methylation EPIC BeadChip. Expression levels of 91 inflammatory proteins were determined by proximity extension assay. Statistical correlations between depressive state, TLR1-10 methylation and inflammatory proteins were investigated. Four additional cohorts were studied to evaluate the generalizability of the findings. In the discovery cohort, methylation grade of cg05429895 (TLR4) in blood was inversely correlated with depressive symptoms score in young adults. After correction for multiple testing, plasma levels of macrophage inflammatory protein 1β (MIP-1β/CCL4) were associated with both TLR4 methylation and depressive symptom severity. A similar inverse association between TLR4 methylation in blood and affective symptoms score was also found in a cohort of 148 both males and females (<40 years of age) from the Danish Twin Registry. These findings were not, however, replicated in three other external cohorts; which differed from the first two cohorts by a higher age and mixed ethnicities, thus limiting the generalizability of our findings. However, TLR4 methylation inversely correlated with TLR4 mRNA expression in the Danish Twin Study indicating a functional significance of methylation at this particular CpG. Higher depression scores in young Scandinavian adults was associated with decreased methylation of TLR4 in blood.
Socio-economic position as a moderator of cardiometabolic outcomes in patients receiving psychotropic treatment associated with weight gain: results from a prospective 12-month inception cohort study and a large population-based cohort
Authors: Dubath Céline , Gholam-Rezaee Mehdi , Sjaarda Jennifer , Levier Axel , Saigi-Morgui Nuria , Delacrétaz Aurélie , Glatard Anaïs , Panczak Radoslaw , Correll Christoph U. , Solida Alessandra , Plessen Kerstin Jessica , von Gunten Armin , Kutalik Zoltan , Conus Philippe , Eap Chin B.
Published: July 2021

Weight gain and metabolic complications are major adverse effects of many psychotropic drugs. We aimed to understand how socio-economic status (SES), defined as the Swiss socio-economic position (SSEP), is associated with cardiometabolic parameters after initiation of psychotropic medications known to induce weight gain. Cardiometabolic parameters were collected in two Swiss cohorts following the prescription of psychotropic medications. The SSEP integrated neighborhood-based income, education, occupation, and housing condition. The results were then validated in an independent replication sample (UKBiobank), using educational attainment (EA) as a proxy for SES. Adult patients with a low SSEP had a higher risk of developing metabolic syndrome over one year versus patients with a high SSEP (Hazard ratio (95% CI) = 3.1 (1.5–6.5), n = 366). During the first 6 months of follow-up, a significant negative association between SSEP and body mass index (BMI), weight change, and waist circumference change was observed (25 ≤ age < 65, n = 526), which was particularly important in adults receiving medications with the highest risk of weight gain, with a BMI difference of 0.86 kg/m2 between patients with low versus high SSEP (95% CI: 0.03–1.70, n = 99). Eventually, a causal effect of EA on BMI was revealed using Mendelian randomization in the UKBiobank, which was notably strong in high-risk medication users (beta: −0.47 SD EA per 1 SD BMI; 95% CI: −0.46 to −0.27, n = 11,314). An additional aspect of personalized medicine was highlighted, suggesting the patients’ SES represents a significant risk factor. Particular attention should be paid to patients with low SES when initiating high cardiometabolic risk psychotropic medications.
Possible posttraumatic stress disorder in Chinese frontline healthcare workers who survived COVID-19 6 months after the COVID-19 outbreak: prevalence, correlates, and symptoms
Authors: Xiong Li-Juan , Zhong Bao-Liang , Cao Xiong-Jing , Xiong Huang-Guo , Huang Ming , Ding Jing , Li Wen-Tian , Tong Jun , Shen He-Yong , Xia Jia-Hong , Hu Yu
Published: July 2021

Suffering from COVID-19 and witnessing the suffering and deaths of patients with COVID-19 may place frontline healthcare workers (HCWs) at particularly high risk for posttraumatic stress disorder (PTSD); however, few data are available on the clinical characteristics of PTSD among frontline HCWs who survived COVID-19 (“surviving HCWs” hereafter). The present study examined the prevalence, correlates, and clinical symptoms of possible PTSD in surviving HCWs 6 months after the COVID-19 outbreak in China. A total of 291 surviving HCWs and 42 age- and gender-matched COVID-19-free frontline HCWs (control group) were recruited and administered the Chinese Essen Trauma Inventory, which was used to assess the presence of possible PTSD according to DSM-IV-TR criteria. Survivors’ clinical data and characteristics of exposure to COVID-19 were collected via self-report questionnaires. Surviving HCWs had significantly higher rates of possible PTSD than controls (19.9% vs. 4.8%, P = 0.017). Correlates of PTSD in survivors were ICU admission (OR = 8.73, P = 0.003), >10 respiratory symptoms during the most symptomatic period of COVID-19 (OR = 3.08, P = 0.006), the residual symptom of dizziness (OR = 2.43, P = 0.013), the residual symptom of difficult breathing (OR = 2.23, P = 0.027), life in danger due to COVID-19 (OR = 16.59, P = 0.006), and exposure to other traumatic events (OR = 2.94, P = 0.035). Less commonly seen PTSD symptoms in survivors were having nightmares about the event (34.5%), suddenly feeling like they were living through the event suddenly (25.9%), being unable to remember an important part of the event (32.8%), and overalertness (31.0%). Nearly one-fifth of the surviving HCWs had possible PTSD 6 months after the COVID-19 outbreak. Mental health services for this vulnerable population should include periodic screening for PTSD, expanded social support, and, when necessary, psychotherapy and psychopharmacological treatment.
Valproic acid stimulates myogenesis in pluripotent stem cell-derived mesodermal progenitors in a NOTCH-dependent manner
Authors: Breuls Natacha , Giarratana Nefele , Yedigaryan Laura , Garrido Gabriel Miró , Carai Paolo , Heymans Stephane , Ranga Adrian , Deroose Christophe , Sampaolesi Maurilio
Published: July 2021

Muscular dystrophies are debilitating neuromuscular disorders for which no cure exists. As this disorder affects both cardiac and skeletal muscle, patients would benefit from a cellular therapy that can simultaneously regenerate both tissues. The current protocol to derive bipotent mesodermal progenitors which can differentiate into cardiac and skeletal muscle relies on the spontaneous formation of embryoid bodies, thereby hampering further clinical translation. Additionally, as skeletal muscle is the largest organ in the human body, a high myogenic potential is necessary for successful regeneration. Here, we have optimized a protocol to generate chemically defined human induced pluripotent stem cell-derived mesodermal progenitors (cdMiPs). We demonstrate that these cells contribute to myotube formation and differentiate into cardiomyocytes, both in vitro and in vivo. Furthermore, the addition of valproic acid, a clinically approved small molecule, increases the potential of the cdMiPs to contribute to myotube formation that can be prevented by NOTCH signaling inhibitors. Moreover, valproic acid pre-treated cdMiPs injected in dystrophic muscles increase physical strength and ameliorate the functional performances of transplanted mice. Taken together, these results constitute a novel approach to generate mesodermal progenitors with enhanced myogenic potential using clinically approved reagents.
A novel Keap1 inhibitor iKeap1 activates Nrf2 signaling and ameliorates hydrogen peroxide-induced oxidative injury and apoptosis in osteoblasts
Authors: Zheng Yue-huan , Yang Jian-jun , Tang Pei-jun , Zhu Yuan , Chen Zhe , She Chang , Chen Gang , Cao Peng , Xu Xiang-yang
Published: July 2021

An ultra-large structure-based virtual screening has discovered iKeap1 as a direct Keap1 inhibitor that can efficiently activate Nrf2 signaling. We here tested its potential effect against hydrogen peroxide (H2O2)-induced oxidative injury in osteoblasts. In primary murine and human osteoblasts, iKeap1 robustly activated Nrf2 signaling at micromole concentrations. iKeap1 disrupted Keap1-Nrf2 association, causing Nrf2 protein stabilization, cytosol accumulation and nuclear translocation in murine and human osteoblasts. The anti-oxidant response elements (ARE) activity and transcription of Nrf2-ARE-dependent genes (including HO1, NQO1 and GCLC) were increased as well. Significantly, iKeap1 pretreatment largely ameliorated H2O2-induced reactive oxygen species production, lipid peroxidation and DNA damage as well as cell apoptosis and programmed necrosis in osteoblasts. Moreover, dexamethasone- and nicotine-induced oxidative injury and apoptosis were alleviated by iKeap1. Importantly, Nrf2 shRNA or CRISPR/Cas9-induced Nrf2 knockout completely abolished iKeap1-induced osteoblast cytoprotection against H2O2. Conversely, CRISPR/Cas9-induced Keap1 knockout induced Nrf2 cascade activation and mimicked iKeap1-induced cytoprotective actions in murine osteoblasts. iKeap1 was ineffective against H2O2 in the Keap1-knockout murine osteoblasts. Collectively, iKeap1 activated Nrf2 signaling cascade to inhibit H2O2-induced oxidative injury and death of osteoblasts.
m6A modification promotes miR-133a repression during cardiac development and hypertrophy via IGF2BP2
Authors: Qian Benheng , Wang Ping , Zhang Donghong , Wu Lianpin
Published: July 2021

Both N6-methyladenosine (m6A) RNA modification and microRNAs (miRNAs) are common regulatory mechanisms for gene post-transcription by modulating mRNA stability and translation. They also share the same 3′-untranslated regions (UTRs) regions for their target gene. However, little is known about their potential interaction in cell development and biology. Here, we aimed to investigate how m6A regulates the specific miRNA repression during cardiac development and hypertrophy. Our multiple lines of bioinformatic and molecular biological evidence have shown that m6A modification on cardiac miR-133a target sequence promotes miR-133a repressive effect via AGO2-IGF2BP2 (Argonaute 2—Insulin-like growth factor 2 mRNA binding protein 2) complex. Among 139 cardiac miRNAs, only the seed sequence of miR-133a was inversely complement to m6A consensus motif “GGACH” by sequence alignment analysis. Immunofluorescence staining, luciferase reporter, and m6A-RIP (RNA immunoprecipitation) assays revealed that m6A modification facilitated miR-133a binding to and repressing their targets. The inhibition of the miR-133a on cardiac proliferation and hypertrophy could be prevented by silencing of Fto (FTO alpha-ketoglutarate dependent dioxygenase) which induced m6A modification. IGF2BP2, an m6A binding protein, physically interacted with AGO2 and increased more miR-133a accumulation on its target site, which was modified by m6A. In conclusion, our study revealed a novel and precise regulatory mechanism that the m6A modification promoted the repression of specific miRNA during heart development and hypertrophy. Targeting m6A modification might provide a strategy to repair hypertrophic gene expression induced by miR-133a.
4D polycarbonates via stereolithography as scaffolds for soft tissue repair
Authors: Weems Andrew C. , Arno Maria C. , Yu Wei , Huckstepp Robert T. R. , Dove Andrew P.
Published: July 2021

3D printing has emerged as one of the most promising tools to overcome the processing and morphological limitations of traditional tissue engineering scaffold design. However, there is a need for improved minimally invasive, void-filling materials to provide mechanical support, biocompatibility, and surface erosion characteristics to ensure consistent tissue support during the healing process. Herein, soft, elastomeric aliphatic polycarbonate-based materials were designed to undergo photopolymerization into supportive soft tissue engineering scaffolds. The 4D nature of the printed scaffolds is manifested in their shape memory properties, which allows them to fill model soft tissue voids without deforming the surrounding material. In vivo, adipocyte lobules were found to infiltrate the surface-eroding scaffold within 2 months, and neovascularization was observed over the same time. Notably, reduced collagen capsule thickness indicates that these scaffolds are highly promising for adipose tissue engineering and repair.
Velocity bias in intrusive gas-liquid flow measurements
Authors: Hohermuth B. , Kramer M. , Felder S. , Valero D.
Published: July 2021

Gas–liquid flows occur in many natural environments such as breaking waves, river rapids and human-made systems, including nuclear reactors and water treatment or conveyance infrastructure. Such two-phase flows are commonly investigated using phase-detection intrusive probes, yielding velocities that are considered to be directly representative of bubble velocities. Using different state-of-the-art instruments and analysis algorithms, we show that bubble–probe interactions lead to an underestimation of the real bubble velocity due to surface tension. To overcome this velocity bias, a correction method is formulated based on a force balance on the bubble. The proposed methodology allows to assess the bubble–probe interaction bias for various types of gas-liquid flows and to recover the undisturbed real bubble velocity. We show that the velocity bias is strong in laboratory scale investigations and therefore may affect the extrapolation of results to full scale. The correction method increases the accuracy of bubble velocity estimations, thereby enabling a deeper understanding of fundamental gas-liquid flow processes.
Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma
Authors: van Hooren Luuk , Vaccaro Alessandra , Ramachandran Mohanraj , Vazaios Konstantinos , Libard Sylwia , van de Walle Tiarne , Georganaki Maria , Huang Hua , Pietilä Ilkka , Lau Joey , Ulvmar Maria H. , Karlsson Mikael C. I. , Zetterling Maria , Mangsbo Sara M. , Jakola Asgeir S. , Olsson Bontell Thomas , Smits Anja , Essand Magnus , Dimberg Anna
Published: July 2021

Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.
Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity
Authors: Vanderbeke L. , Van Mol P. , Van Herck Y. , De Smet F. , Humblet-Baron S. , Martinod K. , Antoranz A. , Arijs I. , Boeckx B. , Bosisio F. M. , Casaer M. , Dauwe D. , De Wever W. , Dooms C. , Dreesen E. , Emmaneel A. , Filtjens J. , Gouwy M. , Gunst J. , Hermans G. , Jansen S. , Lagrou K. , Liston A. , Lorent N. , Meersseman P. , Mercier T. , Neyts J. , Odent J. , Panovska D. , Penttila P. A. , Pollet E. , Proost P. , Qian J. , Quintelier K. , Raes J. , Rex S. , Saeys Y. , Sprooten J. , Tejpar S. , Testelmans D. , Thevissen K. , Van Buyten T. , Vandenhaute J. , Van Gassen S. , Velásquez Pereira L. C. , Vos R. , Weynand B. , Wilmer A. , Yserbyt J. , Garg A. D. , Matthys P. , Wouters C. , Lambrechts D. , Wauters E. , Wauters J.
Published: July 2021

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.
Purkinje cell axonal swellings enhance action potential fidelity and cerebellar function
Authors: Lang-Ouellette Daneck , Gruver Kim M. , Smith-Dijak Amy , Blot François G. C. , Stewart Chloe A. , de Vanssay de Blavous Pauline , Li Connie H. , Van Eitrem Carter , Rosen Charlotte , Faust Phyllis L. , Schonewille Martijn , Watt Alanna J.
Published: July 2021

Axonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity, yet how morphological changes in an axon impact its function remains poorly understood. Axonal swellings have been found on Purkinje cell axons in the cerebellum both in healthy development and in neurodegenerative diseases, and computational models predicts that axonal swellings impair axonal function. Here we report that in young Purkinje cells, axons with swellings propagated action potentials with higher fidelity than those without, and that axonal swellings form when axonal failures are high. Furthermore, we observed that healthy young adult mice with more axonal swellings learn better on cerebellar-related tasks than mice with fewer swellings. Our findings suggest that axonal swellings underlie a form of axonal plasticity that optimizes the fidelity of action potential propagation in axons, resulting in enhanced learning.
DNA repair glycosylase hNEIL1 triages damaged bases via competing interaction modes
Authors: Liu Menghao , Zhang Jun , Zhu Chenxu , Zhang Xiaoxue , Xiao Weide , Yan Yongchang , Liu Lulu , Zeng Hu , Gao Yi Qin , Yi Chengqi
Published: July 2021

DNA glycosylases must distinguish the sparse damaged sites from the vast expanse of normal DNA bases. However, our understanding of the nature of nucleobase interrogation is still limited. Here, we show that hNEIL1 (human endonuclease VIII-like 1) captures base lesions via two competing states of interaction: an activated state that commits catalysis and base excision repair, and a quarantine state that temporarily separates and protects the flipped base via auto-inhibition. The relative dominance of the two states depends on key residues of hNEIL1 and chemical properties (e.g. aromaticity and hydrophilicity) of flipped bases. Such a DNA repair mechanism allows hNEIL1 to recognize a broad spectrum of DNA damage while keeps potential gratuitous repair in check. We further reveal the molecular basis of hNEIL1 activity regulation mediated by post-transcriptional modifications and provide an example of how exquisite structural dynamics serves for orchestrated enzyme functions.
Chromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver
Authors: Zhang Chi , Macchi Filippo , Magnani Elena , Sadler Kirsten C.
Published: July 2021

We hypothesized that the highly controlled pattern of gene expression that is essential for liver regeneration is encoded by an epigenetic code set in quiescent hepatocytes. Here we report that epigenetic and transcriptomic profiling of quiescent and regenerating mouse livers define chromatin states that dictate gene expression and transposon repression. We integrate ATACseq and DNA methylation profiling with ChIPseq for the histone marks H3K4me3, H3K27me3 and H3K9me3 and the histone variant H2AZ to identify 6 chromatin states with distinct functional characteristics. We show that genes involved in proliferation reside in active states, but are marked with H3K27me3 and silenced in quiescent livers. We find that during regeneration, H3K27me3 is depleted from their promoters, facilitating their dynamic expression. These findings demonstrate that hepatic chromatin states in quiescent livers predict gene expression and that pro-regenerative genes are maintained in active chromatin states, but are restrained by H3K27me3, permitting a rapid and synchronized response during regeneration.
Neurodevelopment regulators miR-137 and miR-34 family as biomarkers for early and adult onset schizophrenia
Authors: Chen Bao-Yu , Lin Jin-Jia , Lu Ming-Kun , Tan Hung-Pin , Jang Fong-Lin , Lin Sheng-Hsiang
Published: July 2021

Early-onset schizophrenia (EOS) may have stronger familial aggregation and a more severe outcome than adult-onset schizophrenia (AOS). MicroRNA (miRNA) takes on dual roles as a genetic and epigenetic modulator, which may mediate the influence of genetic risk. Neurological soft signs (NSS) are neurological abnormalities that may be intermediate phenotypes or endophenotypes for schizophrenia. Our previous study found poorer performance on NSS tests from patients with EOS and their unaffected first-degree relatives. Thus, we aimed to identify a set of aberrant neurodevelopmental-related miRNAs that could serve as potential biomarkers for EOS or schizophrenia with NSS. This study included 215 schizophrenia patients (104 EOS and 111 AOS), 72 unaffected first-degree relatives, 31 patients with bipolar disorder, and 100 healthy controls. Differential expression analysis revealed that miR-137, miR-34b, and miR-34c were significantly up-regulated in patients with schizophrenia and their unaffected first-degree relatives compared to healthy controls. Receiver operating characteristic (ROC) analysis showed that the miR-137 expression signature could be used to discriminate between patients with EOS and healthy controls (AUC = 0.911). Additionally, miR-34b had the highest ability to discriminate between EOS and AOS (AUC = 0.810), which may indicate different aetiological pathways to disease onset. Moreover, miR-137 dysregulation was correlated with almost all NSS subscales (i.e., sensory integration, motor sequencing, etc.) and, when EOS patients with NSS, miR-137 expression discriminated these patients from healthy controls to a greater extent (AUC = 0.957). These findings support the potential for neurodevelopmental-related miRNAs to be used as indicators of vulnerability to EOS.
Holocene life and microbiome profiling in ancient tropical Lake Chalco, Mexico
Authors: Moguel Bárbara , Pérez Liseth , Alcaraz Luis D. , Blaz Jazmín , Caballero Margarita , Muñoz-Velasco Israel , Becerra Arturo , Laclette Juan P. , Ortega-Guerrero Beatriz , Romero-Oliva Claudia S. , Herrera-Estrella Luis , Lozano-García Socorro
Published: July 2021

Metagenomic and traditional paleolimnological approaches are suitable to infer past biological and environmental changes, however, they are often applied independently, especially in tropical regions. We combined both approaches to investigate Holocene Prokaryote and Eukaryote diversity and microbial metabolic pathways in ancient Lake Chalco, Mexico. Here, we report on diversity among a large number of lineages (36,722 OTUs) and functional diversity (27,636,243 non-clustered predicted proteins, and 6,144 annotated protein-family genes). The most abundant domain is Bacteria (81%), followed by Archaea (15%) and Eukarya (3%). We also determined the diversity of protein families and their relationship to metabolic pathways. The early Holocene (> 11,000 cal years BP) lake was characterized by cool, freshwater conditions, which later became warmer and hyposaline (11,000–6,000 cal years BP). We found high abundances of cyanobacteria, and fungi groups associated with mature forests in these sediments. Bacteria and Archaea include mainly anaerobes and extremophiles that are involved in the sulfur, nitrogen, and carbon cycles. We found evidence for early human impacts, including landscape modifications and lake eutrophication, which began ~ 6,000 cal years BP. Subsaline, temperate conditions were inferred for the past 5,000 years. Finally, we found nitrogen-fixing bacteria and protein-family genes that are linked to contaminated environments, as well as several fungal pathogens of crops in near-surface sediments.
Experimental infection of Asian house geckos with Enterococcus lacertideformus demonstrates multiple disease transmission routes and the in-vivo efficacy of antibiotics
Authors: Agius Jessica E. , Rose Karrie , Emery Jon-Paul , Phalen David N.
Published: July 2021

The disease caused by Enterococcus lacertideformus is multisystemic and ultimately fatal. Since its emergence, the bacterium has significantly impacted the captive breeding programs of the extinct in the wild Christmas Island Lister’s gecko (Lepidodactylus listeri) and blue-tailed skink (Cryptoblepharus egeriae). The bacterium’s pathogenicity, inability to grow in-vitro, and occurrence beyond the confines of Christmas Island necessitated the development of an experimental infection and treatment model. Asian house geckos (Hemidactylus frenatus) were challenged with a single dose of E. lacertideformus inoculum either by mouth, application to mucosal abrasion or skin laceration, subcutaneous injection, coelomic injection, or via co-housing with an infected gecko. Five healthy geckos acted as controls. Each transmission route resulted in disease in at least 40% (n = 2) geckos, expanding to 100% (n = 5) when E. lacertideformus was applied to skin laceration and mucosal abrasion groups. Incubation periods post-infection ranged between 54 and 102 days. To determine the efficacy of antibiotic treatment, infected geckos were divided into six groups (enrofloxacin 10 mg/kg, per os (PO), every 24 h (q24), amoxicillin-clavulanic acid 10 mg/kg, PO, q24, enrofloxacin 10 mg/kg combined with amoxicillin-clavulanic acid 10 mg/kg, PO, q24, rifampicin 15 mg/kg, PO, q24, clarithromycin 15 mg/kg, PO, q24, and untreated controls) for 21 days. Response to treatment was assessed by the change in lesion size, bacterial dissemination, and histological evidence of a host immune response. Irrespective of the antibiotic given, histology revealed that geckos inoculated by skin laceration were observed to have more extensive disease spread throughout the animal’s body compared to other inoculation routes. The reduction in the average surface area of gross lesions was 83.6% for geckos treated with enrofloxacin, followed by the combination therapy amoxicillin-clavulanic acid and enrofloxacin (62.4%), amoxicillin-clavulanic acid (58.2%), rifampicin (45.5%), and clarithromycin (26.5%). Lesions in geckos untreated with antibiotics increased in size between 100 and 300%. In summary, enrofloxacin and amoxicillin-clavulanic acid show promising properties for the treatment of E. lacertideformus infection in geckos. The Asian house gecko E. lacertideformus infection model therefore provides foundational findings for the development of effective therapeutic treatment protocols aimed at conserving the health of infected and at-risk reptiles.
UV-induced Zn:Cd/S quantum dots in-situ formed in the presence of thiols for sensitive and selective fluorescence detection of thiols
Authors: Assi Navid , Nejdl Lukas , Zemankova Kristyna , Pavelicova Kristyna , Bezdekova Jaroslava , Macka Mirek , Adam Vojtech , Vaculovicova Marketa
Published: July 2021

In this work, we explored a new approach to a simple and sensitive fluorescence detection of thiols. The approach takes advantage of an in-situ formation of UV light-induced fluorescent nanoparticles (ZnCd/S quantum dots), while utilizing the thiol group of the analyte as a capping agent. The selectivity is ensured by the selective isolation of the thiol analyte by a polydopamine molecularly imprinted polymeric (MIP) layer. Based on this approach, a method for determination of thiols was designed. Key experimental parameters were optimized, including those of molecular imprinting and of effective model thiol molecule (l-cysteine) isolation. The relationship between the fluorescence intensity of ZnCd/S quantum dots and the concentration of l-cysteine in the range of 12–150 µg/mL was linear with a detection limit of 3.6 µg/mL. The molecularly imprinted polymer showed high absorption mass capacity (1.73 mg/g) and an excellent selectivity factor for l-cysteine compared to N-acetyl-l-cysteine and l-homocysteine of 63.56 and 87.48, respectively. The proposed method was applied for l-cysteine determination in human urine with satisfactory results. Due to a high variability of molecular imprinting technology and versatility of in-situ probe formation, methods based on this approach can be easily adopted for analysis of any thiol of interest.
Observation of exceptional point in a PT broken non-Hermitian system simulated using a quantum circuit
Authors: Zhang Geng-Li , Liu Di , Yung Man-Hong
Published: July 2021

Exceptional points (EPs), the degeneracy points of non-Hermitian systems, have recently attracted great attention because of their potential of enhancing the sensitivity of quantum sensors. Unlike the usual degeneracies in Hermitian systems, at EPs, both the eigenenergies and eigenvectors coalesce. Although EPs have been widely explored, the range of EPs studied is largely limited by the underlying systems, for instance, higher-order EPs are hard to achieve. Here we propose an extendable method to simulate non-Hermitian systems and study EPs with quantum circuits. The system is inherently parity-time (PT) broken due to the non-symmetric controlling effects of the circuit. Inspired by the quantum Zeno effect, the circuit structure guarantees the success rate of the post-selection. A sample circuit is implemented in a quantum programming framework, and the phase transition at EP is demonstrated. Considering the scalable and flexible nature of quantum circuits, our model is capable of simulating large-scale systems with higher-order EPs.
Understanding protection from SARS-CoV-2 using metabolomics
Authors: Barberis Elettra , Amede Elia , Tavecchia Matteo , Marengo Emilio , Cittone Micol G. , Rizzi Eleonora , Pedrinelli Anita R. , Tonello Stelvio , Minisini Rosalba , Pirisi Mario , Manfredi Marcello , Sainaghi Pier Paolo
Published: July 2021

The COVID-19 pandemic is still raging in most countries. Although the recent mass vaccination campaign has opened a new chapter in the battle against SARS-CoV-2, the world is still far from herd immunity. There is an urgent need to identify healthy people at high risk of contracting COVID-19, as well as supplements and nutraceuticals that can reduce the risk of infection or mitigate symptoms. In the present study, a metabolic phenotype that could protect individuals from SARS-CoV-2 infection or predispose them to developing COVID-19 was investigated. Untargeted metabolomics was performed on serum samples collected from 51 healthcare workers who were in good health at the beginning of the COVID-19 outbreak in Italy, and who were later exposed to the same risk of developing COVID-19. Half of them developed COVID-19 within three weeks of the blood collection. Our results demonstrate the presence of a specific signature associated with protection from SARS-CoV-2. Circulating monolaurin, which has well-known antiviral and antibacterial properties, was higher in protected subjects, suggesting a potential defensive role against SARS-CoV-2 infection; thus, dietary supplements could boost the immune system against this infection. In addition, our data demonstrate that people with higher levels of cholesterol are at higher risk of developing COVID-19. The present study demonstrates that metabolomics can be of great help for developing personalized medicine and for supporting public healthcare strategies. Studies with larger cohorts of subjects are necessary to confirm our findings.
High glucose induces trafficking of prorenin receptor and stimulates profibrotic factors in the collecting duct
Authors: Gogulamudi Venkateswara R. , Arita Danielle Y. , Bourgeois Camille R. T. , Jorgensen Justine , He Jing , Wimley William C. , Satou Ryosuke , Gonzalez Alexis A. , Prieto Minolfa C.
Published: July 2021

Growing evidence indicates that prorenin receptor (PRR) is upregulated in collecting duct (CD) of diabetic kidney. Prorenin is secreted by the principal CD cells, and is the natural ligand of the PRR. PRR activation stimulates fibrotic factors, including fibronectin, collagen, and transforming growth factor-β (TGF-β) contributing to tubular fibrosis. However, whether high glucose (HG) contributes to this effect is unknown. We tested the hypothesis that HG increases the abundance of PRR at the plasma membrane of the CD cells, thus contributing to the stimulation of downstream fibrotic factors, including TGF-β, collagen I, and fibronectin. We used streptozotocin (STZ) male Sprague–Dawley rats to induce hyperglycemia for 7 days. At the end of the study, STZ-induced rats showed increased prorenin, renin, and angiotensin (Ang) II in the renal inner medulla and urine, along with augmented downstream fibrotic factors TGF-β, collagen I, and fibronectin. STZ rats showed upregulation of PRR in the renal medulla and preferential distribution of PRR on the apical aspect of the CD cells. Cultured CD M-1 cells treated with HG (25 mM for 1 h) showed increased PRR in plasma membrane fractions compared to cells treated with normal glucose (5 mM). Increased apical PRR was accompanied by upregulation of TGF-β, collagen I, and fibronectin, while PRR knockdown prevented these effects. Fluorescence resonance energy transfer experiments in M-1 cells demonstrated augmented prorenin activity during HG conditions. The data indicate HG stimulates profibrotic factors by inducing PRR translocation to the plasma membrane in CD cells, which in perspective, might be a novel mechanism underlying the development of tubulointerstitial fibrosis in diabetes mellitus.
Nutritional quality, nutrient uptake and biomass production of Pennisetum purpureum cv. King grass
Authors: Botero-Londoño Julián M. , Celis-Celis Erika M. , Botero-Londoño Mónica A.
Published: July 2021

The research was conducted to determine the effects of cutting interval and fertilization on the nutritional quality, nutrient uptake, and biomass production of King grass. The experimental design was a randomized complete block, using 4 blocks and 8 treatments per block; treatments consisted of 4 ages of cutting (30, 45, 60, and 90 days), with fertilization and without fertilization. The results showed increases of up to 72,000 kg ha−1 year−1of dry matter (DM) when fertilization was implemented. There was a significant reduction in with an increase in the cutting days (12.70–6.53% protein). Fiber increased (48.79–72.99% NDF) when fertilization treatments were included and cutting days increased. The elements that were included in fertilization (N, P, K) showed a higher foliar content and also presented a reduction in foliar content with growth of the plant. Treatments with fertilization showed a nutrient uptake increase for all the elements up to 60 days, where a reduction in uptake capacity was observed. King grass is a plant with a high nutrient uptake capacity and, therefore, with high biomass and nutrient production. This is an advantage since it can be used in multiple applications, such as animal feed, biofuel production, and as a substrate for biodigestion, among others.
The osseointegration and stability of dental implants with different surface treatments in animal models: a network meta-analysis
Authors: Hao Chun-Ping , Cao Nan-Jue , Zhu Yu-He , Wang Wei
Published: July 2021

Dental implants are commonly used to repair missing teeth. The implant surface plays a critical role in promoting osseointegration and implant success. However, little information is available about which implant surface treatment technology best promotes osseointegration and implant stability. The aim of this network meta-analysis was to evaluate the osseointegration and stability of four commonly used dental implants (SLA, SLActive, TiUnite, and Osseotite). The protocol of the current meta-analysis is registered in PROSPERO (International Prospective Register of Systematic Reviews) under the code CRD42020190907 (https://www.crd.york.ac.uk). We conducted a systematic review following PRISMA and Cochrane Recommendations. Medline (PubMed), Cochrane Library, Embase, and the Web of Science databases were searched. Only randomized controlled trials were considered. Twelve studies were included in the current network meta-analysis, eleven studies were included concerning the osseointegration effect and five studies were included for stability analysis (four studies were used to assess both stability and osseointegration). Rank possibility shows that the SLActive surface best promoted bone formation at an early healing stage and TiUnite seemed to be the best surface for overall osseointegration. For stability, TiUnite seemed to be the best surface. The present network meta-analysis showed that the SLActive surface has the potential to promote osseointegration at an early stage. The TiUnite surface had the best effect on osseointegration regarding the overall healing period. The TiUnite surface also had the best effect in stability.
Natural hazard triggered technological risks in the Yangtze River Economic Belt, China
Authors: Gao Yue , Cao Guozhi , Ni Ping , Tang Yue , Liu Yetong , Bi Jun , Ma Zongwei
Published: July 2021

With the continuous occurrence of natural disasters, natural hazard triggered technological accident (Natech) risks also follow. At present, many countries have performed much research on Natech risks. However, there is still a lack of Natech research at the regional or watershed level in China. The Yangtze River Economic Belt (YREB) is not only an industrially intensive development area but also an area with frequent natural disasters. In this study, we selected the YREB as a typical case to study the Natech risk triggered by floods, geological disasters, and typhoons at the regional or watershed level. Four types of risk indicators representing risk sources, natural hazard factors, control levels, and vulnerabilities were developed to assess the spatial patterns of the Natech risks of the YREB. The results show that the Natech risk triggered by floods and typhoons is more serious in eastern area and central area than in western zone and that the Natech risk triggered by geological disasters is more serious in the west part. Approximately 7.85% of the areas are at relatively high-risk and above the Natech risk level based on the comprehensive assessment of three types of Natech risks. The combined population of these areas accounts for approximately 15.67% of the whole YREB, and the combined GDP accounts for approximately 25.41%. It can be predicted that the occurrence of Natech risks in these areas will cause serious harm to both the people and the economy. This work will provide the basis and key management direction for Natech risk management in the YREB.