bluuebunny/crossref_metadata_2025 huggingface dataset:
The C5a/C5aR1 Axis Contributes to the Pathogenesis of Acute Cystitis Through Enhancement of Adhesion and Colonization of Uropathogenic E. coli
Authors: Wu Kun-Yi , Cao Bo , Wang Chun-Xuan , Yang Xue-Ling , Zhao Shu-Juan , Diao Teng-Yue , Lin Li-Rong , Zhao Guo-Xiu , Zhou Wuding , Yang Ju-Rong , Li Ke
Published: March 2022

Our previous work using a murine model of pyelonephritis demonstrated that the C5a/C5aR1 axis plays a pathogenic role in acute kidney infection. In this study, we report that the C5a/C5aR1 axis also plays a pathogenic role in acute bladder infection. C5aR1-deficient mice had reduced bladder bacterial load and attenuated bladder tissue injury, which is associated with reduced expression of terminal α-mannosyl residues (Man) (a potential ligand for type 1 fimbriae of E. coli) at the luminal surface of the bladder epithelium and reduced early bacterial colonization of the bladder. In vitro, C5a stimulation enhanced mannose expression in and facilitated bacterial adhesion/colonization to human bladder epithelial cells. C5a stimulation also upregulated the activation of ERK1/2 and NF-κB signaling and gene expression of proinflammatory cytokines (i.e., Il6, Il1b, Cxcl1, Ccl2) in the epithelial cells, which could drive pro-inflammatory responses leading to tissue injury. Administration of the C5aR1 antagonist effectively reduced bladder bacterial load and tissue injury. Thus, our findings demonstrate a previously unknown pathogenic role for the C5a/C5aR1 axis in bladder infection and suggest that the C5a/C5aR1 axis-mediated upregulation of Man expression, enhancement of bacterial adhesion/colonization, and excessive inflammatory responses contribute to acute bladder infection. These findings improve our understanding of the pathogenesis of bladder infection with therapeutic implications for UTI.
Immunomodulation as a Protective Strategy in Chronic Otitis Media
Authors: Leichtle Anke , Kurabi Arwa , Leffers David , Därr Markus , Draf Clara Sophia , Ryan Allen Frederic , Bruchhage Karl-Ludwig
Published: March 2022

Introduction

Major features of the pathogenesis in otitis media, the most common disease in childhood, include hyperplasia of the middle ear mucosa and infiltration by leukocytes, both of which typically resolve upon bacterial clearanceviaapoptosis. Activation of innate immune receptors during the inflammatory process leads to the activation of intracellular transcription factors (such as NF-κB, AP-1), which regulate both the inflammatory response and tissue growth. We investigated these leading signaling pathways in otitis media using mouse models, human samples, and human middle ear epithelial cell (HMEEC) lines for therapeutic immunomodulation.

Methods

A stable otitis media model in wild-type mice and immunodeficient KO-mice, as well as human tissue samples from chronic otitis media, skin from the external auditory canal and middle ear mucosa removed from patients undergoing ear surgery, were studied. Gene and protein expression of innate immune signaling molecules were evaluated using microarray, qPCR and IHC.In situapoptosis detection determined the apoptotic rate. The influence of bacterial infection on immunomodulating molecules (TNFα, MDP, Tri-DAP, SB203580, Cycloheximide) in HMEEC was evaluated. HMEEC cells were examined after bacterial stimulation/inhibition for gene expression and cellular growth.

Results

Persistent mucosal hyperplasia of the middle ear mucosa in chronic otitis media resulted from gene and protein expression of inflammatory and apoptotic genes, including NODs, TNFα, Casp3 and cleaved Casp3. In clinical chronic middle ear samples, these molecules were modulated after a specific stimulation. They also induced a hyposensitive response after bacterial/NOD-/TLR-pathway double stimulation of HMEEC cellsin vitro. Hence, they might be suitable targets for immunological therapeutic approaches.

Conclusion

Uncontrolled middle ear mucosal hyperplasia is triggered by TLRs/NLRs immunoreceptor activation of downstream inflammatory and apoptotic molecules.
Vimentin Inhibits Dengue Virus Type 2 Invasion of the Blood-Brain Barrier
Authors: Yu Jianhai , Li Xujuan , Zhou Dongrui , Liu Xuling , He Xiaoen , Huang Sheng-He , Wu Qinghua , Zhu Li , Yu Linzhong , Yao Jinxiu , Zhang Bao , Zhao Wei
Published: March 2022

Dengue virus (DENV) causes dengue fever, which is prevalent in the tropical and subtropical regions, and in recent years, has resulted in several major epidemics. Vimentin, a cytoskeletal component involved in DENV infection, is significantly reorganized during infection. However, the mechanism underlying the association between DENV infection and vimentin is still poorly understood. We generated vimentin-knockout (Vim-KO) human brain microvascular endothelial cells (HBMECs) and a Vim-KO SV129 suckling mouse model, combining the dynamic vimentin changes observed in vitro and differences in disease course in vivo, to clarify the role of vimentin in DENV-2 infection. We found that the phosphorylation and solubility of vimentin changed dynamically during DENV-2 infection of HBMECs, suggesting the regulation of vimentin by DENV-2 infection. The similar trends observed in the phosphorylation and solubility of vimentin showed that these characteristics are related. Compared with that in control cells, the DENV-2 viral load was significantly increased in Vim-KO HBMECs, and after DENV-2 infection, Vim-KO SV129 mice displayed more severe disease signs than wild-type SV129 mice, as well as higher viral loads in their serum and brain tissue, demonstrating that vimentin can inhibit DENV-2 infection. Moreover, Vim-KO SV129 mice had more disordered cerebral cortical nerve cells, confirming that Vim-KO mice were more susceptible to DENV-2 infection, which causes severe brain damage. The findings of our study help clarify the mechanism by which vimentin inhibits DENV-2 infection and provides guidance for antiviral treatment strategies for DENV infections.
Coronary Microvascular Angina: A State-of-the-Art Review
Authors: Spione Francesco , Arevalos Victor , Gabani Rami , Sabaté Manel , Brugaletta Salvatore
Published: March 2022

Up to 60–70% of patients, undergoing invasive coronary angiography due to angina and demonstrable myocardial ischemia with provocative tests, do not have any obstructive coronary disease. Coronary microvascular angina due to a dysfunction of the coronary microcirculation is the underlying cause in almost 50% of these patients, associated with a bad prognosis and poor quality of life. In recent years, progress has been made in the diagnosis and management of this condition. The aim of this review is to provide an insight into current knowledge of this condition, from current diagnostic methods to the latest treatments.
Left Bundle Branch Area Pacing in a Giant Atrium With Atrial Standstill: A Case Report and Literature Review
Authors: Zheng Jing , Yang Qingye , Zheng Jiasheng , Chen Qiang , Jin Qizhi
Published: March 2022

Atrial standstill (AS) is a rare condition defined by the lack of atrial electrical and mechanical activities. It is usually clinically manifested as symptomatic bradycardia, which requires permanent pacemaker (PPM) implantation. Traditional right ventricular apical pacing causes electrical and mechanical dyssynchrony resulting in left ventricular dysfunction, heart failure, and arrhythmias. As a novel physiological pacing strategy, left bundle branch area pacing (LBBaP) has demonstrated effectiveness and safety in recent years, but its application in exceptional conditions is rarely reported. We report the case of a 47-year-old female, who was diagnosed with AS complicated with a giant atrium, and successfully received a single-chamber PPM with LBBaP.
Paleoclimate Records of the Middle Okinawa Trough Since the Middle Holocene: Modulation of the Low-Latitude Climate
Authors: Liu Lei , Guan Hongxiang , Xu Lanfang , Sun Zhilei , Wu Nengyou
Published: March 2022

The ubiquity of glycerol dibiphytanyl glycerol tetraethers (GDGTs) and their temperature sensitivity make them one of the most effective tools for paleoclimate reconstruction. High- and low-latitude climates influence the Okinawa Trough (OT). It receives diverse inputs from the East China Sea, the western Pacific, and the Kuroshio Current, providing good conditions for paleoclimate studies. Here, isoprenoid GDGTs (isoGDGTs), branched GDGTs, and hydroxylated GDGTs (OH-GDGTs) were studied to reconstruct the sea surface temperature (SST) of the central OT for the past 8.2 kyr using the tetraether index of 86 carbon atoms at low latitudes (TEXH86) and the ring index of OH-GDGTs (RI-OH). The GDGT-0/crenarchaeol ratios ranged from 0.39 to 0.98. The branched and isoprenoid tetraether index and the methane index values were lower than 0.1 and 0.5, respectively, indicating that the isoGDGTs were mainly derived from marine Thaumarchaeota and that TEXH86 could be used to reconstruct the paleotemperatures. The TEXH86 SSTs ranged from 21.6 to 27.2°C during 8.2 kyr. The overall range of TEXH86 SSTs is close to the UK’37 SST of the middle OT and reflects the mean annual SST. In contrast, RI-OH temperatures varied from 17.4 to 26.0°C, showing a lower trend than TEXH86 SSTs. The core top RI-OH temperature is 24.1°C, in line with the mean annual seawater temperature at 40 m (24.2°C) in the study area, which likely reflects the subsurface temperature in this case. The small overall warming trend of TEXH86 SSTs agrees with the increasing intensity of the Kuroshio Current during the last 8.2 kyr, indicating that the SST evolution is governed by the Kuroshio Current that transports heat from the western tropical Pacific. The decreasing temperature differences between TEXH86 and RI-OH and between UK’37 and RI-OH showed increased mixing of the upper water column, which was in good accordance with the increasing low-latitude winter insolation decoupling from the East Asian summer monsoon. The cold event that occurred at 7.4–6.6 kyr was magnified (∼5°C) at the TEXH86 and RI-OH temperatures and possibly caused by tephra’s significant input (∼7.3 kyr).
Mechanism of Organic Matter Accumulation in Black Shales of the Yuertusi Formation in the Tarim Basin: Insights From Paleoenvironmental Variation During the Early Cambrian
Authors: Wang Yangyang , Chen Jianfa , Shen Weibing , Li Min
Published: March 2022

The paleoenvironment during the Early Cambrian is closely related to the accumulation mechanism of organic matter (OM) from the Lower Cambrian black shales. However, paleoenvironment remains a controversial issue. Here, we reported a lot of detailed data of sedimentary stratigraphy and geochemistry of the Lower Cambrian Yuertusi Formation in the Aksu area, Tarim Basin. The Yuertusi Formation from the Yutixi outcrop consists mainly of silicalite at the base, two sets of black shales, and crystalline dolostone. Based on the redox conditions traced by U/Th, V/Cr, Ni/Co, and V/Sc, the hydrothermal activity traced by Ce/Ce*, Cr/Zr, U/Th, Fe/Ti, and (Fe + Mn)/Ti ratios, as well as paleo-productivity traced by Ba, Cu, Rb/Sr, and other parameters, variations were observed in the depositional environments of the Yuertusi Formation: 1) the silicalite at the base was deposited under an euxinic condition and intense hydrothermal activity. Mo-U co-variation analysis revealed that the north margin of Tarim Basin belonged to the unrestricted marine during the Early Cambrian, 2) the lower black shales were deposited under an oxygen-poor condition and weak hydrothermal activity, and 3) the upper black shales were deposited under oxygen-poor, sub-oxic conditions and almost no hydrothermal activity. Although the hydrothermal activity improved paleo-productivity, the TOC values were low on the whole, which may be due to the intense hydrothermal activity that damaged the formation of source rocks. Comprehensive studies showed a gradually oxidizing environment and weakening paleo-productivity during the Yuertusi Formation deposited. The anoxic conditions were conducive to the preservation of OM, and the high-quality source rocks represented by the black shales of the Yuertusi Formation were formed, especially the first set of black shales. However, the enrichment of OM may be affected by the intense hydrothermal activity.
Case Report: A New Peroxisome Proliferator-Activated Receptor Gamma Mutation Causes Familial Partial Lipodystrophy Type 3 in a Chinese Patient
Authors: Chen Xi , Ma Zhiqiang , Chen Peng , Song Xiuli , Li Weihua , Yu Xuefeng , Xie Junhui
Published: March 2022

Purpose

Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disease. Patients typically present with loss of adipose tissue and metabolic complications. Here, we reported a Chinese FPLD3 patient with a novel PPARG gene mutation.

Methods

A 16-year-old female patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequencing was performed by using the extracted DNA. Moreover, we identified FPLD3 patients from previous studies, and according to the protein region affected by the gene mutation. We divided the patients into the DNA-binding domain (DBD) group or the ligand-binding domain (LBD) group, and compared the clinical features between the two groups.

Results

We identified a novel gene mutation affecting the LBD of PPARγ c.929T > C (p.F310S). This mutation leads to the substitution of a phenylalanine by a serine. In our case, subcutaneous fat was significantly diminished in her face, hips and limbs. The patient was also presented with insulin resistance, diabetes mellitus, hypertriglyceridemia, fatty liver, liver dysfunction, albuminuria and diabetic peripheral neuropathy. After literature review, a total of 58 FPLD3 patients were identified and we found no difference in clinical features between the DBD group and LBD group (all P > 0.05).

Conclusions

A Chinese FPLD3 patient with a novel PPARG gene mutation is described. Our case emphasized the importance of physical examination and genetic testing in young patients with severe metabolic syndromes.
Identification of Novel Key Molecular Signatures in the Pathogenesis of Experimental Diabetic Kidney Disease
Authors: Diao Meng , Wu Yimu , Yang Jialu , Liu Caiying , Xu Jinyuan , Jin Hongchao , Wang Juan , Zhang Jieping , Gao Furong , Jin Caixia , Tian Haibin , Xu Jingying , Ou Qingjian , Li Ying , Xu Guotong , Lu Lixia
Published: March 2022

Diabetic kidney disease (DKD) is a long-term major microvascular complication of uncontrolled hyperglycemia and one of the leading causes of end-stage renal disease (ESDR). The pathogenesis of DKD has not been fully elucidated, and effective therapy to completely halt DKD progression to ESDR is lacking. This study aimed to identify critical molecular signatures and develop novel therapeutic targets for DKD. This study enrolled 10 datasets consisting of 93 renal samples from the National Center of Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). Networkanalyst, Enrichr, STRING, and Cytoscape were used to conduct the differentially expressed genes (DEGs) analysis, pathway enrichment analysis, protein-protein interaction (PPI) network construction, and hub gene screening. The shared DEGs of type 1 diabetic kidney disease (T1DKD) and type 2 diabetic kidney disease (T2DKD) datasets were performed to identify the shared vital pathways and hub genes. Strepotozocin-induced Type 1 diabetes mellitus (T1DM) rat model was prepared, followed by hematoxylin & eosin (HE) staining, and Oil Red O staining to observe the lipid-related morphological changes. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was conducted to validate the key DEGs of interest from a meta-analysis in the T1DKD rat. Using meta-analysis, 305 shared DEGs were obtained. Among the top 5 shared DEGs, Tmem43, Mpv17l, and Slco1a1, have not been reported relevant to DKD. Ketone body metabolism ranked in the top 1 in the KEGG enrichment analysis. Coasy, Idi1, Fads2, Acsl3, Oxct1, and Bdh1, as the top 10 down-regulated hub genes, were first identified to be involved in DKD. The qRT-PCR verification results of the novel hub genes were mostly consistent with the meta-analysis. The positive Oil Red O staining showed that the steatosis appeared in tubuloepithelial cells at 6 w after DM onset. Taken together, abnormal ketone body metabolism may be the key factor in the progression of DKD. Targeting metabolic abnormalities of ketone bodies may represent a novel therapeutic strategy for DKD. These identified novel molecular signatures in DKD merit further clinical investigation.
Effect of Incident Angle of Wear-Ring Clearance on Pressure Pulsation and Vibration Performance of Centrifugal Pump
Authors: Jia XiaoQi , Yu Jilin , Li Bo , Zhang Li , Zhu ZuChao
Published: March 2022

A wear-ring is an important part of the centrifugal pump. The leakage flow in the wear-ring clearance and main flow at the impeller inlet form crossed mixed flows perpendicular to each other. Large eddies and shocks are produced at the intersection of the two flows due to great velocity difference and different directions, resulting in flow losses, unsteady flow, and even flow-induced vibration. Consequently, the pump performance, pressure pulsation and vibration, and other characteristics will be greatly affected. In this paper, 5 incident angles between the incident section of the wear-ring clearance and the circumferential direction of impeller inlet, i.e., the original angle (90°), 75°, 60°, 45°, and 30°, were formed with a low-specific-speed centrifugal pump as the study object. Unsteady flow calculation and fluid–structure interaction calculation were performed on centrifugal pumps with different wear-ring clearances; the effect of the incident angle of the wear-ring clearance on the distribution of pressure pulsation and vibration performance of centrifugal pump was analyzed. The results showed that the improved efflux angle of the wear-ring clearance could effectively weaken the impact disturbance of the leakage flow in the wear-ring clearance to the main flow at the inlet. Accordingly, the flow status at the inlet of the centrifugal pump was improved, flow losses were reduced, the efficiency of the centrifugal pump was improved, and the vibration amplitude and vibration energy of the pump were also reduced.
Predicting Source Populations of Vagrants Using Breeding Population Data: A Case Study of the Lesser Black-Backed Gull (Larus fuscus)
Authors: Zawadzki Lucinda C. , Hallgrimsson Gunnar T. , Veit Richard R. , Rasmussen Lars M. , Boertmann David , Gillies Natasha , Guilford Tim
Published: March 2022

Vagrancy is critical in facilitating range expansion and colonization through exploration and occupation of potentially suitable habitat. Uncovering origins of vagrants will help us better understand not only species-specific vagrant movements, but how the dynamics of a naturally growing population influence vagrancy, and potentially lead to range expansion. Under the premise that occurrence of vagrants is linked to increasing population growth in the core of the breeding range, we assessed the utility of breeding population survey data to predict source populations of vagrants. Lesser Black-backed Gulls (LBBG) (Larus fuscus) served as our focal species due to their dramatic and well-documented history of vagrancy to North America in the last 30 years. We related annual occurrence of vagrants to indices of breeding population size and growth rate of breeding populations. We propose that the fastest growing population is the most likely source of recent vagrants to North America. Our study shows that it is possible to predict potential source populations of vagrants with breeding population data, but breeding surveys require increased standardization across years to improve models. For the Lesser Black-backed Gull, Iceland’s breeding population likely influenced vagrancy during the early years of colonization, but the major increase in vagrants occurred during a period of growth of Greenland’s population, suggesting that Greenland is the source population of the most recent pulse of vagrant LBBG to North America.
New Insight on Vitality Differences for the Penaeid Shrimp, Fenneropenaeus chinensis, in Low Salinity Environment Through Transcriptomics
Authors: Liu Jun , Zhang Daizhen , Zhang Lei , Wang Zhengfei , Shen Jie
Published: March 2022

Excessive rainfall changes salinity in shrimp farming ponds in short period and exerts low salinity stress on the outdoor breeding shrimp under global warming. Fenneropenaeus chinensis can have different performance on vitality in low salinity environments. To reveal mechanisms of vitality difference in shrimp living in low saline environments. This study based on the normal and moribund F. chinensis in 10 ppt salinity environment using high-throughput sequencing identifies 1,429 differentially expressed genes (DEGs), 586 of which are upregulated, while 843 of which are downregulated in the normal group (FCN10) as compared to the moribund group (FCM10). Meanwhile, another transcriptomic analysis is conducted on the normal and moribund shrimp from 25 ppt (FCN25 vs. FCM25) salinity environment as the control, in which 1,311 DEGs (upregulated: 327 genes, downregulated: 984 genes) are identified. In this study, intersective pathways, GO (Gene Ontology) categories and DEGs from the two groups of comparative transcriptome are investigated. The two intersective pathways (Metabolism of xenobiotics by cytochrome P450, Pentose, and glucuronate interconversions) significantly enriched by DEGs are related to detoxification. In these two pathways, there is one vitality regulation-related gene (VRRG), the Dhdh (dihydrodiol dehydrogenase), which is upregulated in both the groups of FCN10 and FCN25 as compared to the groups of FCM10 and FCM25, respectively. Similarly, in the 25 top intersective GO categories, four VRRGs are revealed. Three of them are upregulated (Itgbl, kielin/chordin-like protein, Slc2a8, solute carrier family 2, facilitated glucose transporter member 8-like protein and Cyp3a30, cytochrome P450 3A30-like protein); one of them is downregulated (Slc6a9, sodium-dependent nutrient amino acid transporter 1-like protein isoform X2). These GO categories are related to transmembrane transporter activity of substance, enzyme inhibitor activity, monooxygenase activity. RT-qPCR analysis further verifies the VRRGs. The study gives new insight into understanding the vitality differences for F. chinensis, in low salinity environment. The pathways and DEGs in response to low salinity stress in modulating the vitality of F. chinensis that could serve as tools in future genetic studies and molecular breeding.
Determinants of Fire Impact in the Brazilian Biomes
Authors: Oliveira Ubirajara , Soares-Filho Britaldo , Bustamante Mercedes , Gomes Leticia , Ometto Jean P. , Rajão Raoni
Published: March 2022

More and more, wildfires are raging in large parts of the world due to a warmer climate, more frequent and severe droughts, and continued land-use changes. In Brazil, the weakening of public environmental policies has further aggravated wildfires with widespread impacts across the country. Here, we investigated the determinants of the impact of fire in the Brazilian biomes using a dataset of burned areas between 2001 and 2019 to simulate its future impact under alternative policy and climate scenarios. We began by deriving a fire impact index using a principal component (PC) analysis comprising the variables: 1. fire intensity, 2. fire recurrence, 3. burned area size, 4. mean time interval between successive fires, and 5. predominance of fires in the dry season. We considered as High Impact Fires (HIF) those areas whose values of the first PC were above the 90th percentile. HIF occurred in the Amazon, Cerrado, and Pantanal, but not in the Atlantic Forest, Pampa, and Caatinga biomes. As the main drivers of HIF, our spatial autoregressive models (SAR) (Amazônia R2 = 0.66, Pantanal R2 = 0.86 and Cerrado R2 = 0.79) indicated the climate (Amazon, 25%, Pantanal, 53%, and Cerrado, 56%) together with land-use change (Amazon, 75%, Pantanal, 25%, and Cerrado, 38%). Most HIF occurred in native vegetation remnants (NVR) (55% in the Amazon, 86% in the Pantanal and 94% in the Cerrado), especially in places close to areas deforested over the last two decades. Only in Pantanal fuel loads (dry biomass) play a major role in HIF (22% of explanation). In the Cerrado, it only accounted for 4% of the observed variability and in the Amazon, it was not a significant factor. Over the analyzed period, HIF imposed a loss of 23%, on average, on the NDVI response of the native vegetation in the Amazon, 19% in the Cerrado and 16% in the Pantanal, thus indicating physiological stress. Simulations of future climate and land-use change pointed to a dramatic increase in HIF by 2050. Under the RCP4.5 and strong environmental governance scenario, HIF in the Cerrado would expand from the current 3% of the biome to 15%, from 7 to 8% in the Pantanal and from 0.7 to 1.2% in the Amazon. In addition, the impact of fire would intensify in 95% of the Cerrado, 97% of the Amazon and 74% of the Pantanal. Effective public and private policies will be vital to mitigate the growing threat of HIF. In this sense, our spatially explicit models can help direct prevention and firefighting programs.
Mouse Paternal RNAs Initiate a Pattern of Metabolic Disorders in a Line-Dependent Manner
Authors: Satir-Basaran Guzide , Kianmehr Leila , Mehmetbeyoglu Ecmel , Korkmaz Bayram Kezban , Memis Mehmet , Yilmaz Zeynep , Tufan Esra , Taheri Serpil , Kelestimur Fahrettin , Rassoulzadegan Minoo
Published: March 2022

A wide range of diseases result from environmental effects, and the levels of many native transcripts are altered. The alteration of non-coding RNAs (ncRNAs) and transmission of the variation to the next generation is increasingly recognized as a marker of disease. However, the determining signals and mechanisms of RNA-induced heritability remain unclear. We performed functional tests with four different genotypes of mice maintained on a high-fat diet to trace the transfer of the obesity/diabetes phenotype to the next generation in order to detect common signals. Two founders of four mouse lines (B6/D2 hybrid and Dnmt2−/−C57BL/6) resist and do not change their phenotype while their sperm RNAs after microinjection into fertilized mouse eggs transfer the newly acquired phenotypes in a susceptible inbred line (C57BL/6 or Balb/c). Unexpectedly, in the same line of experiments, sperm RNA from animals raised on a normal diet when mixed with the sperm RNA from animals raised on a diet high in fat or synthetic miR-19b (inducer of obesity) affects or prevents the development of obesity and diabetes. However, it remains unclear what happens to ncRNA signaling under diet. With a comprehensive new analysis of the transcripts maintained as an RNA/DNA hybrid in sperm, we suggest that a fraction of the RNAs are stably attached to the genome. Thus, we propose that changes in the dynamics of ncRNA retention on DNA by factors such as transcriptional variations or lack of adequate methylation could serve as molecular markers to trace these epigenetics events.
Alterations of Urinary Microbial Metabolites and Immune Indexes Linked With COVID-19 Infection and Prognosis
Authors: Jing Yixian , Wang Jing , Zhang Haiyan , Yang Kun , Li Jungang , Zhao Ting , Liu Jiaxiu , Wu Jing , Chen Yaokai
Published: March 2022

Coronavirus disease 2019 (COVID-19) has evolved into an established global pandemic. Metabolomic studies in COVID-19 patients is worth exploring for further available screening methods. In our study, we recruited a study cohort of 350 subjects comprising 248 COVID-19 patients (161 non-severe cases, 60 asymptomatic cases, and 27 severe cases) and 102 healthy controls (HCs), and herein present data with respect to their demographic features, urinary metabolome, immunological indices, and follow-up health status. We found that COVID-19 resulted in alterations of 39 urinary, mainly microbial, metabolites. Using random forest analysis, a simplified marker panel including three microbial metabolites (oxoglutaric acid, indoxyl, and phenylacetamide) was constructed (AUC=0.963, 95% CI, 0.930-0.983), which exhibited higher diagnostic performance than immune feature-based panels between COVID-19 and HC groups (P<0.0001). Meanwhile, we observed that urine metabolic markers enabled discriminating asymptomatic patients (ASY) from HCs (AUC = 0.981, 95% CI, 0.946-0.996), and predicting the incidence of high-risk sequalae in COVID-19 individuals (AUC=0.931, 95% CI, 0.877-0.966). Co-expression network analysis showed that 13 urinary microbial metabolites (e.g., oxoglutaric acid) were significantly correlated with alterations of CD4+, CD3+, and CD8+ T-cells, as well as IFN-γ, IL-2 and IL-4 levels, suggesting close interactions between microbial metabolites and host immune dysregulation in COVID-19. Taken together, our findings indicate that urinary metabolites may have promising potential for screening of COVID-19 in different application scenarios, and provide a new entry point to understand the microbial metabolites and related immune dysfunction in COVID-19.
IL-33/ST2 Axis Protects Against Traumatic Brain Injury Through Enhancing the Function of Regulatory T Cells
Authors: Xie Di , Miao Wanying , Xu Fei , Yuan Chunling , Li Sicheng , Wang Chujun , Junagade Aditi , Hu Xiaoming
Published: March 2022

Traumatic brain injury (TBI) is a devastating condition due to its long-term sequelae on neurological functions. Inflammatory responses after TBI are critical for injury expansion and repair. Recent research in central nervous system (CNS) disorders reveals the importance of IL-33 and its receptor (ST2) as an alarmin system to initiate immune responses. This study explored the role of IL-33/ST2 signaling in TBI. TBI was induced in adult male C57BL/6J mice using a controlled cortical impact (CCI) model. We found that the expression of IL-33 increased in the injured brain and blood, and ST2 was elevated in the circulating and infiltrating regulatory T cells (Tregs) early after TBI. ST2 deficient mice exhibited reduced Treg numbers in the blood and brain 5 days after TBI. The brain lesion size was enlarged in ST2 knockout mice, which was accompanied by deteriorated sensorimotor function 5 days after TBI. In contrast, post-TBI treatment with IL-33 (2 μg/30 g body weight, intranasal) for 3 days significantly reduced brain lesion size and improved neurological functions 5 days after TBI. Meanwhile, IL-33 treatment increased ST2 expression in circulating and brain infiltrating Tregs. To further explore the involvement of Tregs in IL-33/ST2-mediated neuroprotection, Tregs were depleted by CD25 antibody injection. The absence of Tregs significantly reduced the protective effect of IL-33 after TBI. In vitro study confirmed that IL-33 (50 ng/ml) increased the production of IL-10 and TGFβ from activated Tregs and boosted the inhibitory effect of Tregs on T effector cell proliferation. Taken together, this study suggests that the activation of IL-33/ST2 signaling reduces brain lesion size and alleviates functional deficits after TBI at least partially through regulating the Treg response. IL-33 may represent a new immune therapeutic strategy to improve TBI outcomes.
Effect of Direct Bilirubin Level on Clinical Outcome and Prognoses in Severely/Critically Ill Patients With COVID-19
Authors: Chen Wensen , Liu Hanting , Yang Gang , Wang Wei , Liu Qiongfang , Huang Chaolin , Zou Zhuoru , Liu Yun , Zhuang Guihua , Zhang Lei
Published: March 2022

Objectives

We aimed to investigate how changes in direct bilirubin (DBiL) levels in severely/critically ill the coronavirus disease (COVID-19) patients during their first week of hospital admission affect their subsequent prognoses and mortality.

Methods

We retrospectively enrolled 337 severely/critically ill COVID-19 patients with two consecutive blood tests at hospital admission and about 7 days after. Based on the trend of the two consecutive tests, we categorized patients into the normal direct bilirubin (DBiL) group (224), declined DBiL group (44) and elevated DBiL group (79).

Results

The elevated DBiL group had a significantly larger proportion of critically ill patients (χ2-test, p < 0.001), a higher risk of ICU admission, respiratory failure, and shock at hospital admission (χ2-test, all p < 0.001). During hospitalization, the elevated DBiL group had significantly higher risks of shock, acute respiratory distress syndrome (ARDS), and respiratory failure (χ2-test, all p < 0.001). The same findings were observed for heart damage (χ2-test, p = 0.002) and acute renal injury (χ2-test, p = 0.009). Cox regression analysis showed the risk of mortality in the elevated DBiL group was 2.27 (95% CI: 1.50–3.43, p < 0.001) times higher than that in the normal DBiL group after adjusted age, initial symptom, and laboratory markers. The Receiver Operating Characteristic curve (ROC) analysis demonstrated that the second test of DBiL was consistently a better indicator of the occurrence of complications (except shock) and mortality than the first test in severely/critically ill COVID-19 patients. The area under the ROC curve (AUC) combined with two consecutive DBiL levels for respiratory failure and death was the largest.

Conclusion

Elevated DBiL levels are an independent indicator for complication and mortality in COVID-19 patients. Compared with the DBiL levels at admission, DBiL levels on days 7 days of hospitalization are more advantageous in predicting the prognoses of COVID-19 in severely/critically ill patients.
Self-Reported Anxiety and Depression in a Monocentric Cohort of Patients With Systemic Lupus Erythematosus: Analysis of Prevalence, Main Determinants, and Impact on Quality of Life
Authors: Elefante Elena , Tani Chiara , Stagnaro Chiara , Signorini Viola , Lenzi Beatrice , Zucchi Dina , Trentin Francesca , Carli Linda , Ferro Francesco , Mosca Marta
Published: March 2022

Aims of the study

To analyze the prevalence of self-reported anxiety and depression in a monocentric cohort of patients with Systemic Lupus Erythematosus (SLE); to study the main determinants and the impact on quality of life (QoL).

Methods

A cross-sectional observational study including adult outpatients with SLE. Demographic and clinical data were analyzed: indices of disease activity (SELENA-SLEDAI); damage (SLICC-DI); comorbidities and concomitant therapies. The definitions for remission (DORIS) and “Lupus Low Disease Activity State” (LLDAS) were applied. At enrollment, each patient completed the following questionnaires: SF-36, FACIT-Fatigue, Lupus Impact Tracker (LIT), Systemic Lupus Activity Questionnaire (SLAQ), and the Hospital Anxiety and Depression Scale (HADS) in order to self-assess anxiety and depression symptoms. The Student t-test and Chi2 tests were conducted for univariate analysis. The Spearman test was used for linear correlation between continuous data. Multivariate analysis was performed by multiple linear and logistic regression.

Results

One hundred fifty-four consecutive patients with SLE were enrolled, the majority female and Caucasian with a mean age = 43.3 ± 13.7 years. 79.9% were in LLDAS or remission. 36.4% had a SDI > 1. 13.7% of patients had concomitant fibromyalgia. 37.4% had symptoms indicating anxiety and 25% of depression according to the HADS questionnaire. In the multivariate analysis, patients with active disease were significantly more anxious and depressed (p < 0.01) compared to patients in LLDAS or remission. Fibromyalgia and older age were independently associated with anxiety and depression, respectively (p < 0.05). Active skin involvement was significantly linked to depression (p < 0.05). Higher scores on the HADS questionnaire (higher levels of anxiety and depression) were found to be significantly linked to patients’ perception of higher disease activity and worse quality of life, irrespective of disease activity, age and fibromyalgia.

Conclusion

Symptoms of anxiety and depression are frequent in SLE patients, including outpatients with mild/moderate disease. Such symptoms have a significant negative impact on QoL and perception of disease activity, regardless of other factors. Moreover, disease activity, advanced age and fibromyalgia appear to be significantly linked to mood disorders. Assessing symptoms of the anxious-depressive spectrum in patients with SLE could lead to improvement in patients’ perception of health status and quality of life.
From Mating to Milk Access: A Review of Reproductive Vocal Communication in Mice
Authors: Capas-Peneda Sara , Saavedra Torres Yolanda , Prins Jan-Bas , Olsson I. Anna S.
Published: March 2022

Vocalisations play a central role in rodent communication, especially in reproduction related behaviours. In adult mice (Mus musculus) the emission of ultrasonic vocalisations (USVs) has been observed in courtship and mating behaviour, especially by males. These have been found to have distinctive individual signatures that influence female choice of mating partner. The most recent findings show that vocal communication also has a role in parental cooperation, in that female mice communicate with male partners in ultrasonic frequencies to induce paternal behaviour. Infant vocalisations form the other important part of reproductive vocal communication. Although born deaf, neonatal mice are capable of producing vocalisations since birth. As an altricial species, successful mother-infant communication is essential for survival, and these vocalisations are important modulators of maternal behaviour. Three main types of infant vocalisations have been identified and characterised. Most research has addressed pure USVs, related to stressful situations (e.g., cold, isolation, handling, presence of unfamiliar males or predators), which usually elicit maternal search and retrieval. In addition, broad-band spectrum signals, emitted post-partum during cleaning of foetal membranes, inhibit biting and injury by adults and “wriggling calls,” emitted during suckling, release maternal behaviour (such as licking). Several variables have been identified to modulate vocalisations in mice, including individual characteristics such as strain/genotype, age, sex, and experimental factors such as pharmacological compounds and social context. In recent years, there has been a big increase in the knowledge about the characteristics of vocal communication in rodents due to recent technological advances as well as a growing interest from the neuroscience community. Vocalisation analysis has become an essential tool for phenotyping and evaluating emotional states. In this review, we will (i) provide a comprehensive summary of the current knowledge on mouse reproductive vocal communication and (ii) discuss the most recent findings in order to provide a broad overview on this topic.
Heterogeneous CaMKII-Dependent Synaptic Compensations in CA1 Pyramidal Neurons From Acute Hippocampal Slices
Authors: Vergara Pablo , Pino Gabriela , Vera Jorge , Arancibia Felipe , Sanhueza Magdalena
Published: March 2022

Prolonged changes in neural activity trigger homeostatic synaptic plasticity (HSP) allowing neuronal networks to operate within functional ranges. Cell-wide or input-specific adaptations can be induced by pharmacological or genetic manipulations of activity, and by sensory deprivation. Reactive functional changes caused by deafferentation may partially share mechanisms with HSP. Acute hippocampal slices are a suitable model to investigate relatively rapid (hours) modifications occurring after denervation and explore the underlying mechanisms. As during slicing many afferents are cut, we conducted whole-cell recordings of miniature excitatory postsynaptic currents (mEPSCs) in CA1 pyramidal neurons to evaluate changes over the following 12 h. As Schaffer collaterals constitute a major glutamatergic input to these neurons, we also dissected CA3. We observed an average increment in mEPSCs amplitude and a decrease in decay time, suggesting synaptic AMPA receptor upregulation and subunit content modifications. Sorting mEPSC by rise time, a correlate of synapse location along dendrites, revealed amplitude raises at two separate domains. A specific frequency increase was observed in the same domains and was accompanied by a global, unspecific raise. Amplitude and frequency increments were lower at sites initially more active, consistent with local compensatory processes. Transient preincubation with a specific Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor either blocked or occluded amplitude and frequency upregulation in different synapse populations. Results are consistent with the concurrent development of different known CaMKII-dependent HSP processes. Our observations support that deafferentation causes rapid and diverse compensations resembling classical slow forms of adaptation to inactivity. These results may contribute to understand fast-developing homeostatic or pathological events after brain injury.
Predictive Factors for Early-Onset Seizures in Patients With Cerebral Venous Sinus Thrombosis
Authors: Mu Shuwen , Li Jun , Lin Kunzhe , Fang Yi , Lin Feng , Li Ziqi , Xu Yongjun , Wang Shousen
Published: March 2022

Seizures are reported to be important factors contributing to poor prognosis in patients with cerebral venous sinus thrombosis (CVST). However, the predictive factors for concurrent early onset seizures in patients with CVST remain unclear. To identify the predictive factors of early seizures in patients with CVST, this study retrospectively evaluated the clinical data of patients diagnosed with CVST at two centers from January 2011 to December 2020 and analyzed the relationship between admission characteristics and early onset seizures. A total of 112 CVST patients (63 men and 49 women; mean age 39.82 ± 15.70 years) were enrolled in this study, of whom 34 (30.36%) had seizures. For patients with seizures, cerebral hemorrhage, cortical vein thrombosis, anterior superior sagittal sinus (SSS) thrombosis, middle SSS thrombosis, CVST score, modified Rankin Scale, National Institute of Health Stroke Scale (NIHSS) score, neutrophil percentage, and D-dimer level were more severe than those without seizures. Logistic regression analysis showed that cerebral hemorrhage (P = 0.002), anterior SSS thrombosis (P = 0.003), NIHSS score ≥5 (P = 0.003), and D-dimer ≥0.88 mg/L (P = 0.004) were all significant predictive factors of early-onset seizures in CVST patients. Combining the four factors further improved the predictive capability with an area under the curve of 0.871 (95% confidence interval = 0.803–0.939). Further large-scale prospective studies are required to confirm these findings.
Analysis of nAChR Autoantibodies Against Extracellular Epitopes in MG Patients
Authors: Michail Maria , Zouvelou Vasiliki , Belimezi Maria , Haroniti Anna , Zouridakis Marios , Zisimopoulou Paraskevi
Published: March 2022

Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies targeting components of the postsynaptic membrane of the neuromuscular junction (NMJ), leading to neuromuscular transmission deficiency. In the vast majority of patients, these autoantibodies target the nicotinic acetylcholine receptor (nAChR), a heteropentameric ion channel anchored to the postsynaptic membrane of the NMJ. Autoantibodies in patients with MG may target all the subunits of the receptor at both their extracellular and intracellular regions. Here, we combine immunoadsorption with a cell-based assay to examine the specificity of the patients' autoantibodies against the extracellular part of the nAChR. Our results reveal that these autoantibodies can be divided into distinct groups, based on their target, with probably different impacts on disease severity. Although our findings are based on a small sample group of patients, they strongly support that additional analysis of the specificity of the autoantibodies of patients with MG could serve as a valuable tool for the clinicians' decision on the treatment strategy to be followed.
Automated Multiclass Artifact Detection in Diffusion MRI Volumes via 3D Residual Squeeze-and-Excitation Convolutional Neural Networks
Authors: Ettehadi Nabil , Kashyap Pratik , Zhang Xuzhe , Wang Yun , Semanek David , Desai Karan , Guo Jia , Posner Jonathan , Laine Andrew F.
Published: March 2022

Diffusion MRI (dMRI) is widely used to investigate neuronal and structural development of brain. dMRI data is often contaminated with various types of artifacts. Hence, artifact type identification in dMRI volumes is an essential pre-processing step prior to carrying out any further analysis. Manual artifact identification amongst a large pool of dMRI data is a highly labor-intensive task. Previous attempts at automating this process are often limited to a binary classification (“poor” vs. “good” quality) of the dMRI volumes or focus on detecting a single type of artifact (e.g., motion, Eddy currents, etc.). In this work, we propose a deep learning-based automated multiclass artifact classifier for dMRI volumes. Our proposed framework operates in 2 steps. In the first step, the model predicts labels associated with 3D mutually exclusive collectively exhaustive (MECE) sub-volumes or “slabs” extracted from whole dMRI volumes. In the second step, through a voting process, the model outputs the artifact class present in the whole volume under investigation. We used two different datasets for training and evaluating our model. Specifically, we utilized 2,494 poor-quality dMRI volumes from the Adolescent Brain Cognitive Development (ABCD) and 4,226 from the Healthy Brain Network (HBN) dataset. Our results demonstrate accurate multiclass volume-level main artifact type prediction with 96.61 and 97.52% average accuracies on the ABCD and HBN test sets, respectively. Finally, in order to demonstrate the effectiveness of the proposed framework in dMRI pre-processing pipelines, we conducted a proof-of-concept dMRI analysis exploring the relationship between whole-brain fractional anisotropy (FA) and participant age, to test whether the use of our model improves the brain-age association.
Spectrally Matched Near-Threshold Noise for Subjective Tinnitus Loudness Attenuation Based on Stochastic Resonance
Authors: Tziridis Konstantin , Brunner Sarah , Schilling Achim , Krauss Patrick , Schulze Holger
Published: March 2022

Recently, we proposed a model of tinnitus development based on a physiological mechanism of permanent optimization of information transfer from the auditory periphery to the central nervous system by means of neuronal stochastic resonance utilizing neuronal noise to be added to the cochlear input, thereby improving hearing thresholds. In this view, tinnitus is a byproduct of this added neuronal activity. Interestingly, in healthy subjects auditory thresholds can also be improved by adding external, near-threshold acoustic noise. Based on these two findings and a pilot study we hypostatized that tinnitus loudness (TL) might be reduced, if the internally generated neuronal noise is substituted by externally provided individually adapted acoustic noise. In the present study, we extended the data base of the first pilot and further optimized our approach using a more fine-grained adaptation of the presented noise to the patients’ audiometric data. We presented different spectrally filtered near-threshold noises (−2 dB to +6 dB HL, 2 dB steps) for 40 s each to 24 patients with tonal tinnitus and a hearing deficit not exceeding 40 dB. After each presentation, the effect of the noise on the perceived TL was obtained by patient’s response to a 5-scale question. In 21 out of 24 patients (13 women) TL was successfully subjectively attenuated during acoustic near-threshold stimulation using noise spectrally centered half an octave below the individual’s tinnitus pitch (TP). Six patients reported complete subjective silencing of their tinnitus percept during stimulation. Acoustic noise is able to reduce TL, but the TP has to be taken into account. Based on our findings, we speculate about a possible future treatment of tinnitus by near-threshold bandpass filtered acoustic noise stimulation, which could be implemented in hearing aids with noise generators.