bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical Properties of Isolated Primary Cilia Measured by Micro-tensile Test and Atomic Force Microscopy
Authors: Do Tien-Dung , Katsuyoshi Jimuro , Cai Haonai , Ohashi Toshiro
Published: November 2021

Mechanotransduction is a well-known mechanism by which cells sense their surrounding mechanical environment, convert mechanical stimuli into biochemical signals, and eventually change their morphology and functions. Primary cilia are believed to be mechanosensors existing on the surface of the cell membrane and support cells to sense surrounding mechanical signals. Knowing the mechanical properties of primary cilia is essential to understand their responses, such as sensitivity to mechanical stimuli. Previous studies have so far conducted flow experiments or optical trap techniques to measure the flexural rigidity EI (E: Young’s modulus, I: second moment of inertia) of primary cilia; however, the flexural rigidity is not a material property of materials and depends on mathematical models used in the determination, leading to a discrepancy between studies. For better characterization of primary cilia mechanics, Young’s modulus should be directly and precisely measured. In this study, the tensile Young’s modulus of isolated primary cilia is, for the first time, measured by using an in-house micro-tensile tester. The different strain rates of 0.01–0.3 s−1 were applied to isolated primary cilia, which showed a strain rate–dependent Young’s modulus in the range of 69.5–240.0 kPa on average. Atomic force microscopy was also performed to measure the local Young’s modulus of primary cilia, showing the Young’s modulus within the order of tens to hundreds of kPa. This study could directly provide the global and local Young’s moduli, which will benefit better understanding of primary cilia mechanics.
Accurate Analysis of Anisotropic Carrier Mobility and Structure–property Relationships in Organic BOXD Crystalline Materials
Authors: Wang Shi-Ping , Wang Yu , Chen Fang-Yi , Wang Hai-Tao , Sheong Fu-Kit , Bai Fu-Quan , Zhang Hong-Xing
Published: November 2021

Charge mobility is an essential factor of organic crystalline materials. Although many investigators have made important progress, the exact relationship between the crystal structure and carrier mobility remains to be clarified. Fortunately, a series of bis-1,3,4-oxadiazole derivatives have been successfully prepared and reported. They have similar main molecular fragments but different crystal packing modes, which provide an ideal research objective for studying the effect of molecular packing on charge mobility in organic photoelectric conversion systems. In this work, the charge mobilities of these molecules are systematically evaluated from the perspective of first-principles calculation, and the effect of a molecular overlap on orbital overlap integral and final charge carrier mobility is fully discussed. It can be seen that the small intermolecular distance (less than 6 Å) is the decisive factor to achieve high electron mobility in π stacking, and better mobility can be obtained by increasing the hole migration distance appropriately. A larger dihedral angle of anisotropy is an important point limiting the charge mobility in the herringbone arrangement. It is hoped that the correlation results between the crystal structure and mobility can assist the experimental study and provide an effective way to improve the photoelectric conversion efficiency of the organic semiconductor devices and multiple basis for multiscale material system characterization and material information.
Computational Simulation of the Electronic State Transition in the Ternary Hexagonal Compound BaAgBi
Authors: Chang Yu , Wang Xin , Na Sanggyun , Zhang Weiwei
Published: November 2021

Topological properties in metals or semimetals have sparked tremendous scientific interest in quantum chemistry because of their exotic surface state behavior. The current research focus is still on discovering ideal topological metal material candidates. We propose a ternary compound with a hexagonal crystal structure, BaAgBi, which was discovered to exhibit two Weyl nodal ring states around the Fermi energy level without the spin–orbit coupling (SOC) effect using theoretical calculations. When the SOC effect is considered, the topological phases transform into two Dirac nodal line states, and their locations also shift from the Weyl nodal rings. The surface states of both the Weyl nodal ring and Dirac nodal lines were calculated on the (001) surface projection using a tight-binding Hamiltonian, and clear drumhead states were observed, with large spatial distribution areas and wide energy variation ranges. These topological features in BaAgBi can be very beneficial for experimental detection, inspiring further experimental investigation.
Post-interventional Evaluation and Follow-Up in Children With Patent Ductus Arteriosus Complicated With Moderate to Severe Pulmonary Arterial Hypertension: A Retrospective Study
Authors: Rong Xing , Ye Qiaofang , Wang Qiaoyu , Wang Jiajun , Zhu Qiongjun , Chen Youran , Wu Rongzhou
Published: November 2021

Background:Transcatheter closure is an important treatment for patent ductus arteriosus (PDA) complicated with moderate and severe pulmonary arterial hypertension (PAH). This report presents our experience with transcatheter closure of PDA complicated with moderate and severe PAH.

Methods:The 49 cases of PDA complicated with moderate and severe PAH were collected in the Second Affiliated Hospital and Yuying Children's Hospital from January 2014 to December 2019 with transcatheter closure of PDA and follow-up. All patients were invited for transthoracic echocardiography, electrocardiogram, and thoracic radiography check-up.

Results:Device implantation was successful in 48 of 49 patients (98.0%). Among them, 30 cases were in the PAH after defect correction (CD) group, and 19 examples were in the Non-PAH after defect correction (NCD) group. Pulmonary systolic pressure, left atrial diameter, and left ventricular end-diastolic diameter immediately after interventional therapy and 6 months later were lower than the pre-operative levels (p< 0.05). The incidence of the immediate residual shunt (RS) in this study was 34.9%, most of which were minimal amount shunt. RS disappeared in all patients within 1 year of therapy. Four patients had thrombocytopenia and one patient had left pulmonary artery stenosis. No other serious adverse event occurred during the follow-up period. The pressure gradient tricuspid valve regurgitation (PGTI) and the right heart catheterization (RHC) consistency points were 93.75% (15/16) and were within the 95% consistency limit by the Bland-Altman method. The Logistic regression analysis concluded that the pre-operative Pp/Ps and the narrowest diameter of PDA are risk factors for post-operative PAH (p< 0.05). The cut-off point of the pre-operative Pp/Ps and the narrowest diameter of PDA were calculated to be 0.595 and 4.75 mm, respectively.

Conclusion:Interventional occlusion in children with PDA complicated with moderate and severe PAH is safe, effective, and has few complications. Targeted drug therapy has a good clinical effect. The narrowest diameter of PDA and the pre-operative Pp/Ps may be one of the risk factors of residual PAH after interventional therapy.
Neurofilament Light Chain Protein Is a Predictive Biomarker for Stroke After Surgical Repair for Acute Type A Aortic Dissection
Authors: Zhang Kai , Wang Zhu , Zhu Kai , Dong Songbo , Pan Xudong , Sun Lizhong , Li Qing
Published: November 2021

Background: Although great progress has been made in surgery and perioperative care, stroke is still a fatal complication of acute type A aortic dissection (ATAAD). Serum biomarkers may help assess brain damage and predict patient's prognosis.

Methods: From March, 2019 to January, 2020, a total of 88 patients underwent surgical treatment at the Department of Cardiovascular Surgery of Beijing Anzhen Hospital, China, and were enrolled in this study. Patients were divided into two groups according to whether they had suffered a stroke after the operation. Blood samples were collected at 8 time points within 3 days after surgery to determine the level of S100β, neuron-specific enolase (NSE) and neurofilament light chain protein (NFL). Receiver operating characteristic curves (ROC) were established to explore the biomarker predictive value in stroke. The area under the curve (AUC) was used to quantify the ROC curve.

Results: The patient average age was 48.1 ± 11.0 years old and 70 (79.6%) patients were male. Fifteen (17.0%) patients suffered stroke after surgery. The NFL levels of patients in the stroke group at 12 and 24 h after surgery were significantly higher than those in the non-stroke group (all P < 0.001). However, the NSE and S100β levels did not differ significantly at any time point between the two groups. The predictive value of NFL was the highest at 12 and 24 h after surgery, and the AUC was 0.834 (95% CI, 0.723–0.951, P < 0.001) and 0.748 (95% CI, 0.603–0.894, P = 0.004), respectively. Its sensitivity and specificity at 12 h were 86.7 and 71.6%, respectively. The NFL cutoff value for the diagnosis of stroke at 12 h after surgery was 16.042 ng/ml.

Conclusions: This study suggests that NFL is an early and sensitive serum marker for predicting post-operative neurological prognosis of ATAAD patients. Further studies, including large-scale prospective clinical trials, are necessary to test whether the NFL can be used as a biomarker for clinical decision-making.
Cancer and Infective Endocarditis: Characteristics and Prognostic Impact
Authors: Cosyns Bernard , Roosens Bram , Lancellotti Patrizio , Laroche Cécile , Dulgheru Raluca , Scheggi Valentina , Vilacosta Isidre , Pasquet Agnès , Piper Cornelia , Reyes Graciela , Mahfouz Essam , Kobalava Zhanna , Piroth Lionel , Kasprzak Jarosław D. , Moreo Antonella , Faucher Jean-François , Ternacle Julien , Meshaal Marwa , Maggioni Aldo P. , Iung Bernard , Habib Gilbert
Published: November 2021

Background: The interplay between cancer and IE has become of increasing interest. This study sought to assess the prevalence, baseline characteristics, management, and outcomes of IE cancer patients in the ESC EORP EURO-ENDO registry.

Methods: Three thousand and eighty-five patients with IE were identified based on the ESC 2015 criteria. Three hundred and fifty-nine (11.6%) IE cancer patients were compared to 2,726 (88.4%) cancer-free IE patients.

Results: In cancer patients, IE was mostly community-acquired (74.8%). The most frequently identified microorganisms were S. aureus (25.4%) and Enterococci (23.8%). The most frequent complications were acute renal failure (25.9%), embolic events (21.7%) and congestive heart failure (18.1%). Theoretical indication for cardiac surgery was not significantly different between groups (65.5 vs. 69.8%, P = 0.091), but was effectively less performed when indicated in IE patients with cancer (65.5 vs. 75.0%, P = 0.002). Compared to cancer-free IE patients, in-hospital and 1-year mortality occurred in 23.4 vs. 16.1%, P = 0.006, and 18.0 vs. 10.2%; P < 0.001, respectively. In IE cancer patients, predictors of mortality by multivariate analysis were creatinine > 2 mg/dL, congestive heart failure and unperformed cardiac surgery (when indicated).

Conclusions: Cancer in IE patients is common and associated with a worse outcome. This large, observational cohort provides new insights concerning the contemporary profile, management, and clinical outcomes of IE cancer patients across a wide range of countries.
Harnessing the Potential of Human Pluripotent Stem Cell-Derived Motor Neurons for Drug Discovery in Amyotrophic Lateral Sclerosis: From the Clinic to the Laboratory and Back to the Patient
Authors: Lamas Nuno Jorge , Roybon Laurent
Published: November 2021

Amyotrophic Lateral Sclerosis (ALS) is a motor neurodegenerative disorder whose cellular hallmarks are the progressive death of motor neurons (MNs) located in the anterior horn of the spinal cord, brainstem and motor cortex, and the formation of intracellular protein aggregates. Over the course of the disease, progressive paralysis takes place, leading to patient death within 3–5 years after the diagnosis. Despite decades of intensive research, only a few therapeutic options exist, with a limited benefit on the disease progression. Preclinical animal models have been very useful to decipher some aspects of the mechanisms underlying ALS. However, discoveries made using transgenic animal models have failed to translate into clinically meaningful therapeutic strategies. Thus, there is an urgent need to find solutions to discover drugs that could impact on the course of the disease, with the ultimate goal to extend the life of patients and improve their quality of life. Induced pluripotent stem cells (iPSCs), similarly to embryonic stem cells (ESCs), have the capacity to differentiate into all three embryonic germ layers, which offers the unprecedented opportunity to access patient-specific central nervous system cells in an inexhaustible manner. Human MNs generated from ALS patient iPSCs are an exciting tool for disease modelling and drug discovery projects, since they display ALS-specific phenotypes. Here, we attempted to review almost 2 decades of research in the field, first highlighting the steps required to efficiently generate MNs from human ESCs and iPSCs. Then, we address relevant ALS studies which employed human ESCs and iPSC-derived MNs that led to the identification of compounds currently being tested in clinical trials for ALS. Finally, we discuss the potential and caveats of using patient iPSC-derived MNs as a platform for drug screening, and anticipate ongoing and future challenges in ALS drug discovery.
An Investigation of Rainfall-Induced Landslides From the Pre-Failure Stage to the Post-Failure Stage Using the Material Point Method
Authors: Lee Wei-Lin , Martinelli Mario , Shieh Chjeng-Lun
Published: November 2021

The kinematic behavior of rainfall-induced landslides from the pre-failure stage to post-failure stage contains important information for risk assessment and management. Because a complex relationship exists between rainfall conditions, pore water pressure, soil strength, and movement rates, a numerical model is the most efficient way to investigate the behavior of rainfall-induced landslides. In this study, the material point method (MPM) is used to investigate the dynamic behavior of landslides. First, the rainfall boundary conditions are extensively verified by comparing 1-D consolidation tests against other numerical solutions. Then, a numerical model is used to simulate a lab-scale rainfall-induced slope failure. A parametric study shows the influence of rainfall intensity on pore water pressure development, failure triggering time, surface displacement, and velocity. The use of the MPM provides a clear understanding in the failure mechanism and post-failure behavior of a rainfall-induced landslide.
Is It Possible to Expand Oocyte Donors by Decreasing Number of Oocytes for Own Use? Insights From a Large Single-Center Study
Authors: Bu Zhiqin , Zhang Jiaxin , Zhang Yile , Sun Yingpu
Published: November 2021

Background

Currently, in China, only women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles can donate oocytes to others, but at least 15 oocytes must be kept for their own treatment. Thus, the aim of this study was to determine whether oocyte donation compromises the cumulative live birth rate (CLBR) of donors and whether it is possible to expand oocyte donors’ crowd.

Methods

This was a retrospective cohort study from August 2015 to July 2017 including a total of 2,144 patients, in which 830 IVF–embryo transfer (IVF-ET) patients were eligible for oocyte donation and 1,314 patients met all other oocyte donation criteria but had fewer oocytes retrieved (10–17 oocytes). All 830 patients were advised to donate approximately three to five oocytes to others and were eventually divided into two groups: the oocyte donation group (those who donated) and the control group (those who declined). The basic patient parameters and CLBR, as well as the number of supernumerary embryos after achieving live birth, were compared. These two factors were also compared in all patients (2,144) with oocyte ≥10.

Results

In 830 IVF-ET patients who were eligible for oocyte donation, only the oocyte number was significantly different between two groups, and the donation group had more than the control group (25.49 ± 5.76 vs. 22.88 ± 5.11, respectively; p = 0.09). No significant differences were found between the two groups in other factors. The results indicate that the live birth rate in the donation group was higher than that in the control group (81.31% vs. 82.95%, p = 0.371), without significance. In addition, CLBR can still reach as high as 73% when the oocyte number for own use was 10. Supernumerary embryos also increased as the oocyte number increased in all patients (oocyte ≥10).

Conclusions

Currently, oocyte donation did not compromise CLBR, and oocyte donation can decrease the waste of embryos. In addition, in patients with 10 oocytes retrieved, the CLBR was still good (73%). Thus, it is possible to expand oocyte donors if the number of oocyte kept for own use was decreased from 15 to 10 after enough communication with patients.
Effects of Sleeve Gastrectomy on Fecal Gut Microbiota and Short-Chain Fatty Acid Content in a Rat Model of Polycystic Ovary Syndrome
Authors: Lin Wei , Wen Lingying , Wen Junping , Xiang Guangda
Published: November 2021

Purpose

Sleeve gastrectomy (SG) is a surgical intervention for polycystic ovary syndrome (PCOS), especially for patients with obesity. Here, we explored the effects of SG on the gut microbiota of rats with PCOS and investigated the association between the intestinal flora and efficacy of SG in PCOS.

Methods

Dehydroepiandrosterone (DHEA) injection was administered alone and in combination with a high-fat diet to induce PCOS in rats. SG was performed in rats with PCOS, and the effects of SG on the fecal and gut microbiota and the short-chain fatty acid (SCFA) content were observed. Furthermore, the association among gut microbiota, SCFA content and hyperandrogenism or other hallmarks of PCOS was evaluated.

Results

The abundance of Firmicutes reduced and that of Bacteroidetes increased in response to SG in the DHEA-induced PCOS rat model. At the genus level, the abundances of Bacteroides and Blautia increased and those of Ruminococcus, Clostridium, and Alistipes reduced distinctly in the PCOS-SG groups. Moreover, the levels of fecal SCFAs, especially butyric acid, reduced after SG. SG significantly ameliorated PCOS-related symptoms such as hyperandrogenism, disrupted ovary function, and impaired glucose tolerance. Bacteroides and Blautia exhibited a negative correlation and Ruminococcus, Clostridium, and Alistipes exhibited a positive correlation with the levels of fecal SCFAs, luteinizing hormone, testosterone, and inflammatory factors.

Conclusions

The amelioration of PCOS-related reproductive and metabolic disorders following SG was associated with the regulation of microbial taxa and SCFA content. Our findings provide a novel perspective on the microbial mechanisms in PCOS after SG.
Application of SNP in Genetic Sex Identification and Effect of Estradiol on Gene Expression of Sex-Related Genes in Strongylocentrotus intermedius
Authors: Han Ya-Lun , Sun Zhi-Hui , Chang Shuai , Wen Bin , Song Jian , Zuo Ran-Tao , Chang Ya-Qing
Published: November 2021

Sea urchin (Strongylocentrotus intermedius) is an economically important mariculture species in Asia, and its gonads are the only edible part. The efficiency of genetic breeding in sea urchins is hampered due to the inability to distinguish gender by appearance. In this study, we first identified a sex-associated single nucleotide polymorphism (SNP) by combining type IIB endonuclease restriction site-associated DNA sequencing (2b-RAD-seq) and genome survey. Importantly, this SNP is located within spata4, a gene specifically expressed in male. Knocking down of spata4 by RNA interference (RNAi) in male individuals led to the downregulation of other conserved testis differentiation-related genes and germ cell marker genes. We also revealed that sex ratio in this validated culture population of S. intermedius is not 1:1. Moreover, after a 58-day feeding experiment with estradiol, the expression levels of several conserved genes that are related to testis differentiation, ovary differentiation, and estrogen metabolism were dynamically changed. Taken together, our results will contribute toward improving breeding efficiency, developing sex-controlled breeding, and providing a solid base for understanding sex determination mechanisms in sea urchins.
High Incidence of Distant Metastasis Is Associated With Histopathological Subtype of Pediatric Papillary Thyroid Cancer - a Retrospective Analysis Based on SEER
Authors: Zeng Xue , Wang Zhihong , Gui Zhiqiang , Xiang Jingzhe , Cao Mengsu , Sun Wei , He Liang , Dong Wenwu , Huang Jiapeng , Zhang Dalin , Lv Chengzhou , Zhang Ting , Shao Liang , Zhang Ping , Zhang Hao
Published: November 2021

Objective

Children with papillary thyroid cancer (PTC) have a higher invasive rate and distant metastasis rate, but the mortality rate is lower with unknown reasons. The majority of PTC cases comprise classical papillary thyroid carcinoma (CPTC) and follicular variant papillary thyroid carcinoma (FVPTC). This study aimed to determine the relationship between histopathological subtype and rate of distant metastasis and investigate factors influencing distant metastasis in pediatric PTC.

Methods

A total of 102,981 PTC patients were recruited from SEER registry, 2004-2015. Proportion of distant metastasis between children (≤18 years) and adults with different histopathological subtypes was compared by propensity score matching. The cut-off age for distant metastasis in children was calculated by receiver operating characteristic (ROC) curve, and the risk factors for distant metastasis in pediatric patients were analyzed by logistic regression models.

Results

Among the 1,484 children and 101,497 adults included in the study, the incidence of CPTC patients with distant metastasis in children was higher than that in adults (p<0.001). The ROC curve was calculated, which yielded a cut-off age for distant metastasis in CPTC children as 16 years old. In CPTC, the proportion of young children (2-16 years) with distant metastasis was higher than that of adolescents (17-18 years) and adults (>18 years) (both p<0.001). While there was no such trend in FVPTC. In young children (2-16 years), the incidence of CPTC with distant metastasis was higher than FVPTC (p=0.006). There was no difference between the proportion of CPTC and FVPTC with distant metastasis in adolescents (17-18 years) and adults. Logistic regression models revealed that extrathyroidal extension, lymph node metastasis and CPTC histopathological subtype were risk factors for distant metastasis in young children aged 2 -16 years.

Conclusions

In CPTC, the incidence of distant metastasis in young children (2-16 years) was significantly higher than that in adolescents (17-18 years) and adults (>18 years). In patients with distant metastasis aged 2-16 years, the proportion of CPTC was higer than that of FVPTC. Extrathyroidal extension, lymph node metastasis, and CPTC histopathological subtype were risk factors for distant metastasis in young children aged 2-16 years.
Life-Time Environmental Chemical Exposure and Obesity: Review of Epidemiological Studies Using Human Biomonitoring Methods
Authors: Mohanto Nayan Chandra , Ito Yuki , Kato Sayaka , Kamijima Michihiro
Published: November 2021

The exponential global increase in the incidence of obesity may be partly attributable to environmental chemical (EC) exposure. Humans are constantly exposed to ECs, primarily through environmental components. This review compiled human epidemiological study findings of associations between blood and/or urinary exposure levels of ECs and anthropometric overweight and obesity indices. The findings reveal research gaps that should be addressed. We searched MEDLINE (PubMed) for full text English articles published in 2006–2020 using the keywords “environmental exposure” and “obesity”. A total of 821 articles were retrieved; 102 reported relationships between environmental exposure and obesity indices. ECs were the predominantly studied environmental exposure compounds. The ECs were grouped into phenols, phthalates, and persistent organic pollutants (POPs) to evaluate obesogenic roles. In total, 106 articles meeting the inclusion criteria were summarized after an additional search by each group of EC combined with obesity in the PubMed and Scopus databases. Dose-dependent positive associations between bisphenol A (BPA) and various obesity indices were revealed. Both individual and summed di(2-ethylhexyl) phthalate (DEHP) and non-DEHP metabolites showed inconsistent associations with overweight and obesity indices, although mono-butyl phthalate (MBP), mono-ethyl phthalate (MEP), and mono-benzyl phthalate (MBzP) seem to have obesogenic roles in adolescents, adults, and the elderly. Maternal exposure levels of individual POP metabolites or congeners showed inconsistent associations, whereas dichlorodiphenyldichloroethylene (DDE) and perfluorooctanoic acid (PFOA) were positively associated with obesity indices. There was insufficient evidence of associations between early childhood EC exposure and the subsequent development of overweight and obesity in late childhood. Overall, human evidence explicitly reveals the consistent obesogenic roles of BPA, DDE, and PFOA, but inconsistent roles of phthalate metabolites and other POPs. Further prospective studies may yield deeper insights into the overall scenario.
Correlation Between Objective and Subjective High-Pitched Voice Impairment in Patients After Thyroid Surgery
Authors: Huang Tzu-Yen , Yu Wing-Hei Viola , Chiang Feng-Yu , Wu Che-Wei , Fu Shih-Chen , Tai An-Shun , Lin Yi-Chu , Tseng Hsin-Yi , Lee Ka-Wo , Lin Sheng-Hsuan
Published: November 2021

Objectives

High-pitched voice impairment (HPVI) is not uncommon in patients without recurrent laryngeal nerve (RLN) or external branch of superior laryngeal nerve (EBSLN) injury after thyroidectomy. This study evaluated the correlation between subjective and objective HPVI in patients after thyroid surgery.

Methods

This study analyzed 775 patients without preoperative subjective HPVI and underwent neuromonitored thyroidectomy with normal RLN/EBSLN function. Multi-dimensional voice program, voice range profile and Index of voice and swallowing handicap of thyroidectomy (IVST) were performed during the preoperative(I) period and the immediate(II), short-term(III) and long-term(IV) postoperative periods. The severity of objective HPVI was categorized into four groups according to the decrease in maximum frequency (Fmax): <20%, 20-40%, 40-60%, and >60%. Subjective HPVI was evaluated according to the patient’s answers on the IVST.

Results

As the severity of objective HPVI increased, patients were significantly more to receive bilateral surgery (p=0.002) and have subjective HPVI (p<0.001), and there was no correlation with IVST scores. Among 211(27.2%) patients with subjective HPVI, patients were significantly more to receive bilateral surgery (p=0.003) and central neck dissection(p<0.001). These patients had very similar trends for Fmax, pitch range, and mean fundamental frequency as patients with 20-40% Fmax decrease (p>0.05) and had higher Jitter, Shimmer, and IVST scores than patients in any of the objective HPVI groups; subjective HPVI lasted until period-IV.

Conclusion

The factors that affect a patient’s subjective HPVI are complex, and voice stability (Jitter and Shimmer) is no less important than the Fmax level. When patients have subjective HPVI without a significant Fmax decrease after thyroid surgery, abnormal voice stability should be considered and managed. Fmax and IVST scores should be interpreted comprehensively, and surgeons and speech-language pathologists should work together to identify patients with HPVI early and arrange speech therapy for them. Regarding the process of fibrosis formation, anti-adhesive material application and postoperative intervention for HPVI require more future research.
Using Temporal and Spatial Scales to Unravel the Effects of Climatic Factors on Vegetation Variations in China
Authors: Jing Yaodong , Zhu Hongfen , Bi Rutian , Hou Meiting
Published: November 2021

Spatio-temporal variation of climatic factors generally contains spatial and temporal components that have different frequencies, which may significantly affect the overall variance structure of vegetation growth at the original scale. The objective of the study was to explore the temporal- and spatial-scale-specific relationships between vegetation growth and climatic factors based on the data of half-monthly normalized difference vegetation index (NDVI), half-monthly averaged daily mean temperature (DMT), half-monthly averaged daily range of temperature (DRT), and half-monthly accumulated precipitation (AP). The complete ensemble empirical mode decomposition (CEEMD) was used to decompose the temporal series of NDVI and climatic factors, and their temporal-scale-specific relationships were examined based on the original half-month scale. Two-dimensional empirical mode decomposition (2D-EMD) was used to decompose the spatial distributions of temporally averaged NDVI and climatic factors, and their spatial-scale-specific relationships were tested based on the original resolution of 1 km. The dominant temporal scales of NDVI were around 3, 15, and >15 years, while the dominant spatial scales of NDVI were around 2 × 104 and >10 × 104 km2. The temporal-scale-specific effects of climatic factors on NDVI were the strongest under mixed forest and were the weakest under broadleaf forest. On a 15-year time scale, NDVI was positively affected by DMT and AP at the 200–1,000 mm precipitation region and negatively affected by DRT at the 200–600 mm precipitation region. Temporal effects of climatic factors had the greatest effects on NDVI in the precipitation region of 200–600 mm and in Yunnan province, and 98.08% of the study area included multi-temporal scale effects. Relationships between NDVI and climatic factors at the half-month scale and other temporal scales were different under different elevation, latitude, longitude, land types, climatic regions, and precipitation. The spatial-scale-specific effects of climatic factors on NDVI were also differed, and the area with effects of the multi-spatial scale was about 64.38%. This indicated that multi-temporal scale and multi-spatial scale analysis could help to understand the mechanisms of effect of climatic factors on vegetation growth and provide the foundation for future vegetation restoration in fragile ecosystems.
Essential Role of STAT3 Signaling in Hair Follicle Homeostasis
Authors: Miyauchi Kosuke , Ki Sewon , Ukai Masao , Suzuki Yoshie , Inoue Kentaro , Suda Wataru , Matsui Takeshi , Ito Yoshihiro , Honda Kenya , Koseki Haruhiko , Ohara Osamu , Tanaka Reiko J. , Okada-Hatakeyama Mariko , Kubo Masato
Published: November 2021

Dominant-negative mutations associated with signal transducer and activator of transcription 3 (STAT3) signaling, which controls epithelial proliferation in various tissues, lead to atopic dermatitis in hyper IgE syndrome. This dermatitis is thought to be attributed to defects in STAT3 signaling in type 17 helper T cell　specification. However, the role of STAT3 signaling in skin epithelial cells remains unclear. We found that STAT3 signaling in keratinocytes is required to maintain skin homeostasis by negatively controlling the expression of hair follicle-specific keratin genes. These expression patterns correlated with the onset of dermatitis, which was observed in specific pathogen-free conditions but not in germ-free conditions, suggesting the involvement of Toll-like receptor-mediated inflammatory responses. Thus, our study suggests that STAT3-dependent gene expression in keratinocytes plays a critical role in maintaining the homeostasis of skin, which is constantly exposed to microorganisms.
Circulating Exosome Involves in the Pathogenesis of Autoimmune Thyroid Diseases Through Immunomodulatory Proteins
Authors: Jia Xi , Zhai Tianyu , Zhang Jin-an
Published: November 2021

Autoimmune thyroid diseases (AITDs) are chronic organ-specific autoimmune diseases, mainly including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Exosomes, as extracellular vesicles, contain a variety of biologically active substances that play a role in information exchange, thereby affecting the occurrence and progression of diseases. However, it is unclear whether exosomes are involved in the pathogenesis of AITDs. In this study, the role of exosomes in AITDs was explored from a proteomics perspective. Plasma exosomes were isolated from 12 patients with GD, 10 patients with HT, and seven normal controls (NC). Protein profiles were detected using the data-independent acquisition (DIA) method and analyzed to investigate changes in plasma exosome proteins. In the setting of GD, 11 proteins were upregulated while 197 proteins were downregulated compared with healthy people. Among them, MAP1S (log2 FC = 4.669, p = 0.009) and VAMP8 (log2 FC = 3.216, p = 0.003) were the most significantly upregulated, and RSU1 (log2 FC = −6.797, p = 0.001), ACTB (log2 FC = −4.795, p < 0.001), and CXCL7 (log2 FC = −4.674, p < 0.001) were the most significantly downregulated. In the cases of HT, HGFL (log2 FC = 2.766, p = 0.001), FAK1 (log2 FC = 2.213, p < 0.001), and PTN12 (log2 FC = 1.624, p < 0.001) were significantly upregulated, while PSMF1 (log2 FC = −3.591, p < 0.001), PXL2B (log2 FC = −2.622, p = 0.001), and CYTM (log2 FC = −1.609, p < 0.001) were the most downregulated. These differential proteins were mainly enriched in the immune system and metabolic system, indicating that plasma exosomes may play an important role in systemic immune imbalance in AITDs.
Rapid Assessment of Binding Affinity of SARS-COV-2 Spike Protein to the Human Angiotensin-Converting Enzyme 2 Receptor and to Neutralizing Biomolecules Based on Computer Simulations
Authors: Buratto Damiano , Saxena Abhishek , Ji Qun , Yang Guang , Pantano Sergio , Zonta Francesco
Published: November 2021

SARS-CoV-2 infects humans and causes Coronavirus disease 2019 (COVID-19). The S1 domain of the spike glycoprotein of SARS-CoV-2 binds to human angiotensin-converting enzyme 2 (hACE2) via its receptor-binding domain, while the S2 domain facilitates fusion between the virus and the host cell membrane for entry. The spike glycoprotein of circulating SARS-CoV-2 genomes is a mutation hotspot. Some mutations may affect the binding affinity for hACE2, while others may modulate S-glycoprotein expression, or they could result in a virus that can escape from antibodies generated by infection with the original variant or by vaccination. Since a large number of variants are emerging, it is of vital importance to be able to rapidly assess their characteristics: while changes of binding affinity alone do not always cause direct advantages for the virus, they still can provide important insights on where the evolutionary pressure is directed. Here, we propose a simple and cost-effective computational protocol based on Molecular Dynamics simulations to rapidly screen the ability of mutated spike protein to bind to the hACE2 receptor and selected neutralizing biomolecules. Our results show that it is possible to achieve rapid and reliable predictions of binding affinities. A similar approach can be used to perform preliminary screenings of the potential effects of S-RBD mutations, helping to prioritize the more time-consuming and expensive experimental work.
The Expression of CD28 and Its Synergism on the Immune Response of Flounder (Paralichthys olivaceus) to Thymus-Dependent Antigen
Authors: Xing Jing , Liu Wenjing , Tang Xiaoqian , Sheng Xiuzhen , Chi Heng , Zhan Wenbin
Published: November 2021

CD28 is well known as a critical T-cell costimulatory receptor involved in T cell activation by binding to its ligands. In this study, CD28 was cloned, and its expression profiles were characterized in flounder (Paralichthys olivaceus); variations of CD28+ cells after being stimulated with different types of antigens and the function of the CD28 costimulatory pathway on T-cell activation were investigatedin vitro.fCD28consists of four exons and three introns, and the full-length cDNA offCD28was 675-bp encoded 224 amino acids. The conserved motif (121TFPPPF126) binding to the CD80/86 ligand exists in the Ig-superfamily homology domain. The high expression offCD28is in gills, PBLs, head kidney, and spleen. CD28+ cells were co-localized with CD4+ T lymphocytes but not on IgM+ B lymphocyte cells. Moreover, the expression of CD28 was significantly varied in flounder after being stimulated by keyhole limpet hemocyanin (KLH) at both the transcriptional and cellular levels, while no significant differences were observed between lipopolysaccharide (LPS) stimulation and the control group. Notably, treatment of PBLs culturedin vitrowith CD28 molecule-specific antibody (anti-CD28 Abs) and PHA produced more cell colonies and stimulated the proliferation of cultured leukocytes compared to PHA stimulation alone and the control group, and a higher level of IL-2 was detected in the culture medium. Meanwhile, anti-CD28 Abs increased the percent of CD28+ cells (10.41 ± 1.35%), CD4+ T lymphocytes (18.32 ± 2.15%), and CD28+/CD4+ double-positive cells (6.24 ± 1.52%). This effect also resulted in significant variations in the genes of cell membrane-bound molecules, cytokines, and related signaling pathways in cultured leukocytes, with significant changes in the genes ofinterleukin-2 (IL-2)andnuclear factor of activated T cells (NFAT)in the early stages of culture, and the expression of other molecules increased over time. These results proved the localization of the CD28 molecule on T lymphocytes in flounder, and anti-CD28 may act as the B7 ligand involved in T cell activation after antigen stimulation. These data provide a basis for a more in-depth study of the mechanism of the CD28 costimulatory pathway in T cell activation.
Understanding COVID-19: From Dysregulated Immunity to Vaccination Status Quo
Authors: Escobedo Ruby A. , Singh Dhiraj K. , Kaushal Deepak
Published: November 2021

The development of vaccines against infectious diseases has helped us battle the greatest threat to public health. With the emergence of novel viruses, targeted immunotherapeutics ranging from informed vaccine development to personalized medicine may be the very thing that separates us between life and death. Late in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), made a remarkable entrance to human civilization, being one of many to cross the species barrier. This review discusses the important aspects of COVID-19, providing a brief overview of our current understanding of dysregulated immune responses developed using various experimental models, a brief outline of experimental models of COVID-19 and more importantly, the rapid development of vaccines against COVID-19.
Targeted Mass Spectrometry Enables Multiplexed Quantification of Immunomodulatory Proteins in Clinical Biospecimens
Authors: Whiteaker Jeffrey R. , Lundeen Rachel A. , Zhao Lei , Schoenherr Regine M. , Burian Aura , Huang Dongqing , Voytovich Ulianna , Wang Tao , Kennedy Jacob J. , Ivey Richard G. , Lin Chenwei , Murillo Oscar D. , Lorentzen Travis D. , Thiagarajan Mathangi , Colantonio Simona , Caceres Tessa W. , Roberts Rhonda R. , Knotts Joseph G. , Reading Joshua J. , Kaczmarczyk Jan A. , Richardson Christopher W. , Garcia-Buntley Sandra S. , Bocik William , Hewitt Stephen M. , Murray Karen E. , Do Nhan , Brophy Mary , Wilz Stephen W. , Yu Hongbo , Ajjarapu Samuel , Boja Emily , Hiltke Tara , Rodriguez Henry , Paulovich Amanda G.
Published: November 2021

Immunotherapies are revolutionizing cancer care, producing durable responses and potentially cures in a subset of patients. However, response rates are low for most tumors, grade 3/4 toxicities are not uncommon, and our current understanding of tumor immunobiology is incomplete. While hundreds of immunomodulatory proteins in the tumor microenvironment shape the anti-tumor response, few of them can be reliably quantified. To address this need, we developed a multiplex panel of targeted proteomic assays targeting 52 peptides representing 46 proteins using peptide immunoaffinity enrichment coupled to multiple reaction monitoring-mass spectrometry. We validated the assays in tissue and plasma matrices, where performance figures of merit showed over 3 orders of dynamic range and median inter-day CVs of 5.2% (tissue) and 21% (plasma). A feasibility study in clinical biospecimens showed detection of 48/52 peptides in frozen tissue and 38/52 peptides in plasma. The assays are publicly available as a resource for the research community.
Intranasal Delivery of MVA Vector Vaccine Induces Effective Pulmonary Immunity Against SARS-CoV-2 in Rodents
Authors: Bošnjak Berislav , Odak Ivan , Barros-Martins Joana , Sandrock Inga , Hammerschmidt Swantje I. , Permanyer Marc , Patzer Gwendolyn E. , Greorgiev Hristo , Gutierrez Jauregui Rodrigo , Tscherne Alina , Schwarz Jan Hendrik , Kalodimou Georgia , Ssebyatika George , Ciurkiewicz Malgorzata , Willenzon Stefanie , Bubke Anja , Ristenpart Jasmin , Ritter Christiane , Tuchel Tamara , Meyer zu Natrup Christian , Shin Dai-Lun , Clever Sabrina , Limpinsel Leonard , Baumgärtner Wolfgang , Krey Thomas , Volz Asisa , Sutter Gerd , Förster Reinhold
Published: November 2021

Antigen-specific tissue-resident memory T cells (Trms) and neutralizing IgA antibodies provide the most effective protection of the lungs from viral infections. To induce those essential components of lung immunity against SARS-CoV-2, we tested various immunization protocols involving intranasal delivery of a novel Modified Vaccinia virus Ankara (MVA)-SARS-2-spike vaccine candidate. We show that a single intranasal MVA-SARS-CoV-2-S application in mice strongly induced pulmonary spike-specific CD8+ T cells, albeit restricted production of neutralizing antibodies. In prime-boost protocols, intranasal booster vaccine delivery proved to be crucial for a massive expansion of systemic and lung tissue-resident spike-specific CD8+ T cells and the development of Th1 - but not Th2 - CD4+ T cells. Likewise, very high titers of IgG and IgA anti-spike antibodies were present in serum and broncho-alveolar lavages that possessed high virus neutralization capacities to all current SARS-CoV-2 variants of concern. Importantly, the MVA-SARS-2-spike vaccine applied in intramuscular priming and intranasal boosting treatment regimen completely protected hamsters from developing SARS-CoV-2 lung infection and pathology. Together, these results identify intramuscular priming followed by respiratory tract boosting with MVA-SARS-2-S as a promising approach for the induction of local, respiratory as well as systemic immune responses suited to protect from SARS-CoV-2 infections.
Platelet-Mediated NET Release Amplifies Coagulopathy and Drives Lung Pathology During Severe Influenza Infection
Authors: Kim Seok-Joo , Carestia Agostina , McDonald Braedon , Zucoloto Amanda Z. , Grosjean Heidi , Davis Rachelle P. , Turk Madison , Naumenko Victor , Antoniak Silvio , Mackman Nigel , Abdul-Cader Mohamed Sarjoon , Abdul-Careem Mohamed Faizal , Hollenberg Morley D. , Jenne Craig N.
Published: November 2021

The influenza A virus (IAV) causes a respiratory tract infection with approximately 10% of the population infected by the virus each year. Severe IAV infection is characterized by excessive inflammation and tissue pathology in the lungs. Platelet and neutrophil recruitment to the lung are involved in the pathogenesis of IAV, but the specific mechanisms involved have not been clarified. Using confocal intravital microscopy in a mouse model of IAV infection, we observed profound neutrophil recruitment, platelet aggregation, neutrophil extracellular trap (NET) production and thrombin activation within the lung microvasculature in vivo. Importantly, deficiency or antagonism of the protease-activated receptor 4 (PAR4) reduced platelet aggregation, NET production, and neutrophil recruitment. Critically, inhibition of thrombin or PAR4 protected mice from virus-induced lung tissue damage and edema. Together, these data imply thrombin-stimulated platelets play a critical role in the activation/recruitment of neutrophils, NET release and directly contribute to IAV pathogenesis in the lung.
Expanded Hemodialysis Therapy Ameliorates Uremia-Induced Systemic Microinflammation and Endothelial Dysfunction by Modulating VEGF, TNF-α and AP-1 Signaling
Authors: Catar Rusan , Moll Guido , Kamhieh-Milz Julian , Luecht Christian , Chen Lei , Zhao Hongfan , Ernst Lucas , Willy Kevin , Girndt Matthias , Fiedler Roman , Witowski Janusz , Morawietz Henning , Ringdén Olle , Dragun Duska , Eckardt Kai-Uwe , Schindler Ralf , Zickler Daniel
Published: November 2021

Systemic chronic microinflammation and altered cytokine signaling, with adjunct cardiovascular disease (CVD), endothelial maladaptation and dysfunction is common in dialysis patients suffering from end-stage renal disease and associated with increased morbidity and mortality. New hemodialysis filters might offer improvements. We here studied the impact of novel improved molecular cut-off hemodialysis filters on systemic microinflammation, uremia and endothelial dysfunction. Human endothelial cells (ECs) were incubated with uremic serum obtained from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation (PERCI-II) crossover clinical trial, comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes, and then assessed for their vascular endothelial growth factor (VEGF) production and angiogenesis. Compared to HF membranes, dialysis with MCO membranes lead to a reduction in proinflammatory mediators and reduced endothelial VEGF production and angiogenesis. Cytokine multiplex screening identified tumor necrosis factor (TNF) superfamily members as promising targets. The influence of TNF-α and its soluble receptors (sTNF-R1 and sTNF-R2) on endothelial VEGF promoter activation, protein release, and the involved signaling pathways was analyzed, revealing that this detrimental signaling was indeed induced by TNF-α and mediated by AP-1/c-FOS signaling. In conclusion, uremic toxins, in particular TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel MCO membranes.

Translational Perspective and Graphical Abstract

Systemic microinflammation, altered cytokine signaling, cardiovascular disease, and endothelial maladaptation/dysfunction are common clinical complications in dialysis patients suffering from end-stage renal disease. We studied the impact of novel improved medium-cut-off hemodialysis filters on uremia and endothelial dysfunction. We can show that uremic toxins, especially TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel improved medium-cut-off membranes.