bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative Electrophysiology in Patients With Ulnar Nerve Entrapment at the Elbow-Prediction of Surgical Outcome and Influence of Age, Sex and Diabetes
Authors: Anker Ilka , Nyman Erika , Zimmerman Malin , Svensson Ann-Marie , Andersson Gert S. , Dahlin Lars B.
Published: March 2022

The impact of preoperative electrophysiology on outcome of surgical treatment in ulnar nerve entrapment at the elbow (UNE) is not clarified. Our aim was to evaluate influence of preoperative electrophysiologic grading on outcome and analyse how age, sex, and in particular diabetes affect such grading. Electrophysiologic protocols for 406 UNE cases, surgically treated at two hand surgery units reporting to the Swedish National Quality Register for Hand Surgery (HAKIR; 2010-2016), were retrospectively assessed, and graded as normal, reduced conduction velocity, conduction block or axonal degeneration. Outcome of surgery after primary and revision surgery was evaluated using QuickDASH and a doctor reported outcome measure (DROM) grading. No differences in QuickDASH or DROM were found between the four groups with different electrophysiologic grading preoperatively, or at three and 12 months or at follow up, respectively. When dichotomizing the electrophysiologic grading into normal and pathologic electrophysiology, cases with normal electrophysiology had worse QuickDASH than cases with pathologic electrophysiology preoperatively (p=0.046). Presence of a conduction block or axonal degeneration indicated a worse outcome by DROM grading (p=0.011). Primary surgeries had electrophysiologic more pronounced nerve pathology compared to revision surgeries (p=0.017). Cases of older age, men, and those with diabetes had more severe electrophysiologic nerve affection (p<0.0001). In the linear regression analysis, increasing age (unstandardized B=0.03, 95% CI 0.02-0.04; p<0.0001) and presence of diabetes (unstandardized B=0.60, 95% CI 0.25-0.95; p=0.001) were associated with a higher risk of a worse electrophysiologic classification. Female sex was associated with a better electrophysiologic grading (unstandardized B=-0.51, 95% CI -0.75- -0.27; p<0.0001). We conclude that older age, male sex, and concomitant diabetes are associated with more severe preoperative electrophysiologic nerve affection. Preoperative electrophysiologic grade of ulnar nerve affection may influence surgical outcome.
Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver
Authors: Du Chongyangzi , Yang Wanchun , Yu Zongyan , Yuan Qiuyun , Pang Dejiang , Tang Ping , Jiang Wanxiang , Chen Mina , Xiao Bo
Published: March 2022

Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of Rheb causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in Rheb KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.
The Molecular Structure and Role of Humanin in Neural and Skeletal Diseases, and in Tissue Regeneration
Authors: Zhu Sipin , Hu Xiaoyong , Bennett Samuel , Xu Jiake , Mai Yuliang
Published: March 2022

Humanin (HN) belongs to a member of mitochondrial-derived peptides (MDPs) which are encoded by mitochondrial genes. HN shares sequence homology with thirteen HN-like proteins, named MTRNR2L1 to MTRNR2L13, which encompass 24–28 amino acid residues in length. HN mediates mitochondrial status and cell survival by acting via an intracellular mechanism, or as a secreted factor via extracellular signals. Intracellularly, it binds Bcl2-associated X protein (BAX), Bim and tBid, and IGFBP3 to inhibit caspase activity and cell apoptosis. When released from cells as a secreted peptide, HN interacts with G protein-coupled formyl peptide receptor-like 1 (FPRL1/2) to mediate apoptosis signal-regulating kinase (ASK) and c-Jun N-terminal kinase (JNK) signalling pathways. Additionally, it interacts with CNTFR-α/gp130/WSX-1 trimeric receptors to induce JAK2/STA3 signalling cascades. HN also binds soluble extracellular proteins such as VSTM2L and IGFBP3 to modulate cytoprotection. It is reported that HN plays a role in neuronal disorders such as Alzheimer’s disease, as well as in diabetes mellitus, infertility, and cardiac diseases. Its roles in the skeletal system are emerging, where it appears to be involved with the regulation of osteoclasts, osteoblasts, and chondrocytes. Understanding the molecular structure and role of HN in neural and skeletal diseases is vital to the application of HN in tissue regeneration.
Molecular Characterization Clinical and Immunotherapeutic Characteristics of m5C Regulator NOP2 Across 33 Cancer Types
Authors: Liu Taisheng , Zhang Jian , Lin Chunxuan , Liu Guihong , Xie Guofeng , Dai Zili , Yu Peng , Wang Jian , Guo Liyi
Published: March 2022

Background: Recent studies have identified that RNA 5-methylcytosine (m5C) is a wide-spread epigenetic modification in tumorigenesis. However, the clinical and immunotherapeutic values of m5C regulator NOP2 in 33 cancers remain unclear.

Methods: The mRNA expression data and clinical data of 33 cancers were downloaded from The Cancer Genome Atlas (TCGA) database. The immunotherapy data including GSE67501, GSE78220, GSE35640, and IMvigor210 were downloaded from the Gene Expression Omnibus (GEO) database and the website based on the Creative Commons 3.0 license (http://research-pub.Gene.com/imvigor210corebiologies). The expression, survival, clinical parameters, tumor mutation burden (TMB), microsatellite instability (MSI), and tumor microenvironment (TME) were evaluated. Finally, the relationship between NOP2 and immunotherapy response was further explored.

Results: NOP2 was significantly upregulated in most cancers, and high NOP2 expression was associated with poor prognosis. TMB, MSI, and NOP2 activities were involved in the dysregulation of NOP2. NOP2 was closely associated with immune cell infiltration, immune modulators, and immunotherapeutic inactivation.

Conclusions: We comprehensively explored the clinical and immunotherapeutic values of NOP2 in cancers, providing evidence regarding the function of NOP2 and its role in clinical treatment.
RNA-Seq Analyses Reveal Roles of the HVCN1 Proton Channel in Cardiac pH Homeostasis
Authors: Wu Xin , Li Yawei , Maienschein-Cline Mark , Feferman Leonid , Wu Longjun , Hong Liang
Published: March 2022

The voltage-gated proton channel HVCN1 is a member of the voltage-gated ion channel family. HVCN1 channel controls acid extrusion and regulates pH homeostasis in various cell types. Recent evidence indicated that the HVCN1 channel was associated with cardiac function. To investigate the role of HVCN1 in cardiac myocytes, we performed an RNA sequencing analysis of murine hearts and showed that HVCN1 null hearts exhibited a differential transcriptome profile compared with wild-type hearts. The RNA-seq data indicating impaired pH homeostasis in HVCN1 null hearts were the downregulated NADPH oxidoreductases (NOXs) and decreased expression of Cl−/HCO3− exchanger, indicating HVCN1 is a regulator of gene transcriptional networks controlling NOX signaling and CO2 homeostasis in the heart. Additionally, HVCN1 null hearts exhibited differential expression of cardiac ion channels, suggesting a potential role of HVCN1 in cardiac electrophysiological remodeling. The study highlights the importance of HVCN1 in cardiac function and may present a novel target associated with heart diseases.
Recent Development of MOF-Based Photothermal Agent for Tumor Ablation
Authors: Yin Xiuzhao , Ai Fujin , Han Linbo
Published: March 2022

Metal-organic frameworks (MOFs) are 3D-architecture compounds of metal ions and organic molecules with sufficient and permanent porosity, showing great potential as a versatile platform to load various functional moieties to endow the hybrid materials with specific applications. Currently, a variety of photothermal nanometals have been embedded into organic ligands for integrating the unique photothermal effects with the merits of MOFs to improve their performances for cancer therapy. In this review, we have summarized a series of novel MOF-based photothermal materials for this unique therapeutic modality against tumors from three main aspects according to their chemical compositions and structures, i) metal-doped MOF, ii) organic-doped MOF, and iii) polymer-coated MOF. In addition, we have summarized the latest developments and characteristics of MOF-based photothermal agents, such as good biocompatibility, low toxicity, and responsive photothermal conversion without destroying the structure of hybrid photothermal agent. At last, we addressed the future perspectives of MOF-based photothermal agent in the field of phototherapy.
Acid-Base Equilibrium and Dielectric Environment Regulate Charge in Supramolecular Nanofibers
Authors: Nap Rikkert J. , Qiao Baofu , Palmer Liam C. , Stupp Samuel I. , Olvera de la Cruz Monica , Szleifer Igal
Published: March 2022

Peptide amphiphiles are a class of molecules that can self-assemble into a variety of supramolecular structures, including high-aspect-ratio nanofibers. It is challenging to model and predict the charges in these supramolecular nanofibers because the ionization state of the peptides are not fixed but liable to change due to the acid-base equilibrium that is coupled to the structural organization of the peptide amphiphile molecules. Here, we have developed a theoretical model to describe and predict the amount of charge found on self-assembled peptide amphiphiles as a function of pH and ion concentration. In particular, we computed the amount of charge of peptide amphiphiles nanofibers with the sequence C16 − V2A2E2. In our theoretical formulation, we consider charge regulation of the carboxylic acid groups, which involves the acid-base chemical equilibrium of the glutamic acid residues and the possibility of ion condensation. The charge regulation is coupled with the local dielectric environment by allowing for a varying dielectric constant that also includes a position-dependent electrostatic solvation energy for the charged species. We find that the charges on the glutamic acid residues of the peptide amphiphile nanofiber are much lower than the same functional group in aqueous solution. There is a strong coupling between the charging via the acid-base equilibrium and the local dielectric environment. Our model predicts a much lower degree of deprotonation for a position-dependent relative dielectric constant compared to a constant dielectric background. Furthermore, the shape and size of the electrostatic potential as well as the counterion distribution are quantitatively and qualitatively different. These results indicate that an accurate model of peptide amphiphile self-assembly must take into account charge regulation of acidic groups through acid–base equilibria and ion condensation, as well as coupling to the local dielectric environment.
Synthesis and Characterization of Phenylboronic Acid-Modified Insulin With Glucose-Dependent Solubility
Authors: Lin Nai-Pin , Zheng Nan , Purushottam Landa , Zhang Yi Wolf , Chou Danny Hung-Chieh
Published: March 2022

Glucose-responsive insulin represents a promising approach to regulate blood glucose levels. We previously showed that attaching two fluorophenylboronic acid (FPBA) residues to the C-terminal B chain of insulin glargine led to glucose-dependent solubility. Herein, we demonstrated that relocating FPBA from B chain to A chain increased the baseline solubility without affecting its potency. Furthermore, increasing the number of FPBA groups led to increased glucose-dependent solubility.
An Insight Into the microRNA Profile of the Ectoparasitic Mite Varroa destructor (Acari: Varroidae), the Primary Vector of Honey Bee Deformed Wing Virus
Authors: Kumar Deepak , Alburaki Mohamed , Tahir Faizan , Goblirsch Michael , Adamczyk John , Karim Shahid
Published: March 2022

The remarkably adaptive mite Varroa destructor is the most important honey bee ectoparasite. Varroa mites are competent vectors of deformed wing virus (DWV), and the Varroa-virus complex is a major determinant of annual honey bee colony mortality and collapse. MicroRNAs (miRNAs) are 22-24 nucleotide non-coding RNAs produced by all plants and animals and some viruses that influence biological processes through post-transcriptional regulation of gene expression. Knowledge of miRNAs and their function in mite biology remains limited. Here we constructed small RNA libraries from male and female V. destructor using Illumina’s small RNA-Seq platform. A total of 101,913,208 and 91,904,732 small RNA reads (>18 nucleotides) from male and female mites were analyzed using the miRDeep2 algorithm. A conservative approach predicted 306 miRNAs, 18 of which were upregulated and 13 downregulated in female V. destructor compared with males. Quantitative real-time PCR validated the expression of selected differentially-expressed female Varroa miRNAs. This dataset provides a list of potential miRNA targets involved in regulating vital Varroa biological processes and paves the way for developing strategies to target Varroa and their viruses.
Prediction Challenges From Errors in Tropical Pacific Sea Surface Temperature Trends
Authors: L'Heureux Michelle L. , Tippett Michael K. , Wang Wanqiu
Published: March 2022

Models in the North American Multi-Model Ensemble (NMME) predict sea surface temperature (SST) trends in the central and eastern equatorial Pacific Ocean which are more positive than those observed over the period 1982–2020. These trend errors are accompanied by linear trends in the squared error of SST forecasts whose sign is determined by the mean model bias (cold equatorial bias is linked to negative trends in squared error and vice versa). The reason for this behavior is that the overly positive trend reduces the bias of models that are too cold and increases the bias of models that are too warm. The excessive positive SST trends in the models are also linked with overly positive trends in tropical precipitation anomalies. Larger (smaller) SST trend errors are associated with lower (higher) skill in predicting precipitation anomalies over the central Pacific Ocean. Errors in the linear SST trend do not explain a large percentage of variability in precipitation anomaly errors, but do account for large errors in amplitude. The predictions toward a too warm and wet tropical Pacific, especially since 2000, are strongly correlated with an increase in El Niño false alarms. These results may be relevant for interpreting the behavior of uninitialized CMIP5/6 models, which project SST trends that resemble the NMME trend errors.
1α,25-Dihydroxyvitamin D3 Promotes Angiogenesis After Cerebral Ischemia Injury in Rats by Upregulating the TGF-β/Smad2/3 Signaling Pathway
Authors: Zhang Yajie , Mu Yingfeng , Ding Hongmei , Du Bo , Zhou Mingyue , Li Qingqing , Gong Shitong , Zhang Fuchi , Geng Deqin , Wang Yanqiang
Published: March 2022

Stroke is a disease with high morbidity, disability and mortality, which seriously endangers the life span and quality of life of people worldwide. Angiogenesis and neuroprotection are the key to the functional recovery of penumbra function after acute cerebral infarction. In this study, we used the middle cerebral artery occlusion (MCAO) model to investigate the effects of 1α,25-dihydroxyvitamin D3 (1,25-D3) on transforming growth factor-β (TGF-β)/Smad2/3 signaling pathway. Cerebral infarct volume was measured by TTC staining. A laser speckle flow imaging system was used to measure cerebral blood flow (CBF) around the ischemic cortex of the infarction, followed by platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) and isolectin-B4 (IB4) immunofluorescence. The expression of vitamin D receptor (VDR), TGF-β, Smad2/3, p-Smad2, p-Smad3, and vascular endothelial growth factor (VEGF) was analyzed by western blot and RT-qPCR. Results showed that compared with the sham group, the cerebral infarction volume was significantly increased while the CBF was reduced remarkably in the MCAO group. 1,25-D3 reduced cerebral infarction volume, increased the recovery of CBF and expressions of VDR, TGF-β, p-Smad2, p-Smad3, and VEGF, significantly increased IB4+ tip cells and CD31+ vascular length in the peri-infarct area compared with the DMSO group. The VDR antagonist pyridoxal-5-phosphate (P5P) partially reversed the neuroprotective effects of 1,25-D3 described above. In summary, 1,25-D3 plays a neuroprotective role in stroke by activating VDR and promoting the activation of TGF-β, which in turn up-regulates the TGF-β/Smad2/3 signaling pathway, increases the release of VEGF and thus promotes angiogenesis, suggesting that this signaling pathway may be an effective target for ischemic stroke treatment. 1,25-D3 is considered to be a neuroprotective agent and is expected to be an effective drug for the treatment of ischemic stroke and related diseases.
Noble Gases Therapy in Cardiocerebrovascular Diseases: The Novel Stars?
Authors: Zhang Jiongshan , Liu Wei , Bi Mingmin , Xu Jinwen , Yang Hongzhi , Zhang Yaxing
Published: March 2022

Cardiocerebrovascular diseases (CCVDs) are the leading cause of death worldwide; therefore, to deeply explore the pathogenesis of CCVDs and to find the cheap and efficient strategies to prevent and treat CCVDs, these are of great clinical and social significance. The discovery of nitric oxide (NO), as one of the endothelium-derived relaxing factors and its successful utilization in clinical practice for CCVDs, provides new ideas for us to develop drugs for CCVDs: “gas medicine” or “medical gases.” The endogenous gas molecules such as carbon monoxide (CO), hydrogen sulfide (H2S), sulfur dioxide (SO2), methane (CH4), and hydrogen (H2) have essential biological effects on modulating cardiocerebrovascular homeostasis and CCVDs. Moreover, it has been shown that noble gas atoms such as helium (He), neon (Ne), argon (Ar), krypton (Kr), and xenon (Xe) display strong cytoprotective effects and therefore, act as the exogenous pharmacologic preventive and therapeutic agents for CCVDs. Mechanistically, besides the competitive inhibition of N-methyl-D-aspartate (NMDA) receptor in nervous system by xenon, the key and common mechanisms of noble gases are involved in modulation of cell death and inflammatory or immune signals. Moreover, gases interaction and reduction in oxidative stress are emerging as the novel biological mechanisms of noble gases. Therefore, to investigate the precise actions of noble gases on redox signals, gases interaction, different cell death forms, and the emerging field of gasoimmunology, which focus on the effects of gas atoms/molecules on innate immune signaling or immune cells under both the homeostatic and perturbed conditions, these will help us to uncover the mystery of noble gases in modulating CCVDs.
Regional Myocardial Work Measured by Echocardiography for the Detection of Myocardial Ischemic Segments: A Comparative Study With Invasive Fractional Flow Reserve
Authors: Guo Ying , Yang Chenguang , Wang Xiang , Pei Zuowei , Zhu Huolan , Meng Xuyang , Zhou Ziyu , Lang Xiaotong , Ning Sun , Zhang Ruisheng , Wang Fang
Published: March 2022

Purpose

This study is to assess the diagnostic value of noninvasive regional myocardial work (MW) by echocardiography for detecting the functional status of coronary stenosis using fractional flow reserve (FFR) as a standard criterion.

Methods

A total of 84 consecutive patients were included in this study, among which 92 vessels were identified with ≥50% stenosis confirmed by invasive coronary angiography. Patients were investigated by invasive FFR and transthoracic echocardiography. Regional MW indices including myocardial work index (MWI), myocardial constructive work (MCW), myocardial wasted work, and myocardial work efficiency were calculated.

Results

MWI and MCW were significantly impaired in the FFR ≤ 0.75 group compared with the FFR > 0.75 group (both p < 0.01). There were significant positive associations between MWI and MCW with FFR. In total group, MWI <1,623.7 mmHg% [sensitivity, 78.4%; specificity, 72.2%; area under the curve value, 0.768 (0.653–0.883)] and MCW <1,962.4 mmHg% [77.0%; 72.2%; 0.767 (0.661–0.872)], and in single-vessel subgroup, MWI <1,412.1 mmHg% [93.5%; 63.6%; 0.808 (0.652–0.965)] and MCW <1,943.3 mmHg% [(84.8%; 72.7%; 0.800 (0.657–0.943)] were optimal to detect left ventricular segments with an FFR ≤ 0.75. MWI and MCW significantly increased after percutaneous coronary intervention in 13 cases.

Conclusion

In patients with coronary artery disease, especially those with single-vessel stenosis, the regional MW measured by echocardiography exhibited a good diagnostic value in detecting significant myocardial ischemia compared to the standard FFR approach.
Evaluating Changes in Experimentation, Critical Thinking, and Sense of Wonder in Participants of Science North’s In-School Outreach Programs
Authors: Richard Kaitlin , Pisani Katrina , Barriault Chantal L.
Published: March 2022

The aim of this study was to evaluate and report on the impact of an in-school science outreach program on children’s self-reported science knowledge, engagement, and skills through a case study of the Science North in-school outreach program “Mission to Mars.” A logic model method was used to outline the specific inputs, outputs, and measurable outcomes of the program. The program outcomes evaluated in this study were (1) experimentation skills, (2) critical thinking skills, and (3) sense of wonder. Results from pre-post surveys demonstrated that participants had increased program topic knowledge. Students self-reported positive emotions toward science more frequently following exposure to the program. Students’ sense of wonder toward science and toward space also increased post-program. This increase in positive emotion toward science could, in the short-term, increase student motivation toward science, which could lead to lasting interests in science in the long-term. Only a small number of students reported an increase in experimentation and critical thinking skills post-program. These skills take time to develop, and the single short-term program evaluated in this study may not have given students enough exposure to these skills for them to experience and show a noticeable change. The results of this study can provide informal science institutions like science centers with important insights into the potential learning impact of their in-school outreach programs, and can be used to improve current and future programs. Other organizations with in-school science outreach programs can benefit from using the methodology in this study to evaluate their programs, as this research includes a combination of innovative data collection methods such as concept maps to determine what students associate with the word “science,” and the use of an emoji scale to capture student emotions toward science. From a larger perspective, this study evaluating the impacts of in-school science outreach could demonstrate the potential benefits and outcomes of this unique area of informal learning, further solidifying the importance of incorporating these inquiry-based programs into classrooms.
Spatial Electric Load Forecasting Method Based on High-Level Encoding of High-Resolution Remote Sensing Images
Authors: Wang Bowen , Sun Hongbin
Published: March 2022

Spatial load forecasting (SLF) is important for regional power infrastructure construction planning and power grid management. However, for rapidly developing urban regions, SLF is generally inaccurate due to insufficient historical data. Hence, it is important to introduce the spatial load density (SLD) from similar regions to improve the accuracy of SLF. To select similar regions appropriately and acquire SLDs with limited available auxiliary data, this study proposes a spatial electric load forecasting method based on the high-level encoding of high-resolution remote sensing images called SELF-HE. In particular, SELF-HE introduces high-level ground object features as a key index to describe the characteristics of electric loads in a region and can establish connections between the remote sensing image features and SLD similarity. Based on this functionality, SELF-HE achieves more accurate SLF in regions with insufficient historical data. In the experiments, SELF-HE was compared with four traditional methods, and the results revealed that SELF-HE achieved improved SLF accuracy. Given that the high-resolution remote sensing images fully covered urban areas and were readily obtained, the proposed method can improve the accuracy of SLF with extremely low data collection costs and is applicable to rapidly developing urban regions.
Hypoxia Induces Oxidative Injury and Apoptosis via Mediating the Nrf-2/Hippo Pathway in Blood Cells of Largemouth Bass (Micropterus salmoides)
Authors: Xin Yu , Yang Zhixin , Zhu Yuke , Li Yixuan , Yu Jie , Zhong Wanqing , Chen Yanhan , Lv Xiaohui , Hu Junru , Lin Jinjiang , Miao Yutao , Wang Lei
Published: March 2022

Investigating how aquatic animals respond to hypoxia brought about by changes in environmental temperature may be of great significance to avoid oxidative injury and maintain the quality of farmed fish in the background of global warming. Here, we investigated the effects of hypoxia on oxidative injury and environment-sensing pathway in blood cells of Micropterus salmoides. The total blood cell count (TBCC) and Giemsa staining showed that hypoxia could lead to damage of blood cells. Flow cytometry analysis confirmed that the apoptosis rate, Ca2+ level, NO production and ROS of blood cells were significantly increased under hypoxia stress. Environment-sensing pathways, such as Nrf2 pathway showed that hypoxia resulted in significant up-regulation of hiF-1 alpha subunit (Hif-1α), nuclear factor erythroid 2-related factor 2 (Nrf2) and kelch-1ike ECH- associated protein l (Keap1) expression. Meanwhile, the expression of Hippo pathway-related genes such as MOB kinase activator 1 (MOB1), large tumor suppressor homolog 1/2 (Lats1/2), yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ), protein phosphatase 2A (PP2A) were significantly increased in blood cells after hypoxia exposure. In addition, hypoxia stress also increased the expression of catalase (CAT) and glutathione peroxidase (GPx), but decreased the expression of superoxide dismutase (SOD). Consequently, our results suggested that hypoxia could induce oxidative injury and apoptosis via mediating environment-sensing pathway such as Nrf2/Hippo pathway in blood cells of M. salmoides.
Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type
Authors: Wu Jing , Wang Mengru , Jiao Zhouyang , Dou Binghua , Li Bo , Zhang Jianjiang , Zhang Haohao , Sun Yue , Tu Xin , Kong Xiangdong , Bai Ying
Published: March 2022

Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare skeletal dysplasia characterized by severe disproportionate short stature, short hands and feet, normal intelligence, and facial dysmorphism. Homozygous or compound heterozygous mutations in the natriuretic peptide receptor 2 (NPR2) gene produce growth-restricted phenotypes. The current study was designed to identify and characterize NPR2 loss-of-function mutations in patients with AMDM and to explore therapeutic responses to recombinant growth hormone (rhGH). NPR2 was sequenced in two Chinese patients with AMDM via next generation sequencing, and in silico structural analysis or transcript analysis of two novel variants was performed to examine putative protein changes. rhGH treatment was started for patient 1. Three NPR2 mutations were identified in two unrelated cases: two compound heterozygous mutations c.1112G>A p.(Arg371Gln) and c.2887+2T>C in patient 1 and a homozygous mutation c.329G>A p.(Arg110His) in patient 2, yielding distinct phenotypes. RNA extracted from peripheral blood cells of patient 1 showed alternatively spliced transcripts not present in control cells. Homology modeling analyses suggested that the c.1112G>A p.(Arg371Gln) mutation disrupted the binding of NPR-B homodimer to its ligand (C-type natriuretic peptide) in the extracellular domain as a result of global allosteric effects on homodimer formation. Thus, c.2887+2T>C and c.1112G>A p.(Arg371Gln) in NPR2 were loss-of-function mutations. Furthermore, rhGH therapy in patient 1 increased the patient’s height by 0.6SDS over 15 months without adversely affecting the trunk-leg proportion. The short-term growth-promoting effect was equivalent to that reported for idiopathic short stature. Overall, our findings broadened the genotypic spectrum of NPR2 mutations in individuals with AMDM and provided insights into the efficacy of rhGH in these patients.
Pan-Cancer Analyses Identify the CTC1-STN1-TEN1 Complex as a Protective Factor and Predictive Biomarker for Immune Checkpoint Blockade in Cancer
Authors: Wang Lishuai , Ma Tengfei , Liu Weijin , Li Heping , Luo Zhenhua , Feng Xuyang
Published: March 2022

The CTC1-STN1-TEN1 (CST) complex plays a crucial role in telomere replication and genome stability. However, the detailed mechanisms of CST regulation in cancer remain largely unknown. Here, we perform a comprehensive analysis of CST across 33 cancer types using multi-omic data from The Cancer Genome Atlas. In the genomic landscape, we identify CTC1/STN1 deletion and mutation and TEN1 amplification as the dominant alteration events. Expressions of CTC1 and STN1 are decreased in tumors compared to those in adjacent normal tissues. Clustering analysis based on CST expression reveals three cancer clusters displaying differences in survival, telomerase activity, cell proliferation, and genome stability. Interestingly, we find that CTC1 and STN1, but not TEN1, are co-expressed and associated with better survival. CTC1-STN1 is positively correlated with CD8 T cells and B cells and predicts a better response to immune checkpoint blockade in external datasets of cancer immunotherapy. Pathway analysis shows that MYC targets are negatively correlated with CTC1-STN1. We experimentally validated that knockout of CTC1 increased the mRNA level of c-MYC. Furthermore, CTC1 and STN1 are repressed by miRNAs and lncRNAs. Finally, by mining the connective map database, we discover a number of potential drugs that may target CST. In sum, this study illustrates CTC1-STN1 as a protective factor and provides broad molecular signatures for further functional and therapeutic studies of CST in cancer.
HLA-B*13, B*35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil
Authors: Pereira Leonn Mendes Soares , França Eliane dos Santos , Costa Iran Barros , Jorge Erika Vanessa Oliveira , Mattos Patrícia Jeanne de Souza Mendonça , Freire Amaury Bentes Cunha , Ramos Francisco Lúzio de Paula , Monteiro Talita Antonia Furtado , Macedo Olinda , Sousa Rita Catarina Medeiros , Santos Eduardo José Melo dos , Freitas Felipe Bonfim , Costa Igor Brasil , Vallinoto Antonio Carlos Rosário
Published: March 2022

Introduction

Immune reconstitution failure after HIV treatment is a multifactorial phenomenon that may also be associated with a single polymorphism of human leukocyte antigen (HLA); however, few reports include patients from the Brazilian Amazon. Our objective was to evaluate the association of the immunogenic profile of the “classical” HLA-I and HLA-II loci with treatment nonresponse in a regional cohort monitored over 24 months since HIV diagnosis.

Materials and Methods

Treatment-free participants from reference centers in the state of Pará, Brazil, were enrolled. Infection screening was performed using enzyme immunoassays (Murex AG/AB Combination DiaSorin, UK) and confirmed by immunoblots (Bio-Manguinhos, FIOCRUZ). Plasma viral load was quantified by real-time PCR (ABBOTT, Chicago, Illinois, USA). CD4+/CD8+ T lymphocyte quantification was performed by immunophenotyping and flow cytometry (BD Biosciences, San Jose, CA, USA). Infection was monitored via test and logistics platforms (SISCEL and SICLOM). Therapeutic response failure was inferred based on CD4+ T lymphocyte quantification after 1 year of therapy. Loci A, B and DRB1 were genotyped using PCR-SSO (One Lambda Inc., Canoga Park, CA, USA). Statistical tests were applied using GENEPOP, GraphPad Prism 8.4.3 and BioEstat 5.3.

Results

Of the 270 patients monitored, 134 responded to treatment (CD4+ ≥ 500 cells/µL), and 136 did not respond to treatment (CD4+ < 500 cells/µL). The allele frequencies of the loci were similar to heterogeneous populations. The allelic profile of locus B was statistically associated with treatment nonresponse, and the B*13, B*35 and B*39 alleles had the greatest probabilistic influence. The B*13 allele had the highest risk of treatment nonresponse, and carriers of the allele had a detectable viral load and a CD4+ T lymphocyte count less than 400 cells/µL with up to 2 years of therapy. The B*13 allele was associated with a switch in treatment regimens, preferably to efavirenz (EFZ)-based regimens, and among those who switched regimens, half had a history of coinfection with tuberculosis.

Conclusions

The allelic variants of the B locus are more associated with non-response to therapy in people living with HIV (PLHIV) from a heterogeneous population in the Brazilian Amazon.
ATF3 Positively Regulates Antibacterial Immunity by Modulating Macrophage Killing and Migration Functions
Authors: Du Yuzhang , Ma Zhihui , Zheng Juanjuan , Huang Shu , Yang Xiaobao , Song Yue , Dong Danfeng , Shi Liyun , Xu Dakang
Published: March 2022

The clinical severity of Staphylococcus aureus (S. aureus) respiratory infection correlates with antibacterial gene signature. S. aureus infection induces the expression of an antibacterial gene, as well as a central stress response gene, thus activating transcription factor 3 (ATF3). ATF3-deficient mice have attenuated protection against lethal S. aureus pneumonia and have a higher bacterial load. We tested the hypothesis that ATF3-related protection is based on the increased function of macrophages. Primary marrow-derived macrophages (BMDM) were used in vitro to determine the mechanism through which ATF3 alters the bacterial-killing ability. The expression of ATF3 correlated with the expression of antibacterial genes. Mechanistic studies showed that ATF3 upregulated antibacterial genes, while ATF3-deficient cells and lung tissues had a reduced level of antibacterial genes, which was accompanied by changes in the antibacterial process. We identified multiple ATF3 regulatory elements in the antibacterial gene promoters by chromatin immunoprecipitation analysis. In addition, Wild type (WT) mice had higher F4/80 macrophage migration in the lungs compared to ATF3-null mice, which may correlate with actin filament severing through ATF3-targeted actin-modifying protein gelsolin (GSN) for the macrophage cellular motility. Furthermore, ATF3 positively regulated inflammatory cytokines IL-6 and IL-12p40 might be able to contribute to the infection resolution. These data demonstrate a mechanism utilized by S. aureus to induce ATF3 to regulate antibacterial genes for antimicrobial processes within the cell, and to specifically regulate the actin cytoskeleton of F4/80 macrophages for their migration.
The uPA System Differentially Alters Fibroblast Fate and Profibrotic Ability in Skin Fibrosis
Authors: Zou Ming-Li , Teng Ying-Ying , Chen Zhong-hua , Liu Si-Yu , Jia Yuan , Zhang Kai-Wen , Wu Jun-Jie , Yuan Zheng-Dong , Tang Xiao-Yu , Yu Shun , Ye Jun-Xing , Li Xia , Zhou Xiao-Jin , Yuan Feng-Lai
Published: March 2022

Skin fibrosis is a common pathological feature of various diseases, and few treatment strategies are available because of the molecular pathogenesis is poorly understood. The urokinase-type plasminogen activator (uPA) system is the major serine protease system, and its components uPA, urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1(PAI-1) are widely upregulated in fibrotic diseases, including hypertrophic scars, keloids, and scleroderma. Here, we found that the successful binding of uPA and uPAR activates the downstream peroxisome proliferator-activated receptor (PPAR) signalling pathway to reduce the proliferation, migration, and contraction of disease-derived fibroblasts, contributing to the alleviation of skin fibrosis. However, increased or robust upregulation of the inhibitor PAI-1 inhibits these effects, suggesting of the involvement of PAI-1 in skin fibrosis. Subsequent in vivo studies showed that uPAR inhibitors increased skin fibrosis in mouse models, while uPA agonists and PAI-1 inhibitors reversed these effects. Our findings demonstrate a novel role for the uPA system and highlights its relationships with skin fibrosis, thereby suggesting new therapeutic approaches targeting the uPA system.
Glucocorticoid Treatment Strategies in Liver Failure
Authors: Ye Chao , Li Wenyuan , Li Lei , Zhang Kaiguang
Published: March 2022

Liver failure is characterized by serious liver decompensation and high mortality. The activation of systemic immune responses and systemic inflammation are widely accepted as the core pathogenesis of liver failure. Glucocorticoids (GCs) are most regularly utilized to suppress excessive inflammatory reactions and immunological responses. GCs have been used in the clinical treatment of liver failure for nearly 60 years. While there has been no unanimity on the feasibility and application of GC treatment in liver failure until recently. The most recent trials have produced conflicting results when it comes to the dose and time for GC therapy of different etiology of liver failure. Our review outlines the issues and options in managing GC treatment in liver failure based on an investigation of the molecular mechanism that GC may give in the treatment.
Characteristics and Clinical Significance of T-Cell Receptor Repertoire in Hepatocellular Carcinoma
Authors: Wang Zifei , Zhong Yu , Zhang Zefan , Zhou Kaiqian , Huang Zhihao , Yu Hao , Liu Longqi , Liu Shiping , Yang Huanming , Zhou Jian , Fan Jia , Wu Liang , Sun Yunfan
Published: March 2022

Several studies have demonstrated that the T-cell receptor (TCR) repertoire is associated with prognosis and immune therapy response in several types of cancer. However, the comprehensive features of TCR repertoire in tumor-infiltrating and circulating T cells, as well as its clinical significance of diagnosis in hepatocellular carcinoma (HCC) patients, are still unknown. In this study, we perform paired tumor/peritumoral tissues and peripheral blood samples from 58 patients with HCC and sequenced them with high-throughput TCR to comprehensively analyze the characteristics of TCR and the clinical significance of peripheral TCR sequence. By exploring the abundance and diversity of TCR repertoires, we observe that there was a significantly higher TCR diversity in peripheral blood than in tumoral and peritumoral tissues, while tumoral and peritumoral tissues showed similar TCR diversity. A substantial difference in the usage frequencies of several Vβ, Jβ genes, and TCRβ VJ pairings was found among three types of tissues. Moreover, we reveal that HCC patients have a unique profile of TCR repertoire in peripheral blood in contrast to healthy individuals. We further establish an HCC diagnostic model based on TCRβ VJ pairing usage in peripheral blood, which yields a best-fit area under the curve (AUC) of 0.9746 ± 0.0481 (sensitivity = 0.9675 ± 0.0603, specificity = 0.9998 ± 0.0007, average of 100 repeats) in the test set. Our study describes the characteristics of tissue infiltration and circulating T-cell bank in patients with HCC and shows the potential of using circulating TCR sequence as a biomarker for the non-invasive diagnosis of patients with HCC.
Integrative Transcriptomics and Proteomics Analysis Provide a Deep Insight Into Bovine Viral Diarrhea Virus-Host Interactions During BVDV Infection
Authors: Ma Yingying , Wang Li , Jiang Xiaoxia , Yao Xin , Huang Xinning , Zhou Kun , Yang Yaqi , Wang Yixin , Sun Xiaobo , Guan Xueting , Xu Yigang
Published: March 2022

Bovine viral diarrhea virus (BVDV) is the causative agent of bovine viral diarrhea-mucosal disease (BVD-MD), an important viral disease in cattle that is responsible for extensive economic losses to the cattle industry worldwide. Currently, several underlying mechanisms involved in viral replication, pathogenesis, and evading host innate immunity of BVDV remain to be elucidated, particularly during the early stage of virus infection. To further explore the mechanisms of BVDV-host interactions, the transcriptomics and proteomics profiles of BVDV-infected MDBK cells were sequenced using RNA-seq and iTRAQ techniques, respectively, and followed by an integrative analysis. Compared with mock-infected MDBK cells, a total of 665 differentially expressed genes (DEGs) (391 down-regulated, 274 up-regulated) and 725 differentially expressed proteins (DEPs) (461 down-regulated, 264 up-regulated) were identified. Among these, several DEGs and DEPs were further verified using quantitative RT-PCR and western blot. Following gene ontology (GO) annotation and KEGG enrichment analysis, we determined that these DEGs and DEPs were significantly enriched in multiple important cellular signaling pathways including NOD-like receptor, Toll-like receptor, TNF, NF-κB, MAPK, cAMP, lysosome, protein processing in endoplasmic reticulum, lipid metabolism, and apoptosis signaling pathways. Significantly, the down-regulated DEGs and DEPs were predominantly associated with apoptosis-regulated elements, inflammatory factors, and antiviral elements that were involved in innate immunity, thus, indicating that BVDV could inhibit apoptosis and the expression of host antiviral genes to facilitate viral replication. Meanwhile, up-regulated DEGs and DEPs were primarily involved in metabolism and autophagy signaling pathways, indicating that BVDV could utilize the host metabolic resources and cell autophagy to promote replication. However, the potential mechanisms BVDV-host interactions required further experimental validation. Our data provide an overview of changes in transcriptomics and proteomics profiles of BVDV-infected MDBK cells, thus, providing an important basis for further exploring the mechanisms of BVDV-host interactions.
Linkage Between Mangrove Seedling Colonization, Sediment Traits, and Nitrogen Input
Authors: He Ziying , Yen Lingwei , Huang Hongjie , Wang Zihao , Zhao Lili , Chen Zhonghan , Lee Shing Yip , Peng Yisheng
Published: March 2022

Mangroves around the world settle along coasts and estuaries, where they usually encounter aquaculture effluent that causes eutrophication and regulates the nitrogen cycle in their ecosystems. Moreover, the physical–chemical features of sediment in mangrove habitats might be altered by coastal wind, waves, and currents more frequently under the condition of increasing extreme climatic events. These events affect the process of colonization/regeneration of mangroves. To study how exogenous nitrogen input and sediment texture affect root system establishment of mangrove propagules and the early growth of seedlings, in turn, we set up a mesocosm experiment to explore the morphological and physiological responses of the root system of two mangroves, i.e., Kandelia obovata and Sonneratia apetala. We found that the root morphological features of mangrove seedlings mostly showed significant differences across the sediment texture treatment; K. obovata seedlings were more intensively influenced than S. apetala seedlings. It could be ascribed that the roots of K. obovata seedlings were more sensitive to sediment texture than S. apetala seedlings. Conversely, the treatment of exogenous nitrogen input showed a slighter even non-significant influence on the root features of mangrove seedlings. These results suggest that the seedlings of S. apetala and K. obovata performed similarly. In estuaries and coasts featuring eutrophication and various sediment textures, the conservation and restoration of mangroves should consider these conditions to ensure the sustainable development of mangroves.
Detecting Rare Species With Passive Sampling Tools: Optimizing the Duration and Frequency of Sampling for Benthic Taxa
Authors: Ma Kevin C. K. , McKindsey Christopher W. , Johnson Ladd E.
Published: March 2022

The choice of the duration and frequency of sampling to detect relevant patterns in field experiments or for environmental monitoring is always challenging since time and material resources are limited. In practice, duration and frequency of sampling are often chosen based on logistical constraints, experience, or practices described in published works but are rarely justified and almost never optimized before initiating sampling. Settlement plates are commonly used as a passive sampling tool to study recruitment patterns of fouling organisms (including non-indigenous species) and their deployment is amenable to experimentation with respect to manipulating duration and frequency of sampling. This study aimed to determine the optimal sampling strategy to detect rare species (e.g., a non-indigenous species early in the invasion process when its population size is still small). To do so, we deployed a series of settlement plates of various durations (1–32 days) and sampling frequencies (daily to biweekly) during the seasonal onset of recruitment, when larval supply was low, a situation that mimics the low propagule pressure of the early stages of the invasion process. We demonstrated that a combination of longer sampling duration and higher sampling frequency was the best strategy to maximize taxonomic richness. However, we found that an intermediate sampling duration of 1–2 weeks was optimal for detecting most species. These results can guide species-specific and assemblage-level sampling strategies using settlement plates. Additionally, this study can serve as a practical template for optimizing sampling of other taxonomic groups that were not examined in the present study as well as for the use of other methods.