bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating Adaptive Immune Cells Expressing the Gut Homing Marker α4β7 Integrin Are Decreased in COVID-19
Authors: Müller Tanja M. , Becker Emily , Wiendl Maximilian , Schulze Lisa Lou , Voskens Caroline , Völkl Simon , Kremer Andreas E. , Neurath Markus F. , Zundler Sebastian
Published: April 2021

Background

Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide range of symptoms including gastrointestinal manifestations, and intestinal epithelial cells are a target of the virus. However, it is unknown how the intestinal immune system contributes to systemic immune responses in coronavirus disease 2019 (COVID-19).

Methods

We characterized peripheral blood lymphocytes from patients with active COVID-19 and convalescent patients as well as healthy controls by flow cytometry.

Results

The frequency and absolute number of circulating memory T and B cells expressing the gut homing integrin α4β7 integrin was reduced during COVID-19, whether gastrointestinal symptoms were present or not. While total IgA-expressing B cells were increased, gut-imprinted B cells with IgA expression were stable.

Conclusion

COVID-19 is associated with a decrease in circulating adaptive immune cells expressing the key gut homing marker α4β7 suggesting that these cells are preferentially recruited to extra-intestinal tissues independently of α4β7 or that the systemic immune response against SARS-CoV-2 is at least numerically dominated by extraintestinal, particularly pulmonary, immune cell priming.
Single-Cell Profiling of Kidney Transplant Recipients With Immunosuppressive Treatment Reveals the Dynamic Immune Characteristics
Authors: Liu Yongguang , Liu Xiaoyou , Zhou Song , Xu Ruiquan , Hu Jianmin , Liao Guorong , Liao Jun , Guo Zefeng , Li Yuzhu , Yang Siqiang , Li Shichao , Chen Hua , Guo Ying , Li Min , Fan Lipei , Li Liuyang , Zhao Ming , Liu Ding
Published: April 2021

Kidney transplantation is currently the first choice of treatment for various types of end-stage renal failure, but there are major limitations in the application of immunosuppressive protocols after kidney transplantation. When the dose of immunosuppressant is too low, graft rejection occurs easily, while a dose that is too high can lead to graft loss. Therefore, it is very important to explore the immune status of patients receiving immunosuppressive agents after kidney transplantation. To compare the immune status of the recipient’s whole peripheral blood before and after receipt of immunosuppressive agents, we used single-cell cytometry by time-of-flight (CyTOF) to detect the peripheral blood immune cells in five kidney transplant recipients (KTRs) from the Department of Organ Transplantation of Zhujiang Hospital of Southern Medical University before and after receiving immunosuppressive agents. Based on CyTOF analysis, we detected 363,342 live single immune cells. We found that the immune cell types of the KTRs before and after receipt of immunosuppressive agents were mainly divided into CD4+ T cells, CD8+ T cells, B cells, NK cells/γδ T cells, monocytes/macrophages, granulocytes, and dendritic cells (DCs). After further reclustering of the above cell types, it was found that the immune cell subclusters in the peripheral blood of patients underwent major changes after receipt of immunosuppressants. After receiving immunosuppressive therapy, the peripheral blood of KTRs had significantly increased levels of CD57+NK cells and significantly decreased levels of central memory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, effector memory CD8+ T cells and naive CD8+ T cells. This study used CyTOF to classify immune cells in the peripheral blood of KTRs before and after immunosuppressive treatment, further compared differences in the proportions of the main immune cell types and immune cell subgroups before and after receipt of immunosuppressants, and provided relatively accurate information for assessment and treatment strategies for KTRs.
Sediment Profile Imaging: Laboratory Study Into the Sediment Smearing Effect of a Penetrating Plate
Authors: Moser Annabell , Pheasant Iain , MacPherson William N. , Narayanaswamy Bhavani E. , Sweetman Andrew K.
Published: April 2021

Sediment profiling imaging (SPI) is a versatile and widely used method to visually assess the quality of seafloor habitats (e.g., around fish farms and oil and gas rigs) and has been developed and used by both academics and consultancy companies over the last 50 years. Previous research has shown that inserting the flat viewport of an SPI camera into the sediment can have an impact on particle displacement pushing oxygenated surface sediments to deeper sediment depths and making anthropogenically-disturbed sediment appear healthier than they may actually be. To investigate the particle displacement that occurs when a flat plate is inserted into seafloor sediments, a testing device, termed the SPI purpose-built sediment chamber (SPI-PUSH) was designed and used in a series of experiments to quantify smearing where luminophores were used to demonstrate the extent of particle displacement caused by a flat plate being pushed into the sediment. Here, we show that the plate of the SPI-PUSH caused significant smearing, which varied with sediment type and the luminophore grain size. The mean particle smearing measured directly behind the inserted plate was 2.9 ± 1.5 cm for mud sediments with sand-like luminophores, 4.3 ± 2.5 cm for fine sand sediments with sand-like luminophores and 1.9 ± 1.1 cm for medium sand sediments with mud-like luminophores. When the mean depth of particle smearing was averaged over a larger sediment volume (11 cm3) next to the inserted plate, substantial differences were seen between the plate-insertion experiments and controls highlighting the potential extent of smearing artefacts that may be produced when a SPI camera penetrates the seafloor. This experimental data shows that future studies using the SPI camera, or any other periscope-like device (e.g., planar optodes) need to acknowledge that smearing may be significant. Furthermore, it highlights that a correction factor may need to be applied to these data (e.g., the depth of apparent redox potential discontinuity layer) to correctly interpret SPI camera images and better determine the effect of anthropogenic impacts on seafloor habitats.
4D Printing Pre-Strained Structures for Fast Thermal Actuation
Authors: Zou Yu , Huang Zhongyi , Li Xiying , Lv Pengyu
Published: April 2021

Four-dimensional (4D) printing is an emerging technology by adding the dimension of time-dependent reconfiguration into 3D printing. It enables the 3D printed structure to change the shape, property, or functionality under external stimuli such as temperature, magnetic field, and light, etc. Among the existing 4D printed structures, thermal responsive structures are widely used for their easy operation. However, the slow actuation of the thermal responsive structures impedes the applications like soft robotics. In the current work, a pre-strained strategy is proposed to accelerate the actuation of thermal responsive structures. A 4D printing platform that can apply strain during the printing process is constructed to fabricate the pre-strained structures under the aid of in-situ tensile of the printing base. A bilayer structure with one pre-strained layer and the other non-pre-strained layer is integrally printed. Through experiments and the finite element analysis, it is demonstrated that the aspect ratio has little effect on the deformation of the bilayer structure, whereas the pre-strain plays a key role in the deformation and also greatly accelerates the actuation of the bilayer structure. Based on the 4D printed pre-strained bilayer structure, an energy-free gripper is fabricated and a fully soft crawler is printed to achieve a high running speed.
Low Intra-Individual Variation in Mean Platelet Volume Over Time in Systemic Lupus Erythematosus
Authors: Wirestam Lina , Gullstrand Birgitta , Jern Andreas , Jönsen Andreas , Linge Petrus , Tydén Helena , Kahn Robin , Bengtsson Anders A.
Published: April 2021

Platelets have recently emerged as important immune modulators in systemic lupus erythematosus (SLE), in addition to their role in thrombosis and cardiovascular disease. However, studies investigating mean platelet volume (MPV) in SLE are often scarce, conflicting and cross-sectional. In this study, MPV was measured in clinical routine throughout a defined time-period to quantify both individual MPV fluctuations and investigate if such variations are associated with disease activity and clinical phenotypes of SLE. Of our 212 patients, 34 patients had only one MPV value reported with the remaining 178 patients having between 2 and 19 visits with recorded MPV values. The intra-individual MPV variation was low, with a median variation of 0.7 fL. This was further supported by the finding that 84% of patients stayed within their reference interval category (i.e., small, normal or large) over time. In our cohort, no correlation between disease activity and MPV neither cross-sectionally nor longitudinally was found. Mean platelet volume values were significantly smaller in SLE patients (mean 10.5 fL) compared to controls (mean 10.8 fL), p < 0.0001. Based on the reference interval, 2.4% (n = 5) of patients had large-sized platelets, 84.4% (n = 179) had normal-sized and 13.2% (n = 28) had small-sized. A larger proportion (85.7%) of patients with small-sized platelets met the anti-dsDNA criterion (ACR10b; p = 0.003) compared to patients with normal and large (57.6%) sized platelets. In conclusion, the intra-individual MPV variation was of low magnitude and fluctuations in disease activity did not have any significant impact on MPV longitudinally. This lack of variability in MPV over time indicates that measuring MPV at any time-point is sufficient. Further studies are warranted to evaluate MPV as a possible biomarker in SLE, as well as to determine the underlying mechanisms influencing platelet size in SLE.
Opposing Trends in Total Knee and Hip Arthroplasties for Patients With Rheumatoid Arthritis vs. the General Population—A 14-Year Retrospective Study in Taiwan
Authors: Tung Kuan-Kai , Lee Yung-Heng , Lin Chuan-Chao , Lee Cheng-Hung , Lin Mei-Chen , Wei James Cheng-Chung
Published: April 2021

Objective: To determine the trend of incidence rate of total knee arthroplasty (TKA), total hip arthroplasty (THA), and TKA or THA (major joint arthroplasty, MJA) among rheumatoid arthritis (RA) population and compared them with general population (GP) in Taiwan.

Methods: Incidence rates and trends of TKA, THA, and MJA were determined over a 14-year period (2000–2013) among RA patients and compared them with GP. RA of patients was diagnosed based on the ACR 1987 criteria and extracted from GP. Subanalyses of incidences of TKA, THA, and MJA by year, 10-year age group, and gender were further conducted for demographic analysis. Patient profiles were extracted from the National Health Insurance Research Database (NHIRD) for interrupted time-series analysis and cohort studies.

Results: Patients enrolled were 168,457 receiving TKA, 64,543 receiving THA, and 228,191 receiving MJA surgery. Incidences of TKA, THA, and MJA in RA patients were significantly lower by 49.0, 41.5, and 41.0% compared with concomitantly rises in GP by 131.0, 25.1, and 90.0% among the GP during the study period. The dominant age population for TKA, THA, and MJA were those aged 70–79 years in both GP and RA groups.

Conclusions: We found an opposing trend in incidence of TKA, THA, and MJA between RA patients and the GP. The possible influence of pharmacological treatment is implicated for the lower incidence rates of TKA, THA, and MJA surgeries among RA patients.
Related Factors to Streptococcus pneumoniae Invasive Infection and Clinical Manifestations: The Potential Role of Nasopharyngeal Microbiome
Authors: Dietl Beatriz , Henares Desirée , Boix-Palop Lucía , Muñoz-Almagro Carmen , Garau Javier , Calbo Esther
Published: April 2021

Infections of the lower respiratory tract, such as pneumonia, are one of the leading causes of death worldwide. Streptococcus pneumoniae might colonize the upper respiratory tract and is the main aetiological agent of community-acquired pneumonia (CAP). In the last decades, several factors related to the host, the microorganism and the antibiotic therapy have been investigated to identify risk factors associated with the development of invasive pneumococcal disease (IPD). Nevertheless, these factors themselves do not explain the risk of developing disease or its severity. Recently, some studies have focused on the importance of nasopharyngeal (NP) microbiome and its relation to respiratory health. This review presents existing evidence of the potential role of NP microbiome in the development of IPD.
Molecular Attributes Associated With Refolding of Inclusion Body Proteins Using the Freeze–Thaw Method
Authors: Singhvi Priyank , Verma Juhi , Panwar Neha , Wani Tabiya Qayoom , Singh Akansha , Qudratullah Md. , Chakraborty Arnab , Saneja Ankit , Sarkar Debi P. , Panda Amulya K.
Published: April 2021

Understanding the structure–function of inclusion bodies (IBs) in the last two decades has led to the development of several mild solubilization buffers for the improved recovery of bioactive proteins. The recently developed freeze–thaw-based inclusion body protein solubilization method has received a great deal of attention due to its simplicity and cost-effectiveness. The present report investigates the reproducibility, efficiency, and plausible mechanism of the freeze–thaw-based IB solubilization. The percentage recovery of functionally active protein species of human growth hormone (hGH) and L-asparaginase from their IBs in Escherichia coli and the quality attributes associated with the freeze–thaw-based solubilization method were analyzed in detail. The overall yield of the purified hGH and L-asparaginase protein was found to be around 14 and 25%, respectively. Both purified proteins had functionally active species lower than that observed with commercial proteins. Biophysical and biochemical analyses revealed that the formation of soluble aggregates was a major limitation in the case of tough IB protein like hGH. On the other hand, the destabilization of soft IB protein like L-asparaginase led to the poor recovery of functionally active protein species. Our study provides insight into the advantages, disadvantages, and molecular–structural information associated with the freeze–thaw-based solubilization method.
Shark Antibody Variable Domains Rigidify Upon Affinity Maturation—Understanding the Potential of Shark Immunoglobulins as Therapeutics
Authors: Fernández-Quintero Monica L. , Seidler Clarissa A. , Quoika Patrick K. , Liedl Klaus R.
Published: April 2021

Sharks and other cartilaginous fish are the phylogenetically oldest living organisms that have antibodies as part of their adaptive immune system. As part of their humoral adaptive immune response, they produce an immunoglobulin, the so-called immunoglobulin new antigen receptor (IgNAR), a heavy-chain only antibody. The variable domain of an IgNAR, also known as VNAR, binds the antigen as an independent soluble domain. In this study, we structurally and dynamically characterized the affinity maturation mechanism of the germline and somatically matured (PBLA8) VNARto better understand their function and their applicability as therapeutics. We observed a substantial rigidification upon affinity maturation, which is accompanied by a higher number of contacts, thereby contributing to the decrease in flexibility. Considering the static x-ray structures, the observed rigidification is not obvious, as especially the mutated residues undergo conformational changes during the simulation, resulting in an even stronger network of stabilizing interactions. Additionally, the simulations of the VNARin complex with the hen egg-white lysozyme show that the VNARantibodies evidently follow the concept of conformational selection, as the binding-competent state already preexisted even without the presence of the antigen. To have a more detailed description of antibody–antigen recognition, we also present here the binding/unbinding mechanism between the hen egg-white lysozyme and both the germline and matured VNARs. Upon maturation, we observed a substantial increase in the resulting dissociation-free energy barrier. Furthermore, we were able to kinetically and thermodynamically describe the binding process and did not only identify a two-step binding mechanism, but we also found a strong population shift upon affinity maturation toward the native binding pose.
Enhanced siRNA Delivery and Selective Apoptosis Induction in H1299 Cancer Cells by Layer-by-Layer-Assembled Se Nanocomplexes: Toward More Efficient Cancer Therapy
Authors: Sharifiaghdam Maryam , Shaabani Elnaz , Sharifiaghdam Zeynab , De Keersmaecker Herlinde , De Rycke Riet , De Smedt Stefaan , Faridi-Majidi Reza , Braeckmans Kevin , Fraire Juan C.
Published: April 2021

Nanotechnology has made an important contribution to oncology in recent years, especially for drug delivery. While many different nano-delivery systems have been suggested for cancer therapy, selenium nanoparticles (SeNPs) are particularly promising anticancer drug carriers as their core material offers interesting synergistic effects to cancer cells. Se compounds can exert cytotoxic effects by acting as pro-oxidants that alter cellular redox homeostasis, eventually leading to apoptosis induction in many kinds of cancer cells. Herein, we report on the design and synthesis of novel layer-by-layer Se-based nanocomplexes (LBL-Se-NCs) as carriers of small interfering RNA (siRNA) for combined gene silencing and apoptosis induction in cancer cells. The LBL-Se-NCs were prepared using a straightforward electrostatic assembly of siRNA and chitosan (CS) on the solid core of the SeNP. In this study, we started by investigating the colloidal stability and protection of the complexed siRNA. The results show that CS not only functioned as an anchoring layer for siRNA, but also provided colloidal stability for at least 20 days in different media when CS was applied as a third layer. The release study revealed that siRNA remained better associated with LBL-Se-NCs, with only a release of 35% after 7 days, as compared to CS-NCs with a siRNA release of 100% after 48 h, making the LBL nanocarrier an excellent candidate as an off-the-shelf formulation. When applied to H1299 cells, it was found that they can selectively induce around 32% apoptosis, while significantly less apoptosis (5.6%) was induced in NIH/3T3 normal cells. At the same time, they were capable of efficiently inducing siRNA downregulation (35%) without loss of activity 7 days post-synthesis. We conclude that LBL-Se-NCs are promising siRNA carriers with enhanced stability and with a dual mode of action against cancer cells.
Enhanced UnaG With Minimal Labeling Artifact for Single-Molecule Localization Microscopy
Authors: Ko Sangyoon , Kwon Jiwoong , Shim Sang-Hee
Published: April 2021

We introduced enhanced UnaG (eUnaG), a ligand-activatable fluorescent protein, for conventional and super-resolution imaging of subcellular structures in the mammalian cells. eUnaG is a V2L mutant of UnaG with twice brighter bulk fluorescence. We previously discovered the reversible fluorescence switching behavior of UnaG and demonstrated the high photon outputs and high localization numbers in single-molecule localization microscopy (SMLM). In this study, we showed that the fluorescence of eUnaG can be switched off under blue-light illumination, while a high concentration of fluorogenic ligands in the buffer can efficiently restore the fluorescence, as in UnaG. We demonstrated the capacity of eUnaG as an efficient protein label in mammalian cells, as well as for SMLM by utilizing its photoswitchable nature. While cytosolic UnaG proteins showed aggregated patches and fluorescence reduction at high expression levels, eUnaG-labeled protein targets successfully formed their proper structures in mammalian cells without notable distortion from the endogenous structure in the majority of transiently expressing cells. In particular, eUnaG preserved the vimentin filament structures much better than the UnaG. eUnaG provided similarly high single-molecule photon count distribution to UnaG, thus also similarly high resolution in the super-resolution images of various subcellular structures. The sampling coverage analysis of vimentin filaments in SMLM images showed the improvement of labeling efficiency of eUnaG. eUnaG is a high-performance fluorescent protein for fluorescence and single-molecule localization imaging in green emission with minimal labeling artifact.
Improved Functional Outcome After Peripheral Nerve Stimulation of the Impaired Forelimb Post-stroke
Authors: Tsai Shih-Yen , Schreiber Jennifer A. , Adamczyk Natalie S. , Wu Joanna Y. , Ton Son T. , Hofler Ryan C. , Walter James S. , O'Brien Timothy E. , Kartje Gwendolyn L. , Nockels Russ P.
Published: April 2021

Lack of blood flow to the brain, i.e., ischemic stroke, results in loss of nerve cells and therefore loss of function in the effected brain regions. There is no effective treatment to improve lost function except restoring blood flow within the first several hours. Rehabilitation strategies are widely used with limited success. The purpose of this study was to examine the effect of electrical stimulation on the impaired upper extremity to improve functional recovery after stroke. We developed a rodent model using an electrode cuff implant onto a single peripheral nerve (median nerve) of the paretic forelimb and applied daily electrical stimulation. The skilled forelimb reaching test was used to evaluate functional outcome after stroke and electrical stimulation. Anterograde axonal tracing from layer V pyramidal neurons with biotinylated dextran amine was done to evaluate the formation of new neuronal connections from the contralesional cortex to the deafferented spinal cord. Rats receiving electrical stimulation on the median nerve showed significant improvement in the skilled forelimb reaching test in comparison with stroke only and stroke with sham stimulation. Rats that received electrical stimulation also exhibited significant improvement in the latency to initiate adhesive removal from the impaired forelimb, indicating better sensory recovery. Furthermore, axonal tracing analysis showed a significant higher midline fiber crossing index in the cervical spinal cord of rats receiving electrical stimulation. Our results indicate that direct peripheral nerve stimulation leads to improved sensorimotor recovery in the stroke-impaired forelimb, and may be a useful approach to improve post-stroke deficits in human patients.
Fibrin-Platelet Clots in Acute Ischemic Stroke. Predictors and Clinical Significance in a Mechanical Thrombectomy Series
Authors: Hernández-Fernández Francisco , Ramos-Araque María E. , Barbella-Aponte Rosa , Molina-Nuevo Juan David , García-García Jorge , Ayo-Martin Oscar , Pedrosa-Jiménez María José , López-Martinez Lorena , Serrano-Heras Gemma , Julia-Molla Enrique , Segura Tomás
Published: April 2021

Introduction: The histological composition of the clot influences its mechanical properties, affects the efficacy of endovascular treatment (EVT), and could determine the clinical outcome of patients with acute ischemic stroke (AIS). Insights into clot composition may guide therapeutic decision-making prior to EVT and facilitate revascularization therapies.

Material and Methods: Consecutive patients with AIS recorded in a prospective single-center reperfusion registry from December 2015 to December 2019 and treated with EVT were included. Baseline, laboratory [including post-procedural C-reactive protein (CRP)], radiological, and angiographic variables were analyzed. We aimed to study the relationship between histological composition of the clot with basal neuroimaging, laboratory markers, and recanalization technique. The secondary outcome was to analyze the correlation between clot composition and functional outcome at 3 months assessed by the modified Rankin scale (mRS).

Results: From the study period, 360 AIS patients treated with EVT were included, of whom 189 (53%) fulfilled the inclusion criteria. One hundred (53%) cases of fibrin-predominant clot (FPC) were recorded. Full recanalization in FPC cases was achieved with higher probability when stent retrievers (SR) were selected as the first-line device (68.2%, p = 0.039). Patients with FPC had higher levels of CRP (p = 0.02), lower frequency of the hyperdense middle cerebral artery (HMCA) in baseline imaging (p = 0.039), and higher rates of mortality (p = 0.012). The multivariate analysis showed that the absence of HMCA (OR = 0.420; 95% CI 0.197–0.898; p = 0.025) and higher levels of CRP (OR = 1.01; 95% CI 1.003–1.019; p = 0.008) were predictors of FPC. Leukocytes and platelet counts were not associated with clot histology.

Conclusions: The absence of HMCA and higher levels of CRP were markers of FPC. In patients with FPC, complete recanalization was most likely to be achieved when a SR was selected as first line of treatment. Mortality was higher in patients within this histologic group.
BCCT: A GUI Toolkit for Brain Structural Covariance Connectivity Analysis on MATLAB
Authors: Xu Qiang , Zhang Qirui , Liu Gaoping , Dai Xi-jian , Xie Xinyu , Hao Jingru , Yu Qianqian , Liu Ruoting , Zhang Zixuan , Ye Yulu , Qi Rongfeng , Zhang Long Jiang , Zhang Zhiqiang , Lu Guangming
Published: April 2021

Brain structural covariance network (SCN) can delineate the brain synchronized alterations in a long-range time period. It has been used in the research of cognition or neuropsychiatric disorders. Recently, causal analysis of structural covariance network (CaSCN), winner-take-all and cortex–subcortex covariance network (WTA-CSSCN), and modulation analysis of structural covariance network (MOD-SCN) have expended the technology breadth of SCN. However, the lack of user-friendly software limited the further application of SCN for the research. In this work, we developed the graphical user interface (GUI) toolkit of brain structural covariance connectivity based on MATLAB platform. The software contained the analysis of SCN, CaSCN, MOD-SCN, and WTA-CSSCN. Also, the group comparison and result-showing modules were included in the software. Furthermore, a simple showing of demo dataset was presented in the work. We hope that the toolkit could help the researchers, especially clinical researchers, to do the brain covariance connectivity analysis in further work more easily.
Cnr2 Is Important for Ribbon Synapse Maturation and Function in Hair Cells and Photoreceptors
Authors: Colón-Cruz Luis , Rodriguez-Morales Roberto , Santana-Cruz Alexis , Cantres-Velez Juan , Torrado-Tapias Aranza , Lin Sheng-Jia , Yudowski Guillermo , Kensler Robert , Marie Bruno , Burgess Shawn M. , Renaud Olivier , Varshney Gaurav K. , Behra Martine
Published: April 2021

The role of the cannabinoid receptor 2 (CNR2) is still poorly described in sensory epithelia. We found strong cnr2 expression in hair cells (HCs) of the inner ear and the lateral line (LL), a superficial sensory structure in fish. Next, we demonstrated that sensory synapses in HCs were severely perturbed in larvae lacking cnr2. Appearance and distribution of presynaptic ribbons and calcium channels (Cav1.3) were profoundly altered in mutant animals. Clustering of membrane-associated guanylate kinase (MAGUK) in post-synaptic densities (PSDs) was also heavily affected, suggesting a role for cnr2 for maintaining the sensory synapse. Furthermore, vesicular trafficking in HCs was strongly perturbed suggesting a retrograde action of the endocannabinoid system (ECs) via cnr2 that was modulating HC mechanotransduction. We found similar perturbations in retinal ribbon synapses. Finally, we showed that larval swimming behaviors after sound and light stimulations were significantly different in mutant animals. Thus, we propose that cnr2 is critical for the processing of sensory information in the developing larva.
Analysis of the EGFR Amplification and CDKN2A Deletion Regulated Transcriptomic Signatures Reveals the Prognostic Significance of SPATS2L in Patients With Glioma
Authors: Wang Haiwei , Wang Xinrui , Xu Liangpu , Zhang Ji , Cao Hua
Published: April 2021

Purpose: This study was conducted in order to analyze the prognostic effects of epidermal growth factor receptor (EGFR) and CDKN2A alterations and determine the prognostic significance of EGFR and CDKN2A alterations on regulated genes in patients with glioblastoma (GBM) or lower grade glioma (LGG).

Methods: The alteration frequencies of EGFR and CDKN2A across 32 tumor types were derived from cBioPortal based on The Cancer Genome Atlas (TCGA) datasets. The Kaplan–Meier analysis was used to determine the prognostic significance of EGFR and CDKN2A alterations. EGFR and CDKN2A alterations on regulated expression signatures were identified from RNA-seq data in the TCGA GBM datasets. The prognostic significance of EGFR and CDKN2A alterations on regulated genes in patients with glioma was determined using the TCGA and the Chinese Glioma Genome Atlas (CGGA) datasets.

Results: Compared with the other 31 tumor types, EGFR amplification and CDKN2A deletion particularly occurred in patients with GBM. GBM patients with EGFR amplification or CDKN2A deletion demonstrated poor prognosis. Statistical analysis showed the coexistence of EGFR alteration and CDKN2A deletion in GBM patients. We identified 864 genes which were commonly regulated by EGFR amplification and CDKN2A deletion, and those genes were highly expressed in brain tissues and associated with the cell cycle, EBRR2, and MAPK signaling pathways. Spermatogenesis-associated serine-rich 2-like gene (SPATS2L) was upregulated in GBM patients with EGFR amplification or CDKN2A alteration. Higher expression levels of SPATS2L were associated with worse prognosis in patients with GBM in both TCGA and CGGA datasets. Moreover, the expression levels of SPATS2L were higher in patients with a mesenchymal subtype of GBM. Statistical analysis also showed that the coexistence of EGFR alteration and CDKN2A deletion was significant in patients with LGG. SPATS2L was upregulated in LGG patients with EGFR amplification or CDKN2A alteration. Furthermore, higher expression levels of SPATS2L were associated with worse prognosis in patients with LGG in both TCGA and CGGA datasets. The expression levels of SPATS2L were higher in patients with an astrocytoma subtype of LGG. Finally, the coexistence and unfavorable prognostic effects of EGFR amplification and CDKN2A alteration were validated using the Memorial Sloan Kettering Cancer Center (MSKCC) glioma datasets.

Conclusions: EGFR amplification and CDKN2A deletion of the regulated gene SPATS2L have significant prognostic effects in patients with GBM or LGG.
STAM Prolongs Clear Cell Renal Cell Carcinoma Patients' Survival via Inhibiting Cell Growth and Invasion
Authors: Deng Tuo , He Zihao , Duan Xiaolu , Gu Di , Cai Chao , Wu Wenqi , Liu Yongda , Zeng Guohua
Published: April 2021

Background: Signal transducing adaptor molecule 1 (STAM1) was considered to mediate cell growth and be involved in multiple signaling pathways; however, no research on the role of STAM1 in any tumors has been published yet. Our study aimed to investigate the prognostic value of STAM1 for clear cell renal cell carcinoma (ccRCC) and its role in modulating cancer cell function.

Methods: Data from The Cancer Genome Atlas (TCGA) in December 2019 were used to examine the role of STAM1 in indicating ccRCC patients' survival. A purchased tissue microarray (TM) and fresh ccRCC renal tissues were used for further validation. Then, STAM1 was overexpressed in human ccRCC cell lines for in vitro assays. Finally, bioinformatics was performed for STAM1 protein–protein interaction (PPI) network construction and functional analyses.

Results: A total of 539 ccRCC and 72 control samples were included for the TCGA cohort, and 149 ccRCC and 29 control slices were included for the TM cohort. In the TCGA and TM cohorts, we found that STAM1 expression was lower in ccRCC compared with normal adjacent non-cancerous renal tissues (P < 0.0001 for both cohorts). STAM1 downregulation was also related to significantly shorter overall survival (OS) (P < 0.0001 for both cohorts). In the TCGA cohort, reduced STAM1 expression was also associated with aggressive features of the tumor. Under multivariate analyses, STAM1 was demonstrated to be an independent prognostic factor for ccRCC survival in both TCGA (HR = 0.52, 95% CI: 0.33–0.84, P = 0.007) and TM cohorts (HR = 0.12, 95% CI: 0.04–0.32, P < 0.001). Our in vitro experiments showed that STAM1 inhibited cell viability, invasion, and migration in ccRCC cell lines. In PPI network, 10 candidate genes categorized into five biological processes were found to be closely related to STAM1.

Conclusion: STAM1 is a promising prognostic biomarker for predicting ccRCC survival outcomes. Preliminary pathogenesis is demonstrated by our in vitro experiments. Further pathological mechanisms of STAM1 in modulating ccRCC require comprehensive laboratory and clinical studies.
Efficacy, Safety, and Cost-Minimization Analysis of Continuous Infusion of Low-Dose Gemcitabine Plus Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma
Authors: Arrieta Oscar , Muñoz-Montaño Wendy , Muñiz-Hernández Sae , Campos Saul , Catalán Rodrigo , Soto-Molina Herman , Guzmán Vázquez Silvia , Díaz-Álvarez Osvaldo , Martínez-Pacheco Victor , Turcott Jenny G. , Ramos-Ramírez Maritza , Cabrera-Miranda Luis , Barrón Feliciano , Cardona Andrés F.
Published: April 2021

Background

Malignant pleural mesothelioma (MPM) is rare and aggressive neoplasia, with a poor prognosis; furthermore, the monetary cost of its treatment represents a major challenge for many patients. The economic burden this malignancy imposes is underscored by the fact that asbestos exposure, which is the most frequent risk factor, is much more prevalent in the lower socioeconomic population of developing countries. The aims of the present study were to evaluate the efficacy, safety, and cost of continuous infusion of low-dose Gemcitabine plus Cisplatin (CIGC) as a treatment strategy for patients with unresectable MPM.

Methods

We performed a prospective cohort study to determine efficacy and safety of continuous infusion gemcitabine at a dose of 250 mg/m2 in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 of a 21-day cycle in patients with unresectable MPM. We also performed a cost-minimization analysis to determine if this chemotherapy regimen is less expensive than other currently used regimens.

Results

The median number of chemotherapy cycles was six (range 1–11 cycles); objective response rate was documented in 46.2%, and disease control rate was seen in 81.2%. Median PFS was 8.05 months (CI 95% 6.97–9.13); median OS was 16.16 months (CI 95% 12.5–19.9). The cost minimization analysis revealed savings of 66.4, 61.9, and 97.7% comparing CIGC with short-infusion gemcitabine plus cisplatin (SIGC), cisplatin plus pemetrexed (CP), and cisplatin plus pemetrexed and bevacizumab (CPB), respectively. Furthermore, this chemotherapy regimen proved to be safe at the administered dosage.

Conclusion

CIGC is an effective and safe treatment option for patients with unresectable MPM; besides, this combination is a cost-saving option when compared with other frequently used chemotherapy schemes. Therefore, this treatment scheme should be strongly considered for patients with unresectable MPM and limited economic resources.
A Novel Clinical Nomogram for Predicting Cancer-Specific Survival in Adult Patients After Primary Surgery for Epithelial Ovarian Cancer: A Real-World Analysis Based on the Surveillance, Epidemiology, and End Results Database and External Validation in a Tertiary Center
Authors: Li Xianli , Xu Haoya , Yan Limei , Gao Jian , Zhu Liancheng
Published: April 2021

Background

The present study aimed to construct and validate a nomogram that can be used to predict cancer-specific survival (CSS) in patients with epithelial ovarian cancer (EOC).

Methods

A total of 7,129 adult patients with EOC were extracted from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. Patients were randomly divided into the training and validation cohorts (7:3). Cox regression was conducted to evaluate prognostic factors of CSS. The internal validation of the nomogram was performed using concordance index (C-index), AUC, calibration curves, and decision curve analyses (DCAs). Data from 53 adult EOC patients at Shengjing Hospital of China Medical University from 2008 to 2012 were collected for external verification. Kaplan–Meier curves were plotted to compare survival outcomes among risk subgroups.

Results

Age, grade, histological types, stage, residual lesion size, number of regional lymph nodes resected, number of positive lymph nodes, and chemotherapy were independent risk factors for CSS. Based on the above factors, we constructed a nomogram. The C-indices of the training cohort, internal validation cohort, and external verification group were 0.763, 0.750, and 0.920, respectively. The calibration curve indicated good agreement between the nomogram prediction and actual survival. AUC and DCA results indicated great clinical usefulness of the nomogram. The differences in the Kaplan–Meier curves among different risk subgroups were statistically significant.

Conclusions

We constructed a nomogram to predict CSS in adult patients with EOC after primary surgery, which can assist in counseling and guiding treatment decision making.
Identification, Biological Activities and Biosynthetic Pathway of Dendrobium Alkaloids
Authors: Mou Zongmin , Zhao Yi , Ye Fei , Shi Yana , Kennelly Edward J. , Chen Suiyun , Zhao Dake
Published: April 2021

Dendrobium is a genus of flowering plants belonging to the Orchidaceae family with more than 1,400 species. Many Dendrobium species have been used as medicinal plants in several Asian countries for thousands of years. Alkaloids were reported as the major biological markers due to their complex chemical compositions and various types. In this review, we summarized the structural types of alkaloids, their pharmacological activities, as well as the mechanisms of biological activities. More than sixty alkaloids were isolated and identified from the Dendrobium genus. Moreover, the pharmacological effects of Dendrobium alkaloids as hepatic lipid and gluconeogenesis regulation, as neuroprotection, and as anti-tumor, anti-inflammatory, anti-diabetes, and anti-virus factors were described. Besides, the total chemical synthesis of dendrobine is provided, while the biosynthetic pathway of dendrobine has been proposed based on the functions of associated genes. For applications of these invaluable herbs, more researches on the extraction of biological markers from compounds are needed. Further confirmation of the proposed biosynthetic pathways is anticipated as well.
Beneficial Potential of Banha-Sasim-Tang for Stress-Sensitive Functional Dyspepsia via Modulation of Ghrelin: A Randomized Controlled Trial
Authors: Kim Sul-Ki , Joung Jin-Yong , Ahn Yo-Chan , Jung In-Chul , Son Chang-Gue
Published: April 2021

Background: Functional dyspepsia (FD) is a highly complex pathophysiologic disease, which shows low recovery and high relapse rates. Therefore, a growing number of clinicians and patients are looking for alternative herbal medicine. Banha-Sasim-Tang (BST) is an herbal prescription for treating a wide range of dyspepsia in traditional Korean medicine (TKM).

Aim of the study: This study aimed to evaluate the efficacy of BST on FD in patients with psychological stress-related symptoms and to investigate the involvement of ghrelin. This study is registered at https://cris.nih.go.kr/with the identification number KCT 0002811.

Materials and methods: A total of 31 participants with FD who met the Rome IV criteria and the psychological stress-related pattern were enrolled in a double-blind, randomized, and controlled study. Participants were randomly assigned to the BST group (10 g twice daily for 4 weeks) or placebo group. The primary endpoint was a change in the Nepean Dyspepsia Index–Korean (NDI-K) score. The secondary endpoints were changes in the Visual Analog Scale (VAS) scores and plasma ghrelin level.

Results: All participants completed the study (n = 15 for BST, n = 16 for placebo). BST decreased NDI-K scores compared with placebo, but the difference was not statistically significant (37.40 ± 27.40 vs 22.50 ± 23.85, p = 0.12). VAS scores and plasma total ghrelin levels were significantly improved in patients who were treated with BST (3.19 ± 1.60 vs 1.38 ± 2.85, p = 0.03 for VAS and 105.69 ± 287.89 vs -142.31 ± 314.32, p = 0.03 for total ghrelin). No BST-related adverse effects were observed during the trial.

Conclusion: Our results indicate the clinical potential of BST for FD patients and are the first study to show the modulation of plasma ghrelin as one of its corresponding mechanisms.

Clinical Trial Registration:https://cris.nih.go.kr/, identifier KCT 0002811.
Neural and Molecular Contributions to Pathological Jealousy and a Potential Therapeutic Role for Intranasal Oxytocin
Authors: Zheng Xiaoxiao , Kendrick Keith M.
Published: April 2021

Romantic jealousy, especially in its pathological form, is a significant contributor to both domestic abuse, including partner sexual coercion and even murder, although relatively little research has been conducted on it. Both obsessive and delusional forms have been identified although only the latter is currently recognized as a pathological disorder. Studies in both clinical and healthy populations have identified altered fronto-striatal responsivity as being associated primarily with romantic jealousy and to date drug based treatments have targeted both dopaminergic and serotonergic systems. However, there is increasing interest in a potential role for the neuropeptide oxytocin, which can also modulate dopaminergic and serotonin systems in the brain and has been shown to altered in other psychotic conditions, such as schizophrenia and obsessive compulsive disorder. Recent studies in healthy populations have reported that when oxytocin is administered intranasally it can influence the brain to promote strengthening of romantic bonds and reduce romantic jealousy in both men and women evoked in either imagined or real contexts. These findings indicate a possible therapeutic use of intranasal oxytocin administration in pathological jealousy.
Neuroinflammation in HIV-Related Neuropathic Pain
Authors: Lu Huan-Jun , Fu Yuan-Yuan , Wei Qian-Qi , Zhang Zhi-Jun
Published: April 2021

In the management of human immunodeficiency virus (HIV) infection around the world, chronic complications are becoming a new problem along with the prolonged life expectancy. Chronic pain is widespread in HIV infected patients and even affects those with a low viral load undergoing long-term treatment with antiviral drugs, negatively influencing the adherence to disease management and quality of life. A large proportion of chronic pain is neuropathic pain, which defined as chronic pain caused by nervous system lesions or diseases, presenting a series of nervous system symptoms including both positive and negative signs. Injury caused by HIV protein, central and peripheral sensitization, and side effects of antiretroviral therapy lead to neuroinflammation, which is regarded as a maladaptive mechanism originally serving to promote regeneration and healing, constituting the main mechanism of HIV-related neuropathic pain. Gp120, as HIV envelope protein, has been found to be the major toxin that induces neuropathic pain. Particularly, the microglia, releasing numerous pro-inflammatory substances (such as TNFα, IL-1β, and IL-6), not only sensitize the neurons but also are the center part of the crosstalk bridging the astrocytes and oligodendrocytes together forming the central sensitization during HIV infection, which is not discussed detailly in recent reviews. In the meantime, some NRTIs and PIs exacerbate the neuroinflammation response. In this review, we highlight the importance of clarifying the mechanism of HIV-related neuropathic pain, and discuss about the limitation of the related studies as future research directions.
Fibroblast Growth Factor Type 2 (FGF2) Administration Attenuated the Clinical Manifestations of Preeclampsia in a Murine Model Induced by L-NAME
Authors: Martinez-Fierro Margarita L , Hernadez-Delgadillo Gloria Patricia , Flores-Mendoza Jose Feliciano , Alvarez-Zuñiga Claudia Daniela , Diaz-Lozano Martha Lizeth , Delgado-Enciso Ivan , Romero-Diaz Viktor Javier , Lopez-Saucedo Adrian , Rodriguez-Sanchez Iram Pablo , Marino-Martinez Ivan Alberto , Garza-Veloz Idalia
Published: April 2021

Background: In preeclampsia, a hypertensive disorder of pregnancy, the poor remodeling of spiral arteries leads to placental hypoperfusion and ischemia, provoking generalized maternal endothelial dysfunction and, in severe cases, death. Endothelial and placental remodeling is important for correct pregnancy evolution and is mediated by cytokines and growth factors such as fibroblast growth factor type 2 (FGF2). In this study, we evaluated the effect of human recombinant FGF2 (rhFGF2) administration in a murine model of PE induced by NG-nitro-L-arginine methyl ester (L-NAME) to test if rhFGF2 administration can lessen the clinical manifestations of PE.

Methods: Pregnant rats were administrated with 0.9% of NaCl (vehicle), L-NAME (60 mg/kg), FGF2 (666.6 ng/kg), L-NAME+FGF2 or L-NAME + hydralazine (10 mg/kg) from the 10th to 19th days of gestation. Blood pressure (BP), urine protein concentrations and anthropometric values both rat and fetuses were assessed. Histological evaluation of organs from rats delivered by cesarean section was carried out using hematoxylin and eosin staining.

Results: A PE-like model was established, and it included phenotypes such as maternal hypertension, proteinuria, and fetal growth delay. Compared to the groups treated with L-NAME, the L-NAME + FGF2 group was similar to vehicle: the BP remained stable and the rats did not develop enhanced proteinuria. Both the fetuses and placentas from rats treated with L-NAME + FGF2 had similar values of weight and size compared with the vehicle.

Conclusion: The intravenous administration of rhFGF2 showed beneficial and hypotensive effects, reducing the clinical manifestations of PE in the evaluated model.
Does the Brain Function as a Quantum Phase Computer Using Phase Ternary Computation?
Authors: Johnson Andrew S. , Winlow William
Published: April 2021

Here we provide evidence that the fundamental basis of nervous communication is derived from a pressure pulse/soliton capable of computation with sufficient temporal precision to overcome any processing errors. Signalling and computing within the nervous system are complex and different phenomena. Action potentials are plastic and this makes the action potential peak an inappropriate fixed point for neural computation, but the action potential threshold is suitable for this purpose. Furthermore, neural models timed by spiking neurons operate below the rate necessary to overcome processing error. Using retinal processing as our example, we demonstrate that the contemporary theory of nerve conduction based on cable theory is inappropriate to account for the short computational time necessary for the full functioning of the retina and by implication the rest of the brain. Moreover, cable theory cannot be instrumental in the propagation of the action potential because at the activation-threshold there is insufficient charge at the activation site for successive ion channels to be electrostatically opened. Deconstruction of the brain neural network suggests that it is a member of a group of Quantum phase computers of which the Turing machine is the simplest: the brain is another based upon phase ternary computation. However, attempts to use Turing based mechanisms cannot resolve the coding of the retina or the computation of intelligence, as the technology of Turing based computers is fundamentally different. We demonstrate that that coding in the brain neural network is quantum based, where the quanta have a temporal variable and a phase-base variable enabling phase ternary computation as previously demonstrated in the retina.