bluuebunny/crossref_metadata_2025 huggingface dataset:
Microglia/Macrophages and CD4+CD25+ T Cells Enhance the Ability of Injury-Activated Lymphocytes to Reduce Traumatic Optic Neuropathy In Vitro
Authors: Geng Yiqun , Lu Zhihao , Guan Jitian , van Rooijen Nico , Zhi Ye
Published: August 2021

Inflammation after acute CNS injury plays a dual role. The interplay between immune cells and inflammatory mediators is critical to the outcome of injured neurons. Microglia/macrophages are the first sensors and regulators of the immune response. We previously found that the enhancement of macrophages on neuron survival does not persist in thymectomized rats. How T lymphocytes and macrophages interact and benefit neuron survival is not fully elucidated. To this point, we introduce and characterize a cell-retina co-culture model that mimics the recruitment of peripheral lymphocytes at the injury site. Three-day post-optic nerve transection (ONT) in Fischer 344 rats, transected retinas were co-cultured with either peripheral lymph node-derived lymphocytes (injury-activated) or from intact rats as the control. The injury-activated lymphocytes preserved retinal ganglion cells (RGCs) and caused extensive retina microglial/macrophage infiltration. CD4+CD25+ T cells were upregulated in the injury-activated lymphocytes and increased RGC survival, suggesting that CD4+CD25+ T cells suppressed the cytotoxicity of control lymphocytes. When microglia/macrophages were depleted by clodronate, neuron loss was more extensive, the cytotoxicity of control lymphocytes on RGCs was alleviated, and the neuroprotective effect of injury-activated lymphocytes remain unchanged Cytokine detection showed an increase in IL-6 and TNF-α levels that were reduced with microglia/macrophage depletion. Our results suggest that microglial/macrophage infiltration into axotomized retinas promotes RGC survival by secreting cytokines to induce CD4+CD25+ T cells and suppress T cell-mediated RGC toxicity. These findings reveal a specific role for microglia/macrophage and CD4+CD25+ T cells in inflammation after CNS injury, thereby adding to the mechanistic basis for the development of microglial/macrophage modulation therapy for traumatic CNS injury.
A Neoantigen-Based Peptide Vaccine for Patients With Advanced Pancreatic Cancer Refractory to Standard Treatment
Authors: Chen Zheling , Zhang Shanshan , Han Ning , Jiang Jiahong , Xu Yunyun , Ma Dongying , Lu Lantian , Guo Xiaojie , Qiu Min , Huang Qinxue , Wang Huimin , Mo Fan , Chen Shuqing , Yang Liu
Published: August 2021

Background

Neoantigens are critical targets to elicit robust antitumor T-cell responses. Personalized cancer vaccines developed based on neoantigens have shown promising results by prolonging cancer patients’ overall survival (OS) for several cancer types. However, the safety and efficacy of these vaccine modalities remains unclear in pancreatic cancer patients.

Methods

This retrospective study enrolled 7 advanced pancreatic cancer patients. Up to 20 neoantigen peptides per patient identified by our in-house pipeline iNeo-Suite were selected, manufactured and administered to these patients with low tumor mutation burden (TMB) (less than 10 mutations/Mb). Each patient received multiple doses of vaccine depending on the progression of the disease. Peripheral blood samples of each patient were collected pre- and post-vaccination for the analysis of the immunogenicity of iNeo-Vac-P01 through ELISpot assay and flow cytometry.

Results

No severe vaccine-related adverse effects were witnessed in patients enrolled in this study. The mean OS, OS associated with vaccine treatment and progression free survival (PFS) were reported to be 24.1, 8.3 and 3.1 months, respectively. Higher peripheral IFN-γ titer and CD4+ or CD8+ effector memory T cells count post vaccination were found in patients with relatively long overall survival. Remarkably, for patient P01 who had a 21-month OS associated with vaccine treatment, the abundance of antigen-specific TCR clone drastically increased from 0% to nearly 100%, indicating the potential of iNeo-Vac-P01 in inducing the activation of a specific subset of T cells to kill cancer cells.

Conclusions

Neoantigen identification and selection were successfully applied to advanced pancreatic cancer patients with low TMB. As one of the earliest studies that addressed an issue in treating pancreatic cancer with personalized vaccines, it has been demonstrated that iNeo-Vac-P01, a personalized neoantigen-based peptide vaccine, could improve the currently limited clinical efficacy of pancreatic cancer.

Clinical Trial Registration

ClinicalTrials.gov, identifier (NCT03645148).

Registered August 24, 2018 - Retrospectively registered
Immune Infiltrating Cells-Derived Risk Signature Based on Large-scale Analysis Defines Immune Landscape and Predicts Immunotherapy Responses in Glioma Tumor Microenvironment
Authors: Zhang Nan , Zhang Hao , Wang Zeyu , Dai Ziyu , Zhang Xun , Cheng Quan , Liu Zhixiong
Published: August 2021

The glioma tumor microenvironment (TME), composed of several noncancerous cells and biomolecules is known for its complexity of cancer-immune system interaction. Given that, novel risk signature is required for predicting glioma patient responses to immunotherapy. In this study, we systematically evaluated the TME infiltration pattern of 2877 glioma samples. TME phenotypes were determined using the Partitioning Around Medoid method. Machine learning including SVM-RFE and Principal component analysis (PCA) were used to construct a TME scoring system. A total of 857 glioma samples from four datasets were used for external validation of the TME-score. The correlation of TME phenotypes and TME-scores with diverse clinicopathologic characteristics, genomic features, and immunotherapeutic efficacy in glioma patients was determined. Immunohistochemistry staining for the M2 macrophage marker CD68 and CD163, mast cell marker CD117, neutrophil marker CD66b, and RNA sequencing of glioma samples from the XYNS cohort were performed. Two distinct TME phenotypes were identified. High TME-score correlated with a high number of immune infiltrating cells, elevated expression of immune checkpoints, increased mutation rates of oncogenes, and poor survival of glioma patients. Moreover, high TME-score exhibited remarkable association with multiple immunomodulators that could potentially mediate immune escape of cancer. Thus, the TME-score showed the potential to predict the efficacy of anti-PD-1 immunotherapy. Univariate and multivariate analyses demonstrated the TME-score to be a valuable prognostic biomarker for gliomas. Our study demonstrated that TME could potentially influence immunotherapy efficacy in melanoma patients whereas its role in immunotherapy of glioma patients remains unknown. Therefore, a better understanding of the TME landscape in gliomas would promote the development of novel immunotherapy strategies against glioma.
Roles of Neutrophils in Glioma and Brain Metastases
Authors: Lin Ya-Jui , Wei Kuo-Chen , Chen Pin-Yuan , Lim Michael , Hwang Tsong-Long
Published: August 2021

Neutrophils, which are the most abundant circulating leukocytes in humans, are the first line of defense against bacterial and fungal infections. Recent studies have reported the role and importance of neutrophils in cancers. Glioma and brain metastases are the most common malignant tumors of the brain. The tumor microenvironment (TME) in the brain is complex and unique owing to the brain-blood barrier or brain-tumor barrier, which may prevent drug penetration and decrease the efficacy of immunotherapy. However, there are limited studies on the correlation between brain cancer and neutrophils. This review discusses the origin and functions of neutrophils. Additionally, the current knowledge on the correlation between neutrophil-to-lymphocyte ratio and prognosis of glioma and brain metastases has been summarized. Furthermore, the implications of tumor-associated neutrophil (TAN) phenotypes and the functions of TANs have been discussed. Finally, the potential effects of various treatments on TANs and the ability of neutrophils to function as a nanocarrier of drugs to the brain TME have been summarized. However, further studies are needed to elucidate the complex interactions between neutrophils, other immune cells, and brain tumor cells.
Genome-Wide DNA Methylation Pattern in Whole Blood Associated With Primary Intracerebral Hemorrhage
Authors: Zhang Yupeng , Long Hongyu , Wang Sai , Xiao Wenbiao , Xiong Meishan , Liu Jianyi , Chen Lei , Chen Ruijuan , Wei Xueli , Shu Yi , Zeng Yi , Zhang Le
Published: August 2021

Primary intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality throughout the world. ICH is a multifactorial disease that emerges from interactions among multiple genetic and environmental factors. DNA methylation plays an important role in the etiology of complex traits and diseases. We used the Illumina Infinium Human Methylation 850k BeadChip to detect changes in DNA methylation in peripheral blood samples from patients with ICH and healthy controls to explore DNA methylation patterns in ICH. Here, we compared genomic DNA methylation patterns in whole blood from ICH patients (n = 30) and controls (n = 34). The ICH and control groups showed significantly different DNA methylation patterns at 1530 sites (p-value < 5.92E-08), with 1377 hypermethylated sites and 153 hypomethylated sites in ICH patients compared to the methylation status in healthy controls. A total of 371 hypermethylated sites and 35 hypomethylated sites were in promoters, while 738 hypermethylated sites and 67 hypomethylated sites were in coding regions. Furthermore, the differentially methylated genes between ICH patients and controls were largely related to inflammatory pathways. Abnormalities in the DNA methylation pattern identified in the peripheral blood of ICH patients may play an important role in the development of ICH and warranted further investigation.
In-Depth Profiling of T-Cell Responsiveness to Commonly Recognized CMV Antigens in Older People Reveals Important Sex Differences
Authors: Reus Bernhard , Caserta Stefano , Larsen Martin , Morrow George , Bano Aalia , Hallensleben Michael , Rajkumar Chakravarthi , Pera Alejandra , Kern Florian
Published: August 2021

The impact of biological sex on T-cell immunity to Cytomegalovirus (CMV) has not been investigated in detail with only one published study comparing CMV-specific T-cell responses in men and women. Many studies, however, have shown an association between CMV infection and immunosenescence, with broad effects on peripheral blood lymphocyte subsets as well as the T and B-cell repertoires. Here, we provide a detailed analysis of CMV-specific T-cell responses in (n=94) CMV+ older people, including 47 women and 47 men aged between 60 and 93 years. We explore sex differences with respect to 16 different CMV proteins arranged in 14 peptide pools (overlapping peptides). Following ex vivo stimulation, CD4 and CD8 T-cells producing IFN-γ, TNF, and IL-2 were enumerated by flow-cytometry (intracellular cytokine staining). T-cell responses were evaluated in terms of each cytokine separately or in terms of cytokines produced simultaneously (polyfunctionality). Surface memory phenotype and CD3 downmodulation were assessed in parallel. The polyfunctionality index and a memory subset differentiation score were used to identify associations between response size, cytokine production, polyfunctionality, and memory subset distribution. While no significant sex differences were found with respect to overall CMV target protein selection, the T-cell response in men appeared more focused and accompanied by a more prominent accumulation of CMV-specific memory CD4 and CD8 T-cells. T-cell polyfunctionality and differentiation were similar in the sexes, however, CMV-specific T-cells in men produced more pro-inflammatory cytokines. Particularly, TNF production by CD4 T-cells was stronger in men than in women. Also, compared with women, men had larger responses to CMV proteins with immediate-early/early kinetics than women, which might have been driven by CMV reactivation. In conclusion, the CMV-specific T-cell response in men was larger and more pro-inflammatory than in women. Our findings may help explain sex differences in CMV-associated pathologies.
Binding of Staphylococcal Enterotoxin B (SEB) to B7 Receptors Triggers TCR- and CD28-Mediated Inflammatory Signals in the Absence of MHC Class II Molecules
Authors: Kunkl Martina , Amormino Carola , Caristi Silvana , Tedeschi Valentina , Fiorillo Maria Teresa , Levy Revital , Popugailo Andrey , Kaempfer Raymond , Tuosto Loretta
Published: August 2021

The inflammatory activity of staphylococcal enterotoxin B (SEB) relies on its capacity to trigger polyclonal T-cell activation by binding both T-cell receptor (TCR) and costimulatory receptor CD28 on T cells and MHC class II and B7 molecules on antigen presenting cells (APC). Previous studies highlighted that SEB may bind TCR and CD28 molecules independently of MHC class II, yet the relative contribution of these interactions to the pro-inflammatory function of SEB remained unclear. Here, we show that binding to MHC class II is dispensable for the inflammatory activity of SEB, whereas binding to TCR, CD28 and B7 molecules is pivotal, in both human primary T cells and Jurkat T cell lines. In particular, our finding is that binding of SEB to B7 molecules suffices to trigger both TCR- and CD28-mediated inflammatory signalling. We also provide evidence that, by strengthening the interaction between CD28 and B7, SEB favours the recruitment of the TCR into the immunological synapse, thus inducing lethal inflammatory signalling.
High-Frequency Variability of the Surface Ocean Properties Off Central Chile During the Upwelling Season
Authors: Aguirre Catalina , Garreaud René , Belmar Lucy , Farías Laura , Ramajo Laura , Barrera Facundo
Published: August 2021

The ocean off south-central Chile is subject to seasonal upwelling whose intensity is mainly controlled by the latitudinal migration of the southeast Pacific subtropical anticyclone. During austral spring and summer, the mean flow is equatorward favoring coastal upwelling, but periods of strong southerly winds are intermixed with periods of relaxed southerlies or weak northerly winds (downwelling favorable). This sub-seasonal, high-frequency variability of the coastal winds results in pronounced changes in oceanographic conditions and air-sea heat and gas exchanges, whose quantitative description has been limited by the lack of in-situ monitoring. In this study, high frequency fluctuations of meteorological, oceanographic and biogeochemical near surface variables were analyzed during two consecutive upwelling seasons (2016–17 and 2017–18) using observations from a coastal buoy located in the continental shelf off south-central Chile (36.4°S, 73°W), ∼10 km off the coast. The radiative-driven diel cycle is noticeable in meteorological variables but less pronounced for oceanographic and biogeochemical variables [ocean temperature, nitrate (NO3−), partial pressure of carbon dioxide (pCO2sea), pH, dissolved oxygen (DO)]. Fluorescence, as a proxy of chlorophyll-a, showed diel variations more controlled by biological processes. In the synoptic scale, 23 active upwelling events (strong southerlies, lasting between 2 and 15 days, 6 days in average) were identified, alternated with periods of relaxed southerlies of shorter duration (4.5 days in average). Upwelling events were related to the development of an atmospheric low-level coastal jet in response to an intense along-shore pressure gradient. Physical and biogeochemical surface seawater properties responded to upwelling favorable wind stress with approximately a 12-h lag. During upwelling events, SST, DO and pH decrease, while NO3−, pCO2sea, and air-sea fluxes increases. During the relaxed southerly wind periods, opposite tendencies were observed. The fluorescence response to wind variations is complex and diverse, but in many cases there was a reduction in the phytoplankton biomass during the upwelling events followed by higher values during wind relaxations. The sub-seasonal variability of the coastal ocean characterized here is important for biogeochemical and productivity studies.
Activity Levels of 210Po, 210Pb and Other Radionuclides (134Cs, 137Cs, 90Sr, 110mAg, 238U, 226Ra and 40K) in Marine Organisms From Coastal Waters Adjacent to Fuqing and Ningde Nuclear Power Plants (China) and Radiation Dose Assessment
Authors: Sun Jiang , Men Wu , Wang Fenfen , Wu Junwen
Published: August 2021

With the rapid development of nuclear power, the radiation impacts on edible marine organisms, and the potential radiation risks to humans have become of considerable concern to public health. In this study, the activities of 210Po and 210Pb as well as those of other radionuclides in fishes (Mugil cephalus, Konosirus punctatus, Largehead hairtail, and Larimichthys polyactis), crustaceans (Mantis shrimp, Parapenaeopsis hardwickii, and Portunus trituberculatus), bivalves (Crassostrea gigas, Sinonovacula conzcta), and macroalgae (Gracilaria, Porphyra) collected in the coastal area adjacent to the Fuqing and Ningde nuclear power plants (NPPs) were determined. The activity range of 210Po and 210Pb was 0.60–48.09 and 0.07–2.76 Bq/kg freshweight, respectively, with 210Po/210Pb activity ratios of 1.1–189.7. The ranking of 210Po activity levels in marine organisms was bivalve mollusks > crustaceans > fishes > macroalgae. The calculated bioconcentration factors of 210Po and 210Pb were 636–44,944 and 3–1,226 L/kg, respectively. These values provide a new supplement to the IAEA reference database. The radiation dose rates for these marine organisms ranged from 0.037 to 1.531 μSv/h, which was much lower than the ERICA ecosystem screening benchmark of 10 μGy/h. The calculated committed effective dose received by humans from ingestion of these marine organisms was 0.06–2.99 mSv. Overall, 210Po was the dominant radiation dose contributor in marine organisms and humans, whereas the dose contributions from the artificial nuclides 90Sr and 137Cs were negligible.
Phylogeography of Blue Corals (Genus Heliopora) Across the Indo-West Pacific
Authors: Taninaka Hiroki , Maggioni Davide , Seveso Davide , Huang Danwei , Townsend Abram , Richards Zoe T. , Tang Sen-Lin , Wada Naohisa , Kikuchi Taisei , Yuasa Hideaki , Kanai Megumi , De Palmas Stéphane , Phongsuwan Niphon , Yasuda Nina
Published: August 2021

Species delimitation of corals is one of the most challenging issues in coral reef ecology and conservation. Morphology can obscure evolutionary relationships, and molecular datasets are consistently revealing greater within-species diversity than currently understood. Most phylogenetic studies, however, have examined narrow geographic areas and phylogeographic expansion is required to obtain more robust interpretations of within- and among- species relationships. In the case of the blue coral Heliopora, there are currently two valid species (H. coerulea and H. hiberniana) as evidenced by integrated genetic and morphological analyses in northwestern Australia. There are also two distinct genetic lineages of H. coerulea in the Kuroshio Current region that are morphologically and reproductively different from each other. Sampling from all Heliopora spp. across the Indo-Pacific is essential to obtain a more complete picture of phylogeographic patterns. To examine phylogenetic relationships within the genus Heliopora, we applied Multiplexed inter simple sequence repeat (ISSR) Genotyping by sequencing (MIG-seq) on > 1287 colonies across the Indo-West Pacific. Maximum likelihood phylogenetic trees indicated the examined Heliopora samples comprise three genetically distinct groups: H. coerulea group, H. hiberniana group, and a new undescribed Heliopora sp. group with further subdivisions within each group. Geographic structuring is evident among the three species with H. hiberniana group found in the Indo-Malay Archipelago and biased toward the Indian Ocean whilst Heliopora sp. was only found in the Kuroshio Current region and Singapore, indicating that this taxon is distributed in the western Pacific and the Indo-Malay Archipelago. Heliopora coerulea has a wider distribution, being across the Indian Ocean and western Pacific. This study highlights the effectiveness of phylogenetic analysis using genome-wide markers and the importance of examining populations across their distribution range to understand localized genetic structure and speciation patterns of corals.
Seismic Performance and Strengthening of Purlin Roof Structures Using a Novel Damping-Limit Device
Authors: Chen Baokui , Jia Bao , Wen Ming , Li Xiaodong
Published: August 2021

Purlin roof structure houses, which have the advantages of readily accessible materials and simple construction, are widely used in rural areas of China. However, during earthquakes, the wooden purlins tend to fall off and the walls crack. Therefore, it is necessary to monitor the structural parameters of and strengthen the anti-seismic capacity of these structures. To compensate for the seismic deficiencies of the purlin roof structure, a novel damping-limit device installed at the connection position of the gable and the wooden purlin was proposed. In this study, the seismic performance and reinforcement effect of the brick-wood structure with the purlin roof were analyzed through numerical simulation. The research results indicate that the novel damping-limit device proposed in this study can significantly reduce the local stress concentration and the seismic response of the structure, and thereby rectifying the seismic defect of falling purlin. Moreover, compared with the traditional strengthening method, the novel device is more convenient to install and the reinforcement quality is easier to ensure.
Gallbladder Polyps Increase the Risk of Ischaemic Heart Disease Among Korean Adults
Authors: Lee Yong-Jae , Park Byoungjin , Hong Kyung-Won , Jung Dong-Hyuk
Published: August 2021

Background: Gallbladder (GB) polyps and ischaemic heart disease (IHD) share some common risk factors. We investigated the longitudinal effects of gallbladder (GB) polyps, as a surrogate metabolic indicator, on IHD.

Methods: We enrolled 19,612 participants from the health risk assessment study (HERAS) and Korean Health Insurance Review and Assessment Service (HIRA) database. The primary outcome was IHD, which consisted of angina pectoris (ICD-10 code I20) or acute myocardial infarction (ICD-10 code I21) that occurred after enrolment into the study. We calculated hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD according to the presence of GB polyps using multivariate Cox proportional hazards regression models.

Results: The median follow-up period was 29.9 months and a total of 473 individuals (2.4%, 473/19,612) developed IHD. Individuals with GB polyps had an increased risk of IHD compared with the control group after adjusting for potential confounding variables (HR = 1.425; 95% CI, 1.028–1.975). Furthermore, the coexistence of hypertension or dyslipidaemia resulted in an increased risk (HR = 2.14, 95% CI, 1.34–3.44 or HR = 2.09, 95% CI, 1.32–3.31, respectively) of new-onset IHD in the GB polyp group.

Conclusions: GB polyps was an independent risk factor of IHD. Awareness of these associations will inform clinicians on the need to include cardiovascular risk management as part of the routine management of patients with GB polyps.
Laboratory Testing Implications of Risk-Stratification and Management of COVID-19 Patients
Authors: Liu Caidong , Wang Ziyu , Wu Wei , Xiang Changgang , Wu Lingxiang , Li Jie , Hou Weiye , Sun Huiling , Wang Youli , Nie Zhenling , Gao Yingdong , Zhang Ruisheng , Tang Haixia , Wang Qianghu , Li Kening , Xia Xinyi , Li Pengping , Wang Shukui
Published: August 2021

Objective: To distinguish COVID-19 patients and non-COVID-19 viral pneumonia patients and classify COVID-19 patients into low-risk and high-risk at admission by laboratory indicators.

Materials and methods: In this retrospective cohort, a total of 3,563 COVID-19 patients and 118 non-COVID-19 pneumonia patients were included. There are two cohorts of COVID-19 patients, including 548 patients in the training dataset, and 3,015 patients in the testing dataset. Laboratory indicators were measured during hospitalization for all patients. Based on laboratory indicators, we used the support vector machine and joint random sampling to risk stratification for COVID-19 patients at admission. Based on laboratory indicators detected within the 1st week after admission, we used logistic regression and joint random sampling to develop the survival mode. The laboratory indicators of COVID-10 and non-COVID-19 were also compared.

Results: We first identified the significant laboratory indicators related to the severity of COVID-19 in the training dataset. Neutrophils percentage, lymphocytes percentage, creatinine, and blood urea nitrogen with AUC >0.7 were included in the model. These indicators were further used to build a support vector machine model to classify patients into low-risk and high-risk at admission in the testing dataset. Results showed that this model could stratify the patients in the testing dataset effectively (AUC = 0.89). Our model still has good performance at different times (Mean AUC: 0.71, 0.72, 0.72, respectively for 3, 5, and 7 days after admission). Moreover, laboratory indicators detected within the 1st week after admission were able to estimate the probability of death (AUC = 0.95). We identified six indicators with permutation p < 0.05, including eosinophil percentage (p = 0.007), white blood cell count (p = 0.045), albumin (p = 0.041), aspartate transaminase (p = 0.043), lactate dehydrogenase (p = 0.002), and hemoglobin (p = 0.031). We could diagnose COVID-19 and differentiate it from other kinds of viral pneumonia based on these laboratory indicators.

Conclusions: Our risk-stratification model based on laboratory indicators could help to diagnose, monitor, and predict severity at an early stage of COVID-19. In addition, laboratory findings could be used to distinguish COVID-19 and non-COVID-19.
Hyperosmotic Shock Transiently Accelerates Constriction Rate in Escherichia coli
Authors: Sun Jiawei , Shi Handuo , Huang Kerwyn Casey
Published: August 2021

Bacterial cells in their natural environments encounter rapid and large changes in external osmolality. For instance, enteric bacteria such asEscherichia coliexperience a rapid decrease when they exit from host intestines. Changes in osmolality alter the mechanical load on the cell envelope, and previous studies have shown that large osmotic shocks can slow down bacterial growth and impact cytoplasmic diffusion. However, it remains unclear how cells maintain envelope integrity and regulate envelope synthesis in response to osmotic shocks. In this study, we developed an agarose pad-based protocol to assay envelope stiffness by measuring population-averaged cell length before and after a hyperosmotic shock. Pad-based measurements exhibited an apparently larger length change compared with single-cell dynamics in a microfluidic device, which we found was quantitatively explained by a transient increase in division rate after the shock. Inhibiting cell division led to consistent measurements between agarose pad-based and microfluidic measurements. Directly after hyperosmotic shock, FtsZ concentration and Z-ring intensity increased, and the rate of septum constriction increased. These findings establish an agarose pad-based protocol for quantifying cell envelope stiffness, and demonstrate that mechanical perturbations can have profound effects on bacterial physiology.
3dRS, a Web-Based Tool to Share Interactive Representations of 3D Biomolecular Structures and Molecular Dynamics Trajectories
Authors: Bayarri Genís , Hospital Adam , Orozco Modesto
Published: August 2021

3D Representation Sharing (3dRS) is a web-based tool designed to share biomolecular structure representations, including 4D ensembles derived from Molecular Dynamics (MD) trajectories. The server offers a team working in different locations a single URL to share and discuss structural data in an interactive fashion, with the possibility to use it as a live figure for scientific papers. The web tool allows an easy upload of structures and trajectories in different formats. The 3D representation, powered by NGL viewer, offers an interactive display with smooth visualization in modern web browsers. Multiple structures can be loaded and superposed in the same scene. 1D sequences from the loaded structures are presented and linked to the 3D representation. Multiple, pre-defined 3D molecular representations are available. The powerful NGL selection syntax allows the definition of molecular regions that can be then displayed using different representations. Important descriptors such as distances or interactions can be easily added into the representation. Trajectory frames can be explored using a common video player control panel. Trajectories are efficiently stored and transferred to the NGL viewer thanks to an MDsrv-based data streaming. The server design offers all functionalities in one single web page, with a curated user experience, involving a minimum learning curve. Extended documentation is available, including a gallery with a collection of scenes. The server requires no registration and is available at https://mmb.irbbarcelona.org/3dRS.
Computer-Aided Rational Engineering of Signal Sensitivity of Quorum Sensing Protein LuxR in a Whole-Cell Biosensor
Authors: Li Jinyu , Liu Ruicun , Chen Yulu , Liu Shuxia , Chen Cheng , Liu Tuoyu , Yang Shan , Zhuang Yingtan , Yang Ruifu , Cui Yujun , Song Yajun , Wang Tao , Teng Yue
Published: August 2021

LuxR, a bacterial quorum sensing-related transcription factor that responds to the signaling molecule 3-oxo-hexanoyl-homoserine lactone (3OC6-HSL). In this study, we employed molecular dynamics simulation and the Molecular Mechanics Generalized Born Surface Area (MM-GB/SA) method to rationally identify residues in Vibrio fischeri LuxR that are important for its interaction with 3OC6-HSL. Isoleucine-46 was selected for engineering as the key residue for interaction with 3OC6-HSL-LuxR-I46F would have the strongest binding energy to 3OC6-HSL and LuxR-I46R the weakest binding energy. Stable wild-type (WT) LuxR, I46F and I46R variants were produced in Escherichia coli (E. coli) in the absence of 3OC6-HSL by fusion with maltose-binding protein (MBP). Dissociation constants for 3OC6-HSL from MBP-fusions of WT-, I46F- and I46R-LuxR determined by surface plasmon resonance confirmed the binding affinity. We designed and constructed a novel whole-cell biosensor on the basis of LuxR-I46F in E. coli host cells with a reporting module that expressed green fluorescent protein. The biosensor had high sensitivity in response to the signaling molecule 3OC6-HSL produced by the target bacterial pathogen Yersinia pestis. Our work demonstrates a practical, generalizable framework for the rational design and adjustment of LuxR-family proteins for use in bioengineering and bioelectronics applications.
IntelliCage Automated Behavioral Phenotyping Reveals Behavior Deficits in the 3xTg-AD Mouse Model of Alzheimer’s Disease Associated With Brain Weight
Authors: Winslow Wendy , McDonough Ian , Tallino Savannah , Decker Annika , Vural Austin S. , Velazquez Ramon
Published: August 2021

Transgenic rodent models of Alzheimer’s disease (AD) were designed to study mechanisms of pathogenesis and connect these mechanisms with cognitive decline. Measurements of cognition in rodents can be confounded, however, by human handling and interaction; the IntelliCage was created to circumvent these issues while measuring various facets of cognition in a social environment with water consumption as the primary motivator for task completion. Here, for the first time, we examined the behavioral performance of 3xTg-AD mice in the IntelliCage. Seven- to 9-month-old female 3xTg-AD and non-transgenic (NonTg) mice were tested for 29 days in the IntelliCage to measure prefrontal cortical and hippocampal function. We found that a higher percentage of NonTg mice (86.96%) were able to successfully complete the training (adaptation) phases compared to their 3xTg-AD (57.14%) counterparts. Furthermore, the 3xTg-AD mice showed impairments in attention and working memory. Interestingly, we found that differences in body and brain weight between NonTg and 3xTg-AD mice were associated with whether mice were able to complete the IntelliCage tasks. 3xTg-AD mice that completed IntelliCage tasks had lower cortical insoluble amyloid-β40 fractions than their 3xTg-AD counterparts who failed to complete the tasks. Collectively, these results demonstrate deficits in cognition in the 3xTg-AD mouse and inform scientists of important factors to consider when testing this transgenic model in the IntelliCage.
Apolipoprotein E Induced Cognitive Dysfunction: Mediation Analysis of Lipids and Glucose Biomarkers in an Elderly Cohort Study
Authors: Liu Linxin , Li Huichu , Iyer Hari , Liu Andy J. , Zeng Yi , Ji John S.
Published: August 2021

Introduction

Prior evidence suggested Apolipoprotein E (APOE), lipids, and glucose metabolism may act through the same pathways on the pathogenesis of Alzheimer’s disease (AD).

Methods

This prospective study used data from the Chinese Longitudinal Healthy Longevity Study. We tested the associations of APOE genotype (ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε4, and ε4ε4) and cognitive function using generalized estimating equations (GEE). We examined for possible mediation and effect modification by lipids and glucose level in this association.

Results

APOE ε2 showed significant direct protective effect and indirect harmful effect through TC on cognitive function. Abnormal lipids or glucose levels were not consistently associated with cognitive dysfunction in our study. We did not detect significant indirect effects through lipids for APOE ε4 or any indirect effects through glucose.

Discussion

These findings suggested complicated relationships among APOE, lipids, glucose, and cognitive function. Further study can make validations in other populations.
fNIRS Monitoring of Infant Prefrontal Cortex During Crawling and an Executive Functioning Task
Authors: Weibley Hannah , Di Filippo Mina , Liu Xinran , Lazenby Lillian , Goscha Jackson , Ferreira Alyssa , Muscalu Laura , Rader Nancy
Published: August 2021

Functional near-infrared spectroscopy (fNIRS)is a brain-imaging technology used to reveal brain activity by measuring blood oxygenation. Using fNIRS we measured activity in the left prefrontal lobe of 8–14 month-old infants as they crawled or were pushed in a stroller and as they were given a passive attention task or an active executive function (EF) task. For each task, we measured peak total hemoglobin concentration and peak Oxy relative to baseline. Results revealed differences in peak Oxy levels for crawling vs. strolling and between the EF and passive cognitive tasks, with total hemoglobin greater for the EF task than the passive attention task. These results support the theoretical view that both active locomotion and EF engage the prefrontal cortex (PFC) during early development.
Graph-Based Visual Manipulation Relationship Reasoning Network for Robotic Grasping
Authors: Zuo Guoyu , Tong Jiayuan , Liu Hongxing , Chen Wenbai , Li Jianfeng
Published: August 2021

To grasp the target object stably and orderly in the object-stacking scenes, it is important for the robot to reason the relationships between objects and obtain intelligent manipulation order for more advanced interaction between the robot and the environment. This paper proposes a novel graph-based visual manipulation relationship reasoning network (GVMRN) that directly outputs object relationships and manipulation order. The GVMRN model first extracts features and detects objects from RGB images, and then adopts graph convolutional network (GCN) to collect contextual information between objects. To improve the efficiency of relation reasoning, a relationship filtering network is built to reduce object pairs before reasoning. The experiments on the Visual Manipulation Relationship Dataset (VMRD) show that our model significantly outperforms previous methods on reasoning object relationships in object-stacking scenes. The GVMRN model is also tested on the images we collected and applied on the robot grasping platform. The results demonstrated the generalization and applicability of our method in real environment.
The Hippocampal Vulnerability to Herpes Simplex Virus Type I Infection: Relevance to Alzheimer’s Disease and Memory Impairment
Authors: Yong Shin Jie , Yong Min Hooi , Teoh Seong Lin , Soga Tomoko , Parhar Ishwar , Chew Jactty , Lim Wei Ling
Published: August 2021

Herpes simplex virus type 1 (HSV-1) as a possible infectious etiology in Alzheimer’s disease (AD) has been proposed since the 1980s. The accumulating research thus far continues to support the association and a possible causal role of HSV-1 in the development of AD. HSV-1 has been shown to induce neuropathological and behavioral changes of AD, such as amyloid-beta accumulation, tau hyperphosphorylation, as well as memory and learning impairments in experimental settings. However, a neuroanatomical standpoint of HSV-1 tropism in the brain has not been emphasized in detail. In this review, we propose that the hippocampal vulnerability to HSV-1 infection plays a part in the development of AD and amnestic mild cognitive impairment (aMCI). Henceforth, this review draws on human studies to bridge HSV-1 to hippocampal-related brain disorders, namely AD and aMCI/MCI. Next, experimental models and clinical observations supporting the neurotropism or predilection of HSV-1 to infect the hippocampus are examined. Following this, factors and mechanisms predisposing the hippocampus to HSV-1 infection are discussed. In brief, the hippocampus has high levels of viral cellular receptors, neural stem or progenitor cells (NSCs/NPCs), glucocorticoid receptors (GRs) and amyloid precursor protein (APP) that support HSV-1 infectivity, as well as inadequate antiviral immunity against HSV-1. Currently, the established diseases HSV-1 causes are mucocutaneous lesions and encephalitis; however, this review revises that HSV-1 may also induce and/or contribute to hippocampal-related brain disorders, especially AD and aMCI/MCI.
Efficacy and Safety of PARP Inhibitor Combination Therapy in Recurrent Ovarian Cancer: A Systematic Review and Meta-Analysis
Authors: Ren Ning , Zhang Leyin , Yu Jieru , Guan Siqi , Dai Xinyang , Sun Leitao , Ying Minli
Published: August 2021

Objectives

Though it is known to all that PARP inhibitors (PARPis) are effective when used as maintenance alone for women with recurrent ovarian cancer (ROC), little is known about whether using them in combination with other drugs would contribute to a better efficacy. We performed a systematic review and meta-analysis to explore the efficacy and safety of PARPi combination therapy compared with monotherapy.

Materials and Methods

We searched for randomized controlled trials (RCTs) that offered the date we needed in PubMed, Embase, Cochrane, and major conference. Data extraction and processing were completed by three investigators to compare OS, PFS, and ORR both in intervention and in control subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. And we evaluated the within-study heterogeneity by using subgroup and sensitivity analysis.

Results and Conclusion

A total of three eligible RCTs covering 343 women were included. In PFS analysis, PARP inhibitor (PARPi) combination therapy can significantly improve PFS for women with ROC when compared with the controls (HR: 0.46, 95% CI: 0.35 to 0.59), especially for those with mutated BRCA (HR: 0.29, 95% CI: 0.19 to 0.45). And in OS analysis, combination therapy is not inferior to monotherapy (HR: 0.90, 95% CI: 0.50 to 1.61). As for ORR, the effectiveness of combination therapy and monotherapy was almost the same (RR: 1.04, 95% CI: 0.82 to 1.31). Additionally, combination therapy seldom causes more adverse events, both in all-grade and in high grade.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/, International Prospective Register of Systematic Reviews (PROSPERO) (identifier, CRD42018109933).
High-Throughput In Vitro Gene Expression Profile to Screen of Natural Herbals for Breast Cancer Treatment
Authors: Kui Ling , Kong Qinghua , Yang Xiaonan , Pan Yunbing , Xu Zetan , Wang Shouling , Chen Jian , Wei Kunhua , Zhou Xiaolei , Yang Xingzhi , Wu Tingqin , Mastan Anthati , Liu Yao , Miao Jianhua
Published: August 2021

Breast cancer has surpassed lung cancer as the most commonly diagnosed cancer in women worldwide. Some therapeutic drugs and approaches could cause side effects and weaken the immune system. The combination of conventional therapies and traditional Chinese medicine (TCM) significantly improves treatment efficacy in breast cancer. However, the chemical composition and underlying anti-tumor mechanisms of TCM still need to be investigated. The primary aim of this study is to provide unique insights to screen the natural components for breast cancer therapy using high-throughput transcriptome analysis. Differentially expressed genes were identified based on two conditions: single samples and groups were classified according to their pharmaceutical effect. Subsequently, the sample treated with E. cochinchinensis Lour. generated the most significant DEGs set, including 1,459 DEGs, 805 upregulated and 654 downregulated. Similarly, group 3 treatment contained the most DEGs (414 DEGs, 311 upregulated and 103 downregulated). KEGG pathway analyses showed five significant pathways associated with the inflammatory and metastasis processes in cancer, which include the TNF, IL−17, NF-kappa B, MAPK signaling pathways, and transcriptional misregulation in cancer. Samples were classified into 13 groups based on their pharmaceutical effects. The results of the KEGG pathway analyses remained consistent with signal samples; group 3 presents a high significance. A total of 21 genes were significantly regulated in these five pathways, interestingly, IL6, TNFAIP3, and BRIC3 were enriched on at least two pathways, seven genes (FOSL1, S100A9, CXCL12, ID2, PRS6KA3, AREG, and DUSP6) have been reported as the target biomarkers and even the diagnostic tools in cancer therapy. In addition, weighted correlation network analysis (WGCNA) was used to identify 18 modules. Among them, blue and thistle2 were the most relevant modules. A total of 26 hub genes in blue and thistle2 modules were identified as the hub genes. In conclusion, we screened out three new TCM (R. communis L., E. cochinchinensis Lour., and B. fruticosa) that have the potential to develop natural drugs for breast cancer therapy, and obtained the therapeutic targets.
Clinicopathological and Prognostic Characteristics in Dedifferentiated/Poorly Differentiated Chordomas: A Pooled Analysis of Individual Patient Data From 58 Studies and Comparison With Conventional Chordomas
Authors: Liu Fu-Sheng , Zheng Bo-Wen , Zhang Tao-Lan , Li Jing , Lv Guo-Hua , Yan Yi-Guo , Huang Wei , Zou Ming-Xiang
Published: August 2021

Background

Currently, the clinicopathological and prognostic characteristics of dedifferentiated chordoma (DC) and poorly differentiated chordoma (PDC) remain poorly understood. In this study, we sought to characterize clinicopathological parameters in a large PDC/DC cohort and determine their correlations with progression-free survival (PFS) and overall survival (OS) of patients. We also attempted to compare clinical features between PDC/DC and conventional chordoma (CC).

Methods

Literature searches (from inception to June 01, 2020) using Medline, Embase, Google Scholar and Wanfang databases were conducted to identify eligible studies according to predefined criteria. The local database at our center was also retrospectively reviewed to include CC patients for comparative analysis.

Results

Fifty-eight studies from the literature and 90 CC patients from our local institute were identified; in total, 54 PDC patients and 96 DC patients were analyzed. Overall, PDC or DC had distinct characteristics from CC, while PDC and DC shared similar clinical features. Adjuvant radiotherapy and chemotherapy were associated with both PFS and OS in PDC patients in the univariate and/or multivariate analyses. In the DC cohort, tumor resection type, adjuvant chemotherapy and tumor dedifferentiation components significantly affected PFS, whereas none of them were predictive of outcome in the multivariate analysis. By analyzing OS, we found that surgery, resection type and the time to dedifferentiation predicted the survival of DC patients; however, only surgery remained significant after adjusting for other covariables.

Conclusions

These data may offer useful information to better understand the clinical characteristics of PDC/DC and may be helpful in improving the outcome prediction of patients.
Rectal Tumor Stiffness Quantified by In Vivo Tomoelastography and Collagen Content Estimated by Histopathology Predict Tumor Aggressiveness
Authors: Hu Jiaxi , Guo Jing , Pei Yigang , Hu Ping , Li Mengsi , Sack Ingolf , Li Wenzheng
Published: August 2021

Purpose

To investigate the significance of collagen in predicting the aggressiveness of rectal tumors in patients, examined in vivo based on tomoelastography quantified stiffness and ex vivo by histologically measured collagen volume fraction (CVF).

Experimental Design

170 patients with suspected rectal cancer were prospectively enrolled and underwent preoperative magnetic resonance imaging (MRI) and rectal tomoelastography, a technique based on multifrequency magnetic resonance elastography. Histopathologic analysis identified eighty patients with rectal cancer who were divided into subgroups by tumor-node (TN) stage, prognostic stage, and risk level. Rectal tumor stiffness was correlated with histopathologic CVF. Area-under-the-curve (AUC) and contingency analysis were used to evaluate the performance of rectal stiffness in distinguishing tumor stages which was compared to standard clinical MRI

Results

In vivo tomoelastography revealed that rectal tumor stiffened significantly with increased TN stage (p<0.05). Tumors with poorly differentiated status, perineural and lymphovascular invasion also displayed higher stiffness than well-to-moderately differentiated, noninvasive tumors (all p<0.05). Similar to in vivo stiffness, CVF indicated an abnormally high collagen content in tumors with perineural invasion and poor differentiation status. CVF was also positively correlated with stiffness (p<0.05). Most importantly, both stiffness (AUROC: 0.82) and CVF (AUROC: 0.89) demonstrated very good diagnostic accuracy in detecting rectal tumors that have high risk for progressing to an aggressive state with poorer prognosis.

Conclusion

In human rectal carcinomas, overexpression of collagen is correlated with increased tissue stiffness and high risk for tumor advancing more aggressively. In vivo tomoelastography quantifies rectal tumor stiffness which improves the diagnostic performance of standard MRI in the assessment of lymph nodes metastasis. Therefore, in vivo stiffness mapping by tomoelastography can predict rectal tumor aggressiveness and add diagnostic value to MRI.