bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Dissection of the Primase and Polymerase Activities of Deep-Sea Phage NrS-1 Primase-Polymerase
Authors: Huang Fengtao , Lu Xueling , Yu Chunxiao , Sliz Piotr , Wang Longfei , Zhu Bin
Published: December 2021

PrimPols are a class of primases that belong to the archaeo-eukaryotic primase (AEP) superfamily but have both primase and DNA polymerase activities. Replicative polymerase from NrS-1 phage (NrSPol) is a representative of the PrimPols. In this study, we identified key residues for the catalytic activity of NrSPol and found that a loop in NrSPol functionally replaces the zinc finger motif that is commonly found in other AEP family proteins. A helix bundle domain (HBD), conserved in the AEP superfamily, was recently reported to bind to the primase recognition site and to be crucial for initiation of primer synthesis. We found that NrSPol can recognize different primase recognition sites, and that the initiation site for primer synthesis is not stringent, suggesting that the HBD conformation is flexible. More importantly, we found that although the HBD-inactivating mutation impairs the primase activity of NrSPol, it significantly enhances the DNA polymerase activity, indicating that the HBD hinders the DNA polymerase activity. The conflict between the primase activity and the DNA polymerase activity in a single protein with the same catalytic domain may be one reason for why DNA polymerases are generally unable to synthesize DNA de novo.
Retinal Vibrations in Bacteriorhodopsin are Mechanically Harmonic but Electrically Anharmonic: Evidence From Overtone and Combination Bands
Authors: Lorenz-Fonfria Victor A. , Yagi Kiyoshi , Ito Shota , Kandori Hideki
Published: December 2021

Fundamental vibrations of the chromophore in the membrane protein bacteriorhodopsin (BR), a protonated Schiff base retinal, have been studied for decades, both by resonance Raman and by infrared (IR) difference spectroscopy. Such studies started comparing vibrational changes between the initial BR state (all-trans retinal) and the K intermediate (13-cis retinal), being later extended to the rest of intermediates. They contributed to our understanding of the proton-pumping mechanism of BR by exploiting the sensitivity of fundamental vibrational transitions of the retinal to its conformation. Here, we report on new bands in the 2,500 to 1,800 cm−1 region of the K-BR difference FT-IR spectrum. We show that the bands between 2,500 and 2,300 cm−1 originate from overtone and combination transitions from C-C stretches of the retinal. We assigned bands below 2,300 cm−1 to the combination of retinal C-C stretches with methyl rocks and with hydrogen-out-of-plane vibrations. Remarkably, experimental C-C overtone bands appeared at roughly twice the wavenumber of their fundamentals, with anharmonic mechanical constants ≤3.5 cm−1, and in some cases of ∼1 cm−1. Comparison of combination and fundamental bands indicates that most of the mechanical coupling constants are also very small. Despite the mechanical quasi-harmonicity of the C-C stretches, the area of their overtone bands was only ∼50 to ∼100 times smaller than of their fundamental bands. We concluded that electrical anharmonicity, the second mechanism giving intensity to overtone bands, must be particularly high for the retinal C-C stretches. We corroborated the assignments of negative bands in the K-BR difference FT-IR spectrum by ab initio anharmonic vibrational calculations of all-trans retinal in BR using a quantum-mechanics/molecular mechanics approach, reproducing reasonably well the small experimental anharmonic and coupling mechanical constants. Yet, and in spite accounting for both mechanical and electrical anharmonicities, the intensity of overtone C-C transitions was underestimated by a factor of 4–20, indicating room for improvement in state-of-the-art anharmonic vibrational calculations. The relatively intense overtone and combination bands of the retinal might open the possibility to detect retinal conformational changes too subtle to significantly affect fundamental transitions but leaving a footprint in overtone and combination transitions.
Structural Covariance Network as an Endophenotype in Alzheimer’s Disease-Susceptible Single-Nucleotide Polymorphisms and the Correlations With Cognitive Outcomes
Authors: Chang Hsin-I , Chang Yu-Tzu , Huang Chi-Wei , Huang Kuo-Lun , Hsu Jung-Lung , Hsu Shih-Wei , Tsai Shih-Jen , Chang Wen-Neng , Lee Chen-Chang , Huang Shu-Hua , Chang Chiung-Chih
Published: December 2021

The cognitive manifestations of Alzheimer’s disease (AD) are related to brain network degeneration, and genetic differences may mediate network degeneration. Several AD-susceptible loci have been reported to involve amyloid or tau cascades; however, their relationships with gray matter (GM) volume and cognitive outcomes have yet to be established. We hypothesized that single-nucleotide polymorphism genotype groups may interact with apolipoprotein E4 (ApoE4) status or independently exert an effect on cognitive outcomes. We also hypothesized that GM structural covariance networks (SCNs) may serve as an endophenotype of the genetic effect, which, in turn, may be related to neurobehavior test scores. Gray matter SCNs were constructed in 324 patients with AD using T1 magnetic resonance imaging with independent component analysis (ICA). We assessed the effects of 15 genetic loci (rs9349407, rs3865444, rs670139, rs744373, rs3851179, rs11136000, rs3764650, rs610932, rs6887649, rs7849530, rs4866650, rs3765728, rs34011, rs6656401, and rs597668) using additive, recessive, and dominant models on cognitive outcomes. Statistical analysis was performed to explore the independent role of each locus, interactions with ApoE4 status, and relationships to GM ICA network intensity score. For outcome measures, we used the Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI) total score, and short-term memory (STM) subscores, adjusted for the covariates of education, disease duration, and age. Clinically, the CD2AP G allele showed a protective role in MMSE, CASI total, and CASI-STM scores independently or via interactions with non-ApoE4 status, while the CR1 A genotype group was associated with lower STM subscores independent of ApoE4 status. Three loci showed synergic interactions with ApoE4: BIN 1, MS4A6A, and FTMT. Of the 15 meaningful ICA components, 5 SCNs (anterior and posterior hippocampus, right temporal, left thalamus, default mode network) showed relationships with general cognitive performance, in which only the ApoE4 and MS4A6A genotype groups were independently related to the hippocampus network. The genetic loci MS4A6A, BIN1, CLU, CR1, BIN1, PICALM, and FGF1 influenced the networks independently or in synergy. This study suggests that AD-susceptible loci may each exert clinical significance independently through interactions with ApoE4 status or through SCNs as an endophenotype and that this effect is associated with the cognitive outcomes.
Recent Advances on Lignocellulosic-Based Nanopesticides for Agricultural Applications
Authors: Lima Pedro Henrique Correia de , Antunes Débora Ribeiro , Forini Mariana Monteiro de Lima , Pontes Montcharles da Silva , Mattos Bruno Dufau , Grillo Renato
Published: December 2021

Controlled release systems of agrochemicals have been developed in recent years. However, the design of intelligent nanocarriers that can be manufactured with renewable and low-cost materials is still a challenge for agricultural applications. Lignocellulosic building blocks (cellulose, lignin, and hemicellulose) are ideal candidates to manufacture ecofriendly nanocarriers given their low-cost, abundancy and sustainability. Complexity and heterogeneity of biopolymers have posed challenges in the development of nanocarriers; however, the current engineering toolbox for biopolymer modification has increased remarkably, which enables better control over their properties and tuned interactions with cargoes and plant tissues. In this mini-review, we explore recent advances on lignocellulosic-based nanocarriers for the controlled release of agrochemicals. We also offer a critical discussion regarding the future challenges of potential bio-based nanocarrier for sustainable agricultural development.
Impact of Shared Control Modalities on Performance and Usability of Semi-autonomous Prostheses
Authors: Mouchoux Jérémy , Bravo-Cabrera Miguel A. , Dosen Strahinja , Schilling Arndt F. , Markovic Marko
Published: December 2021

Semi-autonomous (SA) control of upper-limb prostheses can improve the performance and decrease the cognitive burden of a user. In this approach, a prosthesis is equipped with additional sensors (e.g., computer vision) that provide contextual information and enable the system to accomplish some tasks automatically. Autonomous control is fused with a volitional input of a user to compute the commands that are sent to the prosthesis. Although several promising prototypes demonstrating the potential of this approach have been presented, methods to integrate the two control streams (i.e., autonomous and volitional) have not been systematically investigated. In the present study, we implemented three shared control modalities (i.e., sequential, simultaneous, and continuous) and compared their performance, as well as the cognitive and physical burdens imposed on the user. In the sequential approach, the volitional input disabled the autonomous control. In the simultaneous approach, the volitional input to a specific degree of freedom (DoF) activated autonomous control of other DoFs, whereas in the continuous approach, autonomous control was always active except for the DoFs controlled by the user. The experiment was conducted in ten able-bodied subjects, and these subjects used an SA prosthesis to perform reach-and-grasp tasks while reacting to audio cues (dual tasking). The results demonstrated that, compared to the manual baseline (volitional control only), all three SA modalities accomplished the task in a shorter time and resulted in less volitional control input. The simultaneous SA modality performed worse than the sequential and continuous SA approaches. When systematic errors were introduced in the autonomous controller to generate a mismatch between the goals of the user and controller, the performance of SA modalities substantially decreased, even below the manual baseline. The sequential SA scheme was the least impacted one in terms of errors. The present study demonstrates that a specific approach for integrating volitional and autonomous control is indeed an important factor that significantly affects the performance and physical and cognitive load, and therefore these should be considered when designing SA prostheses.
Home-Based Therapy After Stroke Using the Hand Spring Operated Movement Enhancer (HandSOME II)
Authors: Casas Rafael , Sandison Melissa , Nichols Diane , Martin Kaelin , Phan Khue , Chen Tianyao , Lum Peter S.
Published: December 2021

We have developed a passive and lightweight wearable hand exoskeleton (HandSOME II) that improves range of motion and functional task practice in laboratory testing. For this longitudinal study, we recruited 15 individuals with chronic stroke and asked them to use the device at home for 1.5 h per weekday for 8 weeks. Subjects visited the clinic once per week to report progress and troubleshoot problems. Subjects were then given the HandSOME II for the next 3 months, and asked to continue to use it, but without any scheduled contact with the project team. Clinical evaluations and biomechanical testing was performed before and after the 8 week intervention and at the 3 month followup. EEG measures were taken before and after the 8 weeks of training to examine any recovery associated brain reorganization. Ten subjects completed the study. After 8 weeks of training, functional ability (Action Research Arm Test), flexor tone (Modified Ashworth Test), and real world use of the impaired limb (Motor Activity Log) improved significantly (p< 0.05). Gains in real world use were retained at the 3-month followup (p= 0.005). At both post-training and followup time points, biomechanical testing found significant gains in finger ROM and hand displacement in a reaching task (p< 0.05). Baseline functional connectivity correlated with gains in motor function, while changes in EEG functional connectivity paralleled changes in motor recovery. HandSOME II is a low-cost, home-based intervention that elicits brain plasticity and can improve functional motor outcomes in the chronic stroke population.
Temporal Lobe Spikes Affect Distant Intrinsic Connectivity Networks
Authors: Mirandola Laura , Ballotta Daniela , Talami Francesca , Giovannini Giada , Pavesi Giacomo , Vaudano Anna Elisabetta , Meletti Stefano
Published: December 2021

Objective: To evaluate local and distant blood oxygen level dependent (BOLD) signal changes related to interictal epileptiform discharges (IED) in drug-resistant temporal lobe epilepsy (TLE).

Methods: Thirty-three TLE patients undergoing EEG–functional Magnetic Resonance Imaging (fMRI) as part of the presurgical workup were consecutively enrolled. First, a single-subject spike-related analysis was performed: (a) to verify the BOLD concordance with the presumed Epileptogenic Zone (EZ); and (b) to investigate the Intrinsic Connectivity Networks (ICN) involvement. Then, a group analysis was performed to search for common BOLD changes in TLE.

Results: Interictal epileptiform discharges were recorded in 25 patients and in 19 (58%), a BOLD response was obtained at the single-subject level. In 42% of the cases, BOLD changes were observed in the temporal lobe, although only one patient had a pure concordant finding, with a single fMRI cluster overlapping (and limited to) the EZ identified by anatomo-electro-clinical correlations. In the remaining 58% of the cases, BOLD responses were localized outside the temporal lobe and the presumed EZ. In every patient, with a spike-related fMRI map, at least one ICN appeared to be involved. Four main ICNs were preferentially involved, namely, motor, visual, auditory/motor speech, and the default mode network. At the single-subject level, EEG–fMRI proved to have high specificity (above 65%) in detecting engagement of an ICN and the corresponding ictal/postictal symptom, and good positive predictive value (above 67%) in all networks except the visual one. Finally, in the group analysis of BOLD changes related to IED revealed common activations at the right precentral gyrus, supplementary motor area, and middle cingulate gyrus.

Significance: Interictal temporal spikes affect several distant extra-temporal areas, and specifically the motor/premotor cortex. EEG–fMRI in patients with TLE eligible for surgery is recommended not for strictly localizing purposes rather it might be useful to investigate ICNs alterations at the single-subject level.
FoxP3− Tr1 Cell in Generalized Myasthenia Gravis and Its Relationship With the Anti-AChR Antibody and Immunomodulatory Cytokines
Authors: Meng Huanyu , Zheng Shuyu , Zhou Qinming , Gao Yining , Ni You , Liang Huafeng , Chen Sheng
Published: December 2021

Introduction: The changes in the number and function of regulatory T cells (Tregs) are thought to play important roles in the pathogenesis of generalized myasthenia gravis (gMG). Previous studies have suggested the decrease of FoxP3+ Treg cells in the MG development. However, there is no study on the pathophysiological mechanism of FoxP3−Treg, especially Tr1 cells, in gMG patients. Therefore, this study was conducted to reveal the effect of Tr1 cells to the pathophysiology of gMG.

Methods: Thirteen patients with gMG and twelve healthy volunteers were enrolled in this study. The titer of anti-AChR Ab was measured by ELISA. The separated PBMCs were labeled for CD4, CD25, CD49b, LAG3 and FoxP3. The CD4+ T cell count, FoxP3+ Treg to CD4+ T cell ratio and Tr1 cell to CD4+ T cell ratio were measured by flow cytometry. Based on the FoxP3+ Treg and Tr1 cell to CD4+ T cell ratios, the patients' Tr1 cell to FoxP3+ Treg ratios were calculated. The IL-6, IL-7, IL-10, TGF-β and IFN-γ concentration in the serum of MG patients and normal controls (NCs) were measured via ELISA.

Results: We found a significantly positive correlation between the Tr1 cell/CD4+ T cell ratio and the anti-AChR Ab (r = 0.6889 ± 0.4414, p = 0.0401). Although there were no significant differences in the relationship between FoxP3+ Treg cells and anti-AChR Ab, a positive correlation between the Tr1 cell/FoxP3+ Treg cell ratio and the anti-AChR Ab (r = 0.7110 ± 0.4227, p = 0.0318) was observed. In addition, the Tr1 cell/CD4+ T cell ratio but not the proportion of FoxP3+ Tregs was positively correlated with IL-10 (p = 0.048). These results suggested that in the process of the immunomodulatory effect of Tr1 cells in patients with gMG, IL-10 and other cytokines may be involved, but the specific mechanism needs further study.

Conclusion: This is the first study of the immunoregulatory mechanism of Tr1 cells in gMG. We conducted this study to elucidate the significance of Tr1 cells in the pathogenesis of MG. We believe that in patients with gMG, Tr1 cells may play an immunomodulatory role in counteracting AChR-related autoimmune responses. In this process, IL-10 and other immunomodulatory cytokines may be involved.
Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings
Authors: Nelson Todd , Zhang Lan-Xin , Guo Hui , Nacul Luis , Song Xiaowei
Published: December 2021

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem medical condition with heterogeneous symptom expression. Currently, there is no effective cure or treatment for the standard care of patients. A variety of ME/CFS symptoms can be linked to the vital life functions of the brainstem, the lower extension of the brain best known as the hub relaying information back and forth between the cerebral cortex and various parts of the body.

Objective/Methods: Over the past decade, Magnetic Resonance Imaging (MRI) studies have emerged to understand ME/CFS with interesting findings, but there has lacked a synthesized evaluation of what has been found thus far regarding the involvement of the brainstem. We conducted this study to review and evaluate the recent MRI findings via a literature search of the MEDLINE database, from which 11 studies met the eligibility criteria.

Findings: Data showed that MRI studies frequently reported structural changes in the white and gray matter. Abnormalities of the functional connectivity within the brainstem and with other brain regions have also been found. The studies have suggested possible mechanisms including astrocyte dysfunction, cerebral perfusion impairment, impaired nerve conduction, and neuroinflammation involving the brainstem, which may at least partially explain a substantial portion of the ME/CFS symptoms and their heterogeneous presentations in individual patients.

Conclusions: This review draws research attention to the role of the brainstem in ME/CFS, helping enlighten future work to uncover the pathologies and mechanisms of this complex medical condition, for improved management and patient care.
Relating Global and Local Connectome Changes to Dementia and Targeted Gene Expression in Alzheimer's Disease
Authors: Elsheikh Samar S. M. , Chimusa Emile R. ,   Alzheimer's Disease Neuroimaging Initiative, Mulder Nicola J. , Crimi Alessandro
Published: December 2021

Networks are present in many aspects of our lives, and networks in neuroscience have recently gained much attention leading to novel representations of brain connectivity. The integration of neuroimaging characteristics and genetics data allows a better understanding of the effects of the gene expression on brain structural and functional connections. The current work uses whole-brain tractography in a longitudinal setting, and by measuring the brain structural connectivity changes studies the neurodegeneration of Alzheimer's disease. This is accomplished by examining the effect of targeted genetic risk factors on the most common local and global brain connectivity measures. Furthermore, we examined the extent to which Clinical Dementia Rating relates to brain connections longitudinally, as well as to gene expression. For instance, here we show that the expression of PLAU gene increases the change over time in betweenness centrality related to the fusiform gyrus. We also show that the betweenness centrality metric impact dementia-related changes in distinct brain regions. Our findings provide insights into the complex longitudinal interplay between genetics and brain characteristics and highlight the role of Alzheimer's genetic risk factors in the estimation of regional brain connectivity alterations.
Quantitative Electroencephalogram Standardization: A Sex- and Age-Differentiated Normative Database
Authors: Ko Juhee , Park Ukeob , Kim Daekeun , Kang Seung Wan
Published: December 2021

We describe the utility of a standardized index (Z-score) in quantitative EEG (QEEG) capable of when referenced to a resting-state, sex- and age-differentiated QEEG normative database (ISB-NormDB). Our ISB-NormDB comprises data for 1,289 subjects (553 males, 736 females) ages 4.5 to 81 years that met strict normative data criteria. A de-noising process allowed stratification based on QEEG variability between normal healthy men and women at various age ranges. The ISB-NormDB data set that is stratified by sex provides a unique, highly accurate ISB-NormDB model (ISB-NormDB: ISB-NormDB-Male, ISB-NormDB-Female). To evaluate the trends and accuracy of the ISB-NormDB, we used actual data to compare Z-scores obtained through the ISB-NormDB with those obtained through a traditional QEEG normative database to confirm that basic trends are maintained in most bands and are sensitive to abnormal test data. Finally, we demonstrate the value of our standardized index of QEEG, and highlight it’s capacity to minimize the confounding variables of sex and age in any analysis.
Cortico-Cerebellar Hyper-Connections and Reduced Purkinje Cells Behind Abnormal Eyeblink Conditioning in a Computational Model of Autism Spectrum Disorder
Authors: Trimarco Emiliano , Mirino Pierandrea , Caligiore Daniele
Published: December 2021

Empirical evidence suggests that children with autism spectrum disorder (ASD) show abnormal behavior during delay eyeblink conditioning. They show a higher conditioned response learning rate and earlier peak latency of the conditioned response signal. The neuronal mechanisms underlying this autistic behavioral phenotype are still unclear. Here, we use a physiologically constrained spiking neuron model of the cerebellar-cortical system to investigate which features are critical to explaining atypical learning in ASD. Significantly, the computer simulations run with the model suggest that the higher conditioned responses learning rate mainly depends on the reduced number of Purkinje cells. In contrast, the earlier peak latency mainly depends on the hyper-connections of the cerebellum with sensory and motor cortex. Notably, the model has been validated by reproducing the behavioral data collected from studies with real children. Overall, this article is a starting point to understanding the link between the behavioral and neurobiological basis in ASD learning. At the end of the paper, we discuss how this knowledge could be critical for devising new treatments.
From Intrauterine to Extrauterine Life—The Role of Endogenous and Exogenous Factors in the Regulation of the Intestinal Microbiota Community and Gut Maturation in Early Life
Authors: Socha-Banasiak Anna , Pawłowska Malwina , Czkwianianc Elżbieta , Pierzynowska Kateryna
Published: December 2021

Differentiation of the digestive tube and formation of the gut unit as a whole, are regulated by environmental factors through epigenetic modifications which enhance cellular plasticity. The critical period of DNA imprinting lasts from conception until approximately the 1,000th day of human life. During pregnancy, besides agents that may directly promote epigenetic programming (e.g., folate, zinc, and choline supplementation), some factors (e.g., antibiotic use, dietary components) can affect the composition of the mother's microbiota, in turn affecting the fetal microbiome which interacts with the offspring's intestinal epithelial cells. According to available literature that confirms intrauterine microbial colonization, the impact of the microbiome and its metabolites on the genome seems to be key in fetal development, including functional gut maturation and the general health status of the offspring, as well as later on in life. Although the origin of the fetal microbiome is still not well-understood, the bacteria may originate from both the vagina, as the baby is born, as well as from the maternal oral cavity/gut, through the bloodstream. Moreover, the composition of the fetal gut microbiota varies depending on gestational age, which in turn possibly affects the regulation of the immune system at the barrier between mother and fetus, leading to differences in the ability of microorganisms to access and survive in the fetal environment. One of the most important local functions of the gut microbiota during the prenatal period is their exposure to foreign antigens which in turn contributes to immune system and tissue development, including fetal intestinal Innate Lymphoid Cells (ILCs). Additional factors that determine further infant microbiome development include whether the infant is born premature or at term, the method of delivery, maternal antibiotic use, and the composition of the mother's milk, among others. However, the latest findings highlight the fact that a more diverse infant gut microbiome at birth facilitates the proliferation of stem cells by microbial metabolites and accelerates infant development. This phenomenon confirms the unique role of microbiome. This review emphasizes the crucial perinatal and postnatal factors that may influence fetal and neonatal microbiota, and in turn gut maturation.
Endoscopic Versus Surgical Therapy for Early Esophagogastric Junction Adenocarcinoma Based on Lymph Node Metastasis Risk: A Population-Based Analysis
Authors: Ye Hua , Chen Ping , Wang Yi-Fan , Cai Xiu-Jun
Published: December 2021

Background

In this study, we aimed to compare the prognosis and lymph node metastasis (LNM) risk in patients with early-stage esophagogastric junction (EGJ) adenocarcinoma after endoscopic treatment (ET) or radical surgery.

Methods

We collected data from eligible patients based on the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. Logistic regression analysis was used to determine independent predictors of LNM (examination of at least 16 lymph nodes). Cox regression analysis and propensity score-matched (PSM) analysis were subsequently utilized to compare the overall survival (OS) and cancer-specific survival (CSS) of patients treated with ET or radical surgery.

Results

In total, 3708 patients were identified. Among them, 856 patients had greater than or equal to 16 examined lymph nodes (LNs) (LNE≥16). The LNM rates were 18.8% in all patients 8.3% in T1a patients and 24.6% in T1b patients. Independent predictors of LNM were submucosal invasion, tumor size ≥3cm and decreasing differentiation (P<0.05). The LNM rate decreased to approximately 5.3% in T1b tumors with well differentiation and tumor size <3cm. However, the LNM incidence increased to 17.9% or 33.3% in T1a tumors with poor differentiation or with both tumor size≥3cm and poor differentiation. Cox regression analysis demonstrated CSS was not significantly different in early-stage EGJ adenocarcinoma patients undergoing ET and those treated with radical surgery (HR= 1.004, P=0.974), which were robustly validated after PSM analysis. Moreover, subgroup analysis stratified by T1a and T1b showed similar results.

Conclusions

The findings of this study indicated ET as an alternative to radical surgery in early EGJ adenocarcinoma.
Maximum Standardized Uptake Value of 18F-deoxyglucose PET Imaging Increases the Effectiveness of CT Radiomics in Differentiating Benign and Malignant Pulmonary Ground-Glass Nodules
Authors: Niu Rong , Gao Jianxiong , Shao Xiaoliang , Wang Jianfeng , Jiang Zhenxing , Shi Yunmei , Zhang Feifei , Wang Yuetao , Shao Xiaonan
Published: December 2021

To investigate whether the maximum standardized uptake value (SUVmax) of 18F-deoxyglucose (FDG) PET imaging can increase the diagnostic efficiency of CT radiomics-based prediction model in differentiating benign and malignant pulmonary ground-glass nodules (GGNs). We retrospectively collected 190 GGNs from 165 patients who underwent 18F-FDG PET/CT examination from January 2012 to March 2020. Propensity score matching (PSM) was performed to select GGNs with similar baseline characteristics. LIFEx software was used to extract 49 CT radiomic features, and the least absolute shrinkage and selection operator (LASSO) algorithm was used to select parameters and establish the Rad-score. Logistic regression analysis was performed combined with semantic features to construct a CT radiomics model, which was combined with SUVmax to establish the PET + CT radiomics model. Receiver operating characteristic (ROC) was used to compare the diagnostic efficacy of different models. After PSM at 1:4, 190 GGNs were divided into benign group (n = 23) and adenocarcinoma group (n = 92). After texture analysis, the Rad-score with three CT texture features was constructed for each nodule. Compared with the Rad-score and CT radiomics model (AUC: 0.704 (95%CI: 0.562-0.845) and 0.908 (95%CI: 0.842-0.975), respectively), PET + CT radiomics model had the best diagnostic efficiency (AUC: 0.940, 95%CI: 0.889-0.990), and there was significant difference between each two of them (P = 0.001-0.030). SUVmax can effectively improve CT radiomics model performance in the differential diagnosis of benign and malignant GGNs. PET + CT radiomics might become a noninvasive and reliable method for differentiating of GGNs.
SAMHD1 Mutations and Expression in Mantle Cell Lymphoma Patients
Authors: Wang Tao , Yue Wenqin , Tang Gusheng , Ye Mingyu , Yu Jiechen , Liu Bin , Jiao Lijuan , Liu Xuefei , Yin Shuyi , Chen Jie , Gao Lei , Yang Jianmin , He Miaoxia
Published: December 2021

SAMHD1 (sterile alpha motif domain and histidine-aspartate domain-containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase regulating innate immune and modulating DNA damage signaling. It plays an important role in the development of some tumors. SAMHD1 was also reported as a barrier to cytarabine, a common chemotherapy drug for mantle cell lymphoma (MCL), and as a biomarker of grim prognosis for acute myelocytic leukemia (AML) patients. However, SAMHD1 expression and function in MCL have not been well-defined. In the present study, we evaluated SAMHD1 expression by immunohistochemistry and its gene structure by Sanger sequencing in MCL. Our results showed that SAMHD1 was positive in 36 (62.1%) patients. Importantly, SAMHD1-positive patients were associated with lower chemotherapy response rate (p = 0.023) and shorter overall survival (p = 0.039) than SAMHD1-negative cases. These results suggest that SAMHD1 is an adverse biomarker for MCL patients, which is due to the high expression of SAMHD1 and rapid cell proliferation. These findings were confirmed in an in vitro study using the siRNA technique. Silencing the SAMHD1 gene in the MCL cell line Jeko-1 significantly decreased cell proliferation and increased cell apoptosis. The MCL cell line with SAMHD1 knockdown showed lower Ki-67 proliferation index, higher caspase-3, and higher sensitivity to cytarabine. Furthermore, for the first time, four previously unreported missense mutations (S302Y, Y432C, E449G, and R451H) in exon 8 and exon 12 of the SAMHD1 gene were discovered by sequencing. The mutations had not been found to corelate with SAMHD1 protein expression detected by immunohistochemistry. The biological functions of this mutated SAMHD1 remain to be investigated.
ITGA5 Predicts Dual-Drug Resistance to Temozolomide and Bevacizumab in Glioma
Authors: Shi Ying , Wu Mengwan , Liu Yuyang , Hu Lanlin , Wu Hong , Xie Lei , Liu Zhiwei , Wu Anhua , Chen Ling , Xu Chuan
Published: December 2021

Aims

Anti-angiotherapy (Bevacizumab) is currently regarded as a promising option for glioma patients who are resistant to temozolomide (TMZ) treatment. But ongoing clinical research failed to meet therapeutic expectations. This study aimed to explore the pivotal genetic feature responsible for TMZ and Bevacizumab resistance in glioma patients.

Methods

We downloaded the transcriptomic and methylation data of glioma patients from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases and grouped these patients into resistant and non-resistant groups based on their clinical profiles. Differentially expressed genes and pathways were identified and exhibited with software in R platform. A TMZ-resistant cell line was constructed for validating the expression change of the candidate gene, ITGA5. An ITGA5-overexpressing cell line was also constructed to investigate its biological function using the CCK8 assay, Western blot, periodic acid–Schiff (PAS) staining, and transcriptional sequencing.

Results

Change of the cell morphology and polarity was closely associated with TMZ mono-resistance and TMZ/Bevacizumab dual resistance in glioma patients. The expression level of ITGA5 was effective in determining drug resistance and the outcome of glioma patients, which is regulated by methylation on two distinct sites. ITGA5 was augmented in TMZ-resistant glioma cells, while overexpressing ITGA5 altered the cell-promoted TMZ resistance through enhancing vascular mimicry (VM) formation correspondingly.

Conclusions

Both the epigenetic and transcriptional levels of ITGA5 are effective in predicting TMZ and Bevacizumab resistance, indicating that ITGA5 may serve as a predictor of the treatment outcomes of glioma patients.
Massive Calcified Epithelioid Hemangioendothelioma With Multifocal Involvement: An Imaging Diagnosis Dilemma and a Rare Case Report
Authors: Che Feng , Yang Cai wei , Hu Xue , Li Qian , Wei Yi , Liu Xi jiao , Song Bin
Published: December 2021

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor that develops from vascular endothelial or pre-endothelial cells. More than 60% patients have single-organ involvement, and involvement of multiple organs including the liver, lungs, and bones is extremely rare. The typical radiographic features of EHE include multiple small nodules in both lungs, which are usually located near small- and medium-sized blood vessels and the bronchi, and solitary, multiple, or diffuse lesions located at the hepatic periphery, spreading within the branches of the portal and hepatic veins. Radiologic calcification has been rarely reported in the literature. Here, we firstly described a case of a 53-year-old woman with EHE who presented with lungs, liver, bone, and right hilar lymph node involvement, manifesting as massive calcification on computed tomography. This case reminds physicians that EHE may present with unusual imaging manifestations, like massive calcification, and should be considered during the diagnostic process.
A Retrospective Study of Lenvatinib Monotherapy or Combined With Programmed Cell Death Protein 1 Antibody in the Treatment of Patients With Hepatocellular Carcinoma or Intrahepatic Cholangiocarcinoma in China
Authors: Zhu Sihui , Liu Chenxi , Dong Yanbing , Shao Jie , Liu Baorui , Shen Jie
Published: December 2021

Lenvatinib has been ratified as a first-line medication for advanced liver tumors by the American Food and Drug Administration. To assess the effectiveness and security of Lenvatinib in the Chinese population in a real-world setting, we enrolled 48 patients with unresectable liver cancer, managed from December 2018 to March 2021. Among them, 9 and 39 (83.30% men) patients had intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), respectively. Twenty-one (43.75%) patients had progressive disease after first-line treatment, and others (56.25%) had not receiving systemic treatment. Lenvatinib was administered alone or in combination with a programmed cell death protein 1 antibody (anti-PD-1). Treatment duration, median progression-free survival (mPFS), and median overall survival (mOS) were examined. The mOS and mPFS were 22.43 and 8.93 months, respectively. Of HCC patients treated with Lenvatinib only, the mOS and mPFS were 22.43 and 11.60 months, respectively. The corresponding values for HCC cases managed with anti-PD-1 combined with Lenvatinib were 21.77 and 7.10 months, respectively. ICC patients did not reach the mOS and their mPFS was 8.63 months. The present findings support the efficacy and security of Lenvatinib in the real-world therapy of Chinese patients with unresectable liver cancer.
Adding Concurrent Chemotherapy Significantly Improves the Survival of Stage II-IVb Nasopharyngeal Carcinoma Patients Treated With Concurrent Anti-EGFR Agents
Authors: Yu Zi-Kun , Chen Xu-Yin , Liu Si-Han , Liu You-Ping , You Rui , Huang Pei-Yu
Published: December 2021

Objective

Anti-EGFR Targeted agents were found to be capable of modulating the antitumor immunity in head and neck cancer and become more and more frequently used in the treatment of nasopharyngeal carcinoma(NPC). We aimed to explore whether adding concurrent chemotherapy influences the survival outcome of patients with stage II-IVb NPC treated with concurrent anti-EGFR agents and intensity-modulated radiation therapy (IMRT) and explore other prognostic factors for the patients.

Materials and Methods

A total of 656 stage II-IVb NPC patients treated with concurrent anti-EGFR agents plus IMRT between January 2011 and November 2015 were enrolled. Firstly, from these patients, a well-balanced cohort of 302 patients who received concurrent chemotherapy was created by matching potential prognostic factors. Furthermore, for all 656 stage II-IVb NPC patients, univariate and multivariate analyses of overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) were conducted to identify prognostic factors and to confirm the findings from the matching cohort.

Results

Compared with concurrent anti-EGFR agents alone, combining concurrent cisplatin and anti-EGFR agents significantly improved the OS (5-year 94.7% versus 84.3%, P=0.012) and PFS (5-year 82.0% versus 71.7%, P=0.039) of NPC patients with more severe hematologic toxicity and mucositis. The independent prognostic factors identified by multivariate analysis of OS and PFS included concurrent chemotherapy, epstein-barr virus(EBV) status and clinical stage. Patients treated without induction chemotherapy (IC) may achieve more benefits from the addition of concurrent chemotherapy to concurrent anti-EGFR agents.

Conclusions

For stage II-IVb NPC patients treated with concurrent anti-EGFR agents, the addition of concurrent chemotherapy can significantly improve the survival outcome.
Evaluation of the Efficacy of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis
Authors: Wu Kan , Liang Jiayu , Shao Yanxiang , Xiong Sanchao , Feng Shuyang , Li Xiang
Published: December 2021

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have breakthrough designations for metastatic castration-resistant prostate cancer (mCRPC). We performed a meta-analysis of current clinical trials to evaluate the efficacy of PARP inhibitors in mCRPC patients based on their genetic status.

Methods: On August 2020, PubMed, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for phase II/III clinical studies on PARP inhibitors in mCRPC patients. Data were extracted independently by two investigators and analyzed using Review Manager software version 5.3. Primary endpoints included overall response rate (ORR) and progression-free survival (PFS).

Results: Nine clinical trials were identified and analyzed for the clinical benefit of PARP inhibitors in mCRPC patients (n = 1,219). Pooled analyses demonstrated that PARP inhibitors could provide a significant improvement of ORR and PFS in patients with homologous recombination deficiency (HRD) when compared with non-HRD patients. Within the HRD subgroup, BRCA mutation patients achieved significantly higher ORR [odds ratio (OR): 9.97, 95% confidence interval (CI): 6.08–16.35] and PFS rates at 12 months (OR: 3.23, 95% CI: 1.71–6.10) when compared with BRCA wild-type patients. Furthermore, patients harboring HRD without BRCA mutations have a higher objective response after PARP inhibitor treatment compared with non-HRD patients.

Conclusion: PARP inhibitor is an effective treatment option for mCRPC patients with mutations in genes related to the HR DNA repair pathway when compared with non-HRD patients. In addition to BRCA mutations, other HRD-related gene aberrations may also be used as novel biomarkers to predict the efficacy of PARP inhibitors.
Geographically Explicit Network Analysis of Urban Living and Working Interaction Pattern in Shenzhen City, South China
Authors: Yuan Zhilu , Lin Haojia , Tang Shengjun , Guo Renzhong
Published: December 2021

Human daily mobility plays an important role in urban research. Commuting of urban residents is an important part of urban daily mobility, especially in working days. However, the characteristic of the mobility network formed by the commuting of urban residents and its impact on the internal structure of the city are still an important work that needs to be explored further. Aiming to study the living–working interaction pattern of meta-populations over urban divisions within cities, a fine-grained dataset of living–working tracking of Shenzhen is curated and used to construct an urban living–working mobility network, and the living–working interaction pattern is analyzed through the community structures of the network. The results show that human daily mobility plays an important role in understanding the formation of urban structure, the administrative divisions of the city affect human daily mobility, and human daily mobility reacts on the formation of urban structure.
Muscle Fatigue Revisited – Insights From Optically Pumped Magnetometers
Authors: Sometti Davide , Semeia Lorenzo , Baek Sangyeob , Chen Hui , Righetti Giulia , Dax Juergen , Kronlage Cornelius , Kirchgässner Milena , Romano Alyssa , Heilos Johanna , Staber Deborah , Oppold Julia , Middelmann Thomas , Braun Christoph , Broser Philip , Marquetand Justus
Published: December 2021

So far, surface electromyography (sEMG) has been the method of choice to detect and evaluate muscle fatigue. However, recent advancements in non-cryogenic quantum sensors, such as optically pumped magnetometers (OPMs), enable interesting possibilities to flexibly record biomagnetic signals. Yet, a magnetomyographic investigation of muscular fatigue is still missing. Here, we simultaneously used sEMG (4 surface electrode) and OPM-based magnetomyography (OPM-MMG, 4 sensors) to detect muscle fatigue during a 3 × 1-min isometric contractions of the left rectus femoris muscle in 7 healthy participants. Both signals exhibited the characteristic spectral compression distinctive for muscle fatigue. OPM-MMG and sEMG slope values, used to quantify the spectral compression of the signals, were positively correlated, displaying similarity between the techniques. Additionally, the analysis of the different components of the magnetic field vector enabled speculations regarding the propagation of the muscle action potentials (MAPs). Altogether these results show the feasibility of the magnetomyographic approach with OPMs and propose a potential alternative to sEMG for the study of muscle fatigue.
Modulation of Ryanodine Receptors Activity Alters the Course of Experimental Autoimmune Encephalomyelitis in Mice
Authors: Osipchuk Natalia C. , Soulika Athena M. , Fomina Alla F.
Published: December 2021

Ryanodine receptors (RyRs), the intracellular Ca2+ release channels, are expressed in T lymphocytes and other types of immune cells. Modulation of RyRs has been shown to affect T cell functions in vitro and immune responses in vivo. The effects of modulation of RyRs on the development of autoimmune diseases have not been investigated. Here we studied how modulation of RyRs through administration of RyR inhibitor dantrolene or introducing a gain-of-function RYR1-p.R163C mutation affects clinical progression of experimental autoimmune encephalomyelitis (EAE) in mice, a T cell-mediated autoimmune neuroinflammatory disease. We found that daily intraperitoneal administration of 5 or 10 mg/kg dantrolene beginning at the time of EAE induction significantly reduced the severity of EAE clinical symptoms and dampened inflammation in the spinal cord. The protective effect of dantrolene on EAE was reversible. Dantrolene administration elicited dose-dependent skeletal muscle weakness: mice that received 10 mg/kg dose developed a waddling gait, while 5 mg/kg dantrolene dose administration produced a reduction in four-limb holding impulse values. Mice bearing the gain-of-function RYR1-p.R163C mutation developed the EAE clinical symptoms faster and more severely than wild-type mice. This study demonstrates that RyRs play a significant role in EAE pathogenesis and suggests that inhibition of RyRs with low doses of dantrolene may have a protective effect against autoimmunity and inflammation in humans.
Comparison Between High- and Low-Intensity Static Stretching Training Program on Active and Passive Properties of Plantar Flexors
Authors: Nakamura Masatoshi , Yoshida Riku , Sato Shigeru , Yahata Kaoru , Murakami Yuta , Kasahara Kazuki , Fukaya Taizan , Takeuchi Kosuke , Nunes João Pedro , Konrad Andreas
Published: December 2021

The purpose of this study was to compare two static stretching (SS) training programs at high-intensity (HI-SS) and low-intensity (LI-SS) on passive and active properties of the plantar flexor muscles. Forty healthy young men were randomly allocated into three groups: HI-SS intervention group (n = 14), LI-SS intervention group (n = 13), and non-intervention control group (n = 13). An 11-point numerical scale (0–10; none to very painful stretching) was used to determine SS intensity. HI-SS and LI-SS stretched at 6–7 and 0–1 intensities, respectively, both in 3 sets of 60 s, 3×/week, for 4 weeks. Dorsiflexion range of motion (ROM), gastrocnemius muscle stiffness, muscle strength, drop jump height, and muscle architecture were assessed before and after SS training program. The HI-SS group improved more than LI-SS in ROM (40 vs. 15%) and decreased muscle stiffness (−57 vs. −24%), while no significant change was observed for muscle strength, drop jump height, and muscle architecture in both groups. The control group presented no significant change in any variable. Performing HI-SS is more effective than LI-SS for increasing ROM and decreasing muscle stiffness of plantar flexor muscles following a 4-week training period in young men. However, SS may not increase muscle strength or hypertrophy, regardless of the stretching discomfort intensity.