bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel immune-related prognostic model and nomogram for breast cancer based on ssGSEA
Authors: Li Linrong , Li Lin , Liu Mohan , Li Yan , Sun Qiang
Published: January 2023

This study aimed to construct an immune-related prognostic model and a nomogram to predict the 1-, 3-, and 5-year overall survival (OS) of breast cancer patients. We applied single-sample gene set enrichment analysis to classify 1,053 breast cancer samples from The Cancer Genome Atlas (TCGA) database into high and low immune cell infiltration clusters. In cluster construction and validation, the R packages “GSVA,” “hclust,” “ESTIMATE,” and “CIBERSORT” and GSEA software were utilized. ImmPort, univariate Cox regression analysis, and Venn analysis were then used to identify 42 prognostic immune-related genes. Eventually, the genes TAPBPL, RAC2, IL27RA, ULBP2, PSMB8, SOCS3, NFKBIE, IGLV6-57, CXCL1, IGHD, AIMP1, and CXCL13 were chosen for model construction utilizing least absolute shrinkage and selection operator regression analysis. The Kaplan–Meier curves of both the training and validation sets indicated that the overall survival of patients in the low-risk group was superior to that of patients in the high-risk group (p < .05). The areas under curves (AUCs) of the model at 1, 3, and 5 years were, respectively, .697, .710, and .675 for the training set and .930, .688, and .712 for the validation set. Regarding clinicopathologic characteristics, breast cancer-related genes, and tumor mutational burden, effective differentiation was achieved between high-risk and low-risk groups. A nomogram integrating the risk model and clinicopathologic factors was constructed using the “rms” R software package. The nomogram’s 1-, 3-, and 5-year AUCs were .828, .783, and .751, respectively. Overall, our study developed an immune-related model and a nomogram that could reliably predict OS for breast cancer patients, and offered insights into tumor immune and pathological mechanisms.
Construction and validation of a nomogram for patients with pancreatic neuroendocrine tumors: A population study of 5,927 patients
Authors: Huang Gaobo , Song Weilun , Zhang Yanchao , Ren Bingyi , Lv Yi , Liu Kang
Published: January 2023

Background

Pancreatic neuroendocrine tumors (pNETs) are a group of uncommon tumors derived from peptide neurons and neuroendocrine cells, and account for roughly 2% to 4% of all pancreatic neoplasms. This study aimed to construct and validate a nomogram for predicting the prognosis of patients with pNETs. Our data came from the SEER database.

Methods

A total of 5927 pNETs patients between 2004 and 2018 were included in this study. The nomogram was constructed base on eight prognostic factors and validated by C-index, ROC curve and calibration curves. A nomogram based on eight independent prognostic factors (patient age, sex, race, tumor grade, AJCC T, AJCC N, AJCC M, surgery, radiation, chemotherapy, tumor function and marital status) was developed for the prediction of CSS at 3 and 5 years.

Results

The C-index and AUCs of the nomogram demonstrated that its superiority in discrimination over AJCC staging system. The calibration plots showed the good consistency between predictions and actual observations.

Conclusions

In conclusion, our nomogram could better predict the prognosis of pNETs patients than AJCC staging system. The nomogram could be improved by integrating more important factors other than SEER database.
T cell activation profiles can distinguish gram negative/positive bacterial sepsis and are associated with ICU discharge
Authors: Huang Canxia , Xiong Hui , Li Weichao , Peng Lu , Zheng Yukai , Liao Wenhua , Zhou Minggen , Xu Ying
Published: January 2023

Introduction

Sepsis is a life-threatening complication resulting from a dysregulated host response to a serious infection, of which bacteria are the most common cause. A rapid differentiation of the gram negative (G-)/gram positive (G+) pathogens facilitates antibiotic treatment, which in turn improves patients’ survival.

Methods

We performed a prospective, observational study of adult patients in intensive care unit (ICU) unit and underwent the analysis of peripheral blood lymphocyte subsets, cytokines and other clinical indexes. The enrolled 94 patients were divided into no infection group (n=28) and bacterial sepsis group (n=66), and the latter group was subdivided into G- (n=46) and G+ (n=20) sepsis subgroups.

Results

The best immune biomarker which differentiated the diagnosis of G- sepsis from G+ sepsis, included activation markers of CD69, human leukocyte antigen DR (HLA-DR) on CD3+CD8+T subset. The ratio of CD3+CD4+CD69+T/CD3+CD8+CD69+T (odds ratio (OR): 0.078(0.012,0.506), P = 0.008), PCT>0.53 ng/ml (OR: 9.31(1.36,63.58), P = 0.023), and CO2CP<26.5 mmol/l (OR: 10.99(1.29, 93.36), P = 0.028) were predictive of G- sepsis (versus G+ sepsis), and the area under the curve (AUC) was 0.947. Additionally, the ratio of CD3+CD4+CD69+T/CD3+CD8+CD69+T ≤ 0.2697 was an independent risk factor for poor ICU discharge in G- sepsis patients (HR: 0.34 (0.13, 0.88), P=0.026).

Conclusion

We conclude that enhanced activation of T cells may regulate the excessive inflammatory response of G- bacterial sepsis, and that T cell activation profiles can rapidly distinguish G- sepsis from G+ sepsis and are associated with ICU discharge.
The multifactorial complexities of autoimmune development in Pemphigus vulgaris: Critical evaluation of the role of environmental and lifestyle “exposome” factors
Authors: Adebiyi Olumayowa T. , Galloway Dominique F. , Augustin Michael S. , Sinha Animesh A.
Published: January 2023

Pemphigus vulgaris (PV) is a potentially life-threatening blistering disorder characterized by autoantibodies directed against cell-cell adhesion molecules that serves as an excellent model to study human autoimmune development. Numerous studies have identified specific Human Leukocyte Antigen (HLA) genes, in particular DRB1*0402 and DQB1*0503, that confer disease risk. Although HLA is required, it is not sufficient for the initiation of disease. As with all autoimmune diseases, the etio-pathogenesis of PV is complex, meaning it is multifactorial. Susceptibility is polygenic, and the search for non-HLA disease-linked genes continues. Moreover, twin studies across autoimmune conditions indicate that non-genetic environmental and lifestyle factors, which can be collectively grouped under the term “exposome”, are also major contributors to disease development. The literature presents evidence for the potential role of multiple triggers such as medications, infections, stress, diet, immunizations, and sleep to influence the etiology, pathophysiology, and prognosis of PV. However, a clear understanding of the degree to which specific factors impact PV is lacking. In this investigation, we comprehensively review the environmental elements listed above and consider the strength of evidence for these factors. The overall goals of this work are to provide greater insights into the factors that influence disease susceptibility, disease development and disease course and ultimately help to better guide clinicians and inform patients in the management of PV.
S100A8 alarmin supports IL-6 and metalloproteinase-9 production by fibroblasts in the synovial microenvironment of peripheral spondyloarthritis
Authors: Arias José L. , Funes Samanta C. , Blas Rodrigo , Callegari Eduardo , Eliçabe Ricardo J. , Páez María D. , Munarriz Alicia , Pardo-Hidalgo Rodolfo , Tamashiro Héctor , Di Genaro María S.
Published: January 2023

Introduction

Spondyloarthritis (SpA) is a common autoinflammatory disease. S100A8/ S100A9 alarmin is strongly expressed in the synovial sublining layers of psoriatic arthritis. S100A8/ S100A9 is the most abundant protein in rheumatoid arthritis synovial fluid (SF) and has a key role in promoting IL-6 expression in fibroblast-like synoviocytes (FLS). The molecular mechanisms and the role of S100-alarmins in the synovial microenvironment of SpA have never been demonstrated.

Methods and Results

Here, we confirm the effect of the synovial microenvironment of peripheral SpA on interleukin-6 (IL-6) and metalloproteinase (MMP)-9 production by FLS. MMP-9 expression and activity were detected, which were reduced in the presence of anti-IL-6R. Analyzing cell signaling mechanisms, we found that stimulation with IL-6 co-triggered MMP-9 and IL-10 secretion. MMP-9 secretion depended on JNK and p38 MAPKs, whereas IL-10 secretion was dependent on the JAK pathway as a potential feedback mechanism controlling IL-6-induced MMP-9 expression. Using a proteomic approach, we identified S100A8 in the peripheral SpA SF. This presence was confirmed by immunoblotting. S100A8 increased the IL-6 secretion via ERK and p38 MAPK pathways. Furthermore, anti-S100A8/A9 reduced both IL-6 and MMP-9 production induced by SpA SF in FLS.

Discussion

Our data reveal a marked relationship between S100A8 alarmin with IL-6 and MMP-9 secretion by FLS in the real synovial microenvironment of peripheral SpA. These results identify a mechanism linking S100A8 to the pathogenesis of peripheral SpA.
Duck gasdermin E is a substrate of caspase-3/-7 and an executioner of pyroptosis
Authors: Li Hanqing , Wang Xin , Yu Lanjie , Wang Junwei , Cao Yongsheng , Ma Bo , Zhang Wenlong
Published: January 2023

Gasdermin (GSDM)-mediated cell death is an ancient immune defensive mechanism that plays an essential role in bacteria, fungi, coral, teleost, and mammals. After being cleaved by proteases of hosts or pathogens, amino-terminal (NT) fragment of GSDMs (GSDM-NTs) form pores in the membrane structure of cells, thereby leading to pyroptotic cell death. However, the expression profile, activation mechanism and function of avian GSDMs have not been studied in depth yet. In the current study, genes encoding duck gasdermin E (duGSDME), caspase-3 (ducaspase-3) and ducaspase-7 were cloned from mRNA of a virus-challenged duck embryo. The cleavage of duGSDME by ducaspase-3/-7 was verified in the cell-free system and/or in human embryonic kidney cells (HEK293). Ducaspase-3/-7 could recognize and cleave duGSDME at 270DAVD273. Overexpression of duGSDME-NT (1-273aa) fragment led to pyroptosis-like morphological change, increased lactic dehydrogenase (LDH) release and propidium iodide uptake of HEK293 cells, which indicated that duGSDME-NTs could cause cell membrane damage. In addition, recombinantly expressed duGSDME-NT showed bactericidal activity to an enterotoxic Escherichia coli (F5+) strain. The expression level of duGSDME was low in duckling tissues. DHAV-3 challenge upregulated the expression of duGSDME and ducaspase-3 in different tissues and led to the activation of ducaspase-3 and cleavage of duGSDME. The results indicated that duGSDME is a substrate of ducapsase-3/-7, and duGSDME-NT can cause pyroptosis. In addition, duGSDME may play a role in the immune defense of ducks against infectious diseases after being cleaved by ducaspase-3. The current study provides essential information for further investigation of the mechanisms of avian innate immunity and avian diseases.
Polyvalent human immunoglobulin for infectious diseases: Potential to circumvent antimicrobial resistance
Authors: Pedraza-Sánchez Sigifredo , Cruz-González Adrián , Palmeros-Rojas Oscar , Gálvez-Romero José Luis , Bellanti Joseph A. , Torres Martha
Published: January 2023

Antimicrobial resistance (AMR) is a global health problem that causes more than 1.27 million deaths annually; therefore, it is urgent to focus efforts on solving or reducing this problem. The major causes of AMR are the misuse of antibiotics and antimicrobials in agriculture, veterinary medicine, and human medicine, which favors the selection of drug-resistant microbes. One of the strategies proposed to overcome the problem of AMR is to use polyvalent human immunoglobulin or IVIG. The main advantage of this classic form of passive immunization is its capacity to enhance natural immunity mechanisms to eliminate bacteria, viruses, or fungi safely and physiologically. Experimental data suggest that, for some infections, local administration of IVIG may produce better results with a lower dose than intravenous application. This review presents evidence supporting the use of polyvalent human immunoglobulin in AMR, and the potential and challenges associated with its proposed usage.
Synergistic multi-altimeter for estimating water level in the coastal zone of Beibu Gulf using SEL, ALES + and BFAST algorithms
Authors: Qin Jiaoling , Li Sunzhe , Yao Hang , Fu Bolin , He Hongchang , Wang Feng , Liu Lilong , Fan Donglin , He Xu , Li Yuyang
Published: January 2023

Accurately monitoring and predicting the large-scale dynamic changes of water levels in coastal zones is essential for its protection, restoration and sustainable development. However, there has been a challenge for achieving this goal using a single radar altimeter and retracking technique due to the diversity and complexity of coastal waveforms. To solve this issue, we proposed an approach of estimating water level of the coastal zone in Beibu Gulf, China, by combination of waveform classifications and multiple sub-waveform retrackers. This paper stacked Random Forest (RF), XGBoost and CatBoost algorithms for building an ensemble learning (SEL) model to classify coastal waveforms, and further evaluated the performance of three retracking strategies in refining waveforms using Cryosat-2, SARAL, Sentinel-3 altimeters. We compared the estimation accuracy of the coastal water levels between the single altimeter and synergistic multi-altimeter, and combined Breaks for Additive Season and Trend (BFAST), Mann-Kendall mutation test (MK) with Long Short-Term Memory (LSTM) algorithms to track the historical change process of coastal water levels, and predict its future development trend. This paper found that: (1) The SEL algorithm achieved high-precision classification of different coastal waveforms with an average accuracy of 0.959, which outperformed three single machine learning algorithms. (2) Combination of Threshold Retracker and ALES+ Retracker (TR_ALES+) achieved the better retracking quality with an improvement of correlation coefficient (R, 0.089~0.475) and root mean square error (RMSE, 0.008∼ 0.029 m) when comparing to the Threshold Retracker & Primary Peak COG Retracker and Threshold Retracker & Primary Peak Threshold Retracker. (3) The coastal water levels of Cryosat-2, SARAL, Sentinel-3 and multi-altimeter were in good agreement (R>0.66, RMSE<0.135m) with Copernicus Climate Change Service (C3S) water level. (4) The coastal water levels of the Beibu Gulf displayed a slowly rising trend from 2011 to 2021 with an average annual growth rate of 8mm/a, its lowest water level focused on May-August, the peak of water level was in October-November, and the average annual growth rate of water level from 2022-2031 was about 0.6mm/a. These results can provide guidance for scientific monitoring and sustainable management of coastal zones.
Failure analysis on fully-transparent deep-sea pressure hulls used at 2,500 m depth
Authors: Wu Yu , Li Youjie , Luo Ruilong , Zhang Zhonggang , Wang Fang , Zhao Bingxiong , Yang Chao , Zhang Jinfei , Gaidai Oleg
Published: January 2023

Fully-transparent deep-sea pressure hulls have been attracted attention in recent years with the increasing demand for underwater observation. So far, public researches on design rule and failure modes for fully-transparent deep-sea pressure hulls are limited and the relevant experience cannot meet the requirements of new cabin design. In this study, the compression test is carried on, in which the material samples are subjected to quasi-static compressive load until failure in tests at different loading rates, and the hyperelastic finite element model is established in LS-DYNA software to simulate the failure process. Simulation results of material properties in finite element analysis on the cylindrical samples are compared with the experimental data, including the characteristic points of the mechanical properties in elastic stage and hardening stage, the ultimate load and failure mode of the samples. Mesh convergence analysis is conducted, and the appropriate mesh quality is accordingly selected in simulation of fully-transparent deep-sea pressure hulls. An equation for prediction of instability-type failure is described, which is derivation based on the classical analytical expression of elastic instability, thus, when 5 times of safety factor is taken, the wall thickness of the pressure hull is calculated to be t/R0 = 0.0685 at 2,500 m depth. Ultimate strength and failure mode of a typical fully-transparent deep-sea pressure hull are simulated. First, the first-order linear buckling modal analysis is carried out to simulate initial geometric imperfections. Then, simulations for the loading and collapse process of two fully-transparent pressure hulls respectively with one opening and two openings are conducted, and the ultimate load of 126 MPa and 128 MPa for the two kinds of hulls are obtained. Finally, simulation of a scaled pressure hull is carried out and simulation results are compared with the experimental data in reference, which are basically consistent. The calculated failure strength shows that the spherical hulls satisfy the safety factor requirement of 5 times. The provided simulation procedure can be referred for failure analysis of fully-transparent pressure hulls.
The antitumor activity of Bax BH3 peptide delivered by gold nanoparticles
Authors: Zhang Xi , Yan Qi , Wang Jingying , Xu Li , Guo Yi
Published: January 2023

Cancer has long remained one of the primary causes of disease and death globally, and it continues to pose a significant threat to human health. Surgery, radiotherapy, and chemotherapy are traditional treatments for cancer which are still widely used. However, while both surgery and radiotherapy remain acceptably effective in addressing a variety of primary tumors, neither possesses therapeutic potential for unknown metastatic lesions which may exist elsewhere in the patient’s body. Conversely, while systemic chemotherapy does have the potential for therapeutic efficacy on both primary and metastatic lesions alike, drug targeting is often poor, side effects are typically high, and treatment efficacy is still often lacking. Nanomedicine presents a promising solution to the above issues. For example, nanocarriers can be used to increase drug selectivity and targeting, increasing efficacy and decreasing side effects. Based on the role of the lethal domain of Bcl-2 family proteins, which play roles in apoptosis, the BH3-only protein, a section of BH3 peptide with a sequence of Asp-Ala-Ser-Thr-Lys-Lys-Leu-Ser-Glu-Cys-Leu-Arg-Arg-Ile-Gly-Asp-Glu-Leu-Asp-Ser. However, treatments based on soluble BH3 peptides, as with those based on other biologically active macromolecules, exhibit low cell membrane permeability, poor stability against proteolysis, and low endosomal escape rates. In this paper, attempt to address these issues by developing a variety of BH3@gold nanoparticle drug systems with different coating ratios. We demonstrate, high loading efficiency and, excellent anti-tumor effects in vitro, including inhibition of proliferation and migration in the human lung adenocarcinoma cell line, A549. Our results present a new possibility for anticancer peptide drugs in the future.
Low circulation of respiratory syncytial and influenza viruses during autumn-winter 2021 in the industrial workplace and long-term healthcare facilities in Athens, Greece
Authors: Papachristou Eleni , Rokka Chrysoula , Sotiriadou Triantafyllia , Maneka Leukothea , Vassilakis Alexandros , Sapounas Spyros , Paraskevis Dimitrios , Jahaj Eddison , Kotanidou Anastasia , Lagiou Pagona , Magiorkinis Gkikas
Published: January 2023

The emergence of SARS-CoV-2 has pinpointed the importance of non-pharmaceutical interventions (NPIs), which have been traditionally used for the prevention of the spread of respiratory viruses among individuals. The aim of our study was to capture the level of circulation of respiratory syncytial and influenza viruses during a period of medium severity NPIs due to SARS-CoV-2 pandemics in Greece. A total of 2,225 nasopharyngeal samples were received during the year 2021 as a part of the routine diagnostic service and were divided into two study groups: (a) January to September 2021 and (b) October to the end of December 2021. The latter is the time of the year when there is a peak of infections from most respiratory viruses, and thus, most of the samples were tested in that period. The samples were taken from three different sites, i.e., (a) industrial workers in a factory, (b) elderly homecare facilities, and c) people who actively asked to be tested for SARS-CoV-2. All the samples were tested simultaneously for SARS-CoV2, RSV, and influenza virus. A total of 2,110 samples were negative for either of the three viruses, 106 were SARS-CoV-2-positive, and 9 were RSV-positive from which 7 were found in the workers’ group. None of the samples was found to be positive for the influenza virus, and no sample had co-infection. Our study shows the low-level circulation of RSV and influenza viruses during autumn-winter 2021 and will provide a reference for future studies of RSV and influenza in Greece.
Involvement of chemokine receptor CXCR3 in the defense mechanism against Neospora caninum infection in C57BL/6 mice
Authors: Abdelbaky Hanan H. , Mitsuhashi Shuichiro , Watanabe Kenichi , Ushio Nanako , Miyakawa Miku , Furuoka Hidefumi , Nishikawa Yoshifumi
Published: January 2023

C-X-C motif chemokine receptor 3 (CXCR3) is an important receptor controlling the migration of leukocytes, although there is no report regarding its role in Neospora caninum infection. Herein, we investigated the relevance of CXCR3 in the resistance mechanism to N. caninum infection in mice. Wild-type (WT) C57BL/6 mice and CXCR3-knockout (CXCR3KO) mice were used in all experiments. WT mice displayed a high survival rate (100%), while 80% of CXCR3KO mice succumbed to N. caninum infection within 50 days. Compared with WT mice, CXCR3KO mice exhibited significantly lower body weights and higher clinical scores at the subacute stage of infection. Flow cytometric analysis revealed CXCR3KO mice as having significantly increased proportions and numbers of CD11c-positive cells compared with WT mice at 5 days post infection (dpi). However, levels of interleukin-6 and interferon-γ in serum and ascites were similar in all groups at 5 dpi. Furthermore, no differences in parasite load were detected in brain, spleen, lungs or liver tissue of CXCR3KO and WT mice at 5 and 21 dpi. mRNA analysis of brain tissue collected from infected mice at 30 dpi revealed no changes in expression levels of inflammatory response genes. Nevertheless, the brain tissue of infected CXCR3KO mice displayed significant necrosis and microglial activation compared with that of WT mice at 21 dpi. Interestingly, the brain tissue of CXCR3KO mice displayed significantly lower numbers of FoxP3+ cells compared with the brain tissue of WT mice at 30 dpi. Accordingly, our study suggests that the lack of active regulatory T cells in brain tissue of infected CXCR3KO mice is the main cause of these mice having severe necrosis and lower survival compared with WT mice. Thus, CXCR3+ regulatory T cells may play a crucial role in control of neosporosis.
Biocontrol and plant growth promotion potential of endophytic Bacillus subtilis JY-7-2L on Aconitum carmichaelii Debx.
Authors: Zou Lan , Wang Qian , Wu Rongxing , Zhang Yaopeng , Wu Qingshan , Li Muyi , Ye Kunhao , Dai Wei , Huang Jing
Published: January 2023

Aconitum carmichaelii Debx. is a famous medicinal plant rich in alkaloids and widely used to treat various human diseases in Asian countries. However, southern blight caused by Sclerotium rolfsii severely hampered the yield of A. carmichaelii. Beneficial microbe-based biological control is becoming a promising alternative and an environmentally friendly approach for the management of plant diseases. In this study, we evaluated the biocontrol potential of an endophytic bacterial strain JY-7-2L, which was isolated from the leaves of A. carmichaelii, against southern blight in vitro and by a series of field experiments. JY-7-2L was identified as Bacillus subtilis based on multi-locus sequence analysis. JY-7-2L showed strong antagonistic activity against S. rolfsii in vitro and on A. carmichaelii root slices by dual-culture assay. Cell-free culture filtrate of JY-7-2L significantly inhibited the hyphal growth, sclerotia formation, and germination of S. rolfsii. In addition, volatile compounds produced by JY-7-2L completely and directly inhibited the growth of S. rolfsii. Furthermore, JY-7-2L was proved to produce hydrolytic enzymes including glucanase, cellulase, protease, indole acetic acid, and siderophore. The presence of bacA, fenA, fenB, fenD, srfAA, and baeA genes by PCR amplification indicated that JY-7-2L was able to produce antifungal lipopeptides and polyketides. Field trials indicated that application of the JY-7-2L fermentation culture significantly reduced southern blight disease severity by up to 30% with a long-acting duration of up to 62 days. Meanwhile, JY-7-2L significantly promoted the fresh and dry weights of the stem, main root, and lateral roots of A. carmichaelii compared to non-inoculation and/or commercial B. subtilis product treatments. Taken together, JY-7-2L can be used as a promising biocontrol agent for the control of southern blight in A. carmichaelii.
The development and characterization of a stable Coxsackievirus A16 infectious clone with Nanoluc reporter gene
Authors: Yu Rui , Wang Min , Liu Lizhen , Yan Jingjing , Fan Jun , Li Xiaohong , Kang Miaomiao , Xu Jianqing , Zhang Xiaoyan , Zhang Shuye
Published: January 2023

Coxsackievirus A16 (CA16) belongs to the Human Enterovirus A species, which is a common pathogen causing hand, foot, and mouth disease in children. Currently, specific vaccines and drugs against CA16 are unavailable, and there is an unmet need to further understand the virus and invent effective treatment. Constructing a CA16 infectious clone with a reporter gene will greatly facilitate its virological studies. Here, we first reported the construction of a CA16 infectious clone (rCA16) whose progeny is highly replicative and virulent in suckling mice. On the basis of rCA16, we further inserted a NanoLuc (Nluc) reporter gene and made the rCA16-Nluc clone. We found that the Nluc gene in rCA16-Nluc is stable during continuous growing in Vero cells and thus allowed detection of a steady luciferase signal in rCA16-Nluc-infected Vero cells over 10 passages. Its application in antivirals characterization and high-throughput screening is exemplified by measuring IC50, CC50, and selection index of guanidine hydrochloride, ribavirin, chloroquine, and ammonium chloride against CA16. Finally, we showed that rCA16-Nluc based assay greatly simplified the CA16 neutralizing antibody tests. Thus, these two CA16 infectious clones will be robust tools for future enterovirus studies and antivirals development.
Age interferes with sensorimotor timing and error correction in the supra-second range
Authors: Pollok Bettina , Hagedorn Amelie , Krause Vanessa , Kotz Sonja A.
Published: January 2023

Introduction

Precise motor timing including the ability to adjust movements after changes in the environment is fundamental to many daily activities. Sensorimotor timing in the sub-and supra-second range might rely on at least partially distinct brain networks, with the latter including the basal ganglia (BG) and the prefrontal cortex (PFC). Since both structures are particularly vulnerable to age-related decline, the present study investigated whether age might distinctively affect sensorimotor timing and error correction in the supra-second range.

Methods

A total of 50 healthy right-handed volunteers with 22 older (age range: 50–60 years) and 28 younger (age range: 20–36 years) participants synchronized the tap-onsets of their right index finger with an isochronous auditory pacing signal. Stimulus onset asynchronies were either 900 or 1,600 ms. Positive or negative step-changes that were perceivable or non-perceivable were occasionally interspersed to the fixed intervals to induce error correction. A simple reaction time task served as control condition.

Results and Discussion

In line with our hypothesis, synchronization variability in trials with supra-second intervals was larger in the older group. While reaction times were not affected by age, the mean negative asynchrony was significantly smaller in the elderly in trials with positive step-changes, suggesting more pronounced tolerance of positive deviations at older age. The analysis of error correction by means of the phase correction response (PCR) suggests reduced error correction in the older group. This effect emerged in trials with supra-second intervals and large positive step-changes, only. Overall, these results support the hypothesis that sensorimotor synchronization in the sub-second range is maintained but synchronization accuracy and error correction in the supra-second range is reduced in the elderly as early as in the fifth decade of life suggesting that these measures are suitable for the early detection of age-related changes of the motor system.
Why the study of comparative psychology is important to neuroscientists
Authors: Abramson Charles I.
Published: January 2023

The purpose of this contribution is threefold. First, is to acquaint neuroscientists with the area of psychology known as comparative psychology. Comparative psychology is the oldest of the organized social sciences with the term appearing as early as 1808. Many of the myriad issues of experimental design routinely faced by comparative psychologists are directly applicable to neuroscience. These issues include consistent definitions of psychological phenomena, the use of Morgan’s canon to reduce unbridled anthropomorphism, and observation oriented modeling as a new statistical procedure to increase replication. Second, is a discussion of early comparative methods that may be of value to contemporary neuroscientists. Third, how the comparative approach can help the neuroscientist limit unfounded generalizations across species and develop more animal-friendly behavioral testing options tailored for the species or strain of interest. The articles closes with some recommendations on how comparative psychologists and neuroscientists can work more closely together.
Brain-computer interface combined with mental practice and occupational therapy enhances upper limb motor recovery, activities of daily living, and participation in subacute stroke
Authors: Zanona Aristela de Freitas , Piscitelli Daniele , Seixas Valquiria Martins , Scipioni Kelly Regina Dias da Silva , Bastos Marina Siqueira Campos , de Sá Leticia Caroline Kaspchak , Monte-Silva Kátia , Bolivar Miburge , Solnik Stanislaw , De Souza Raphael Fabricio
Published: January 2023

Background

We investigated the effects of brain-computer interface (BCI) combined with mental practice (MP) and occupational therapy (OT) on performance in activities of daily living (ADL) in stroke survivors.

Methods

Participants were randomized into two groups: experimental (n= 23, BCI controlling a hand exoskeleton combined with MP and OT) and control (n= 21, OT). Subjects were assessed with the functional independence measure (FIM), motor activity log (MAL), amount of use (MAL-AOM), and quality of movement (MAL-QOM). The box and blocks test (BBT) and the Jebsen hand functional test (JHFT) were used for the primary outcome of performance in ADL, while the Fugl-Meyer Assessment was used for the secondary outcome. Exoskeleton activation and the degree of motor imagery (measured as event-related desynchronization) were assessed in the experimental group. For the BCI, the EEG electrodes were placed on the regions of FC3, C3, CP3, FC4, C4, and CP4, according to the international 10–20 EEG system. The exoskeleton was placed on the affected hand. MP was based on functional tasks. OT consisted of ADL training, muscle mobilization, reaching tasks, manipulation and prehension, mirror therapy, and high-frequency therapeutic vibration. The protocol lasted 1 h, five times a week, for 2 weeks.

Results

There was a difference between baseline and post-intervention analysis for the experimental group in all evaluations: FIM (p= 0.001,d= 0.56), MAL-AOM (p= 0.001,d= 0.83), MAL-QOM (p= 0.006,d= 0.84), BBT (p= 0.004,d= 0.40), and JHFT (p= 0.001,d= 0.45). Within the experimental group, post-intervention improvements were detected in the degree of motor imagery (p< 0.001) and the amount of exoskeleton activations (p< 0.001). For the control group, differences were detected for MAL-AOM (p= 0.001,d= 0.72), MAL-QOM (p= 0.013,d= 0.50), and BBT (p= 0.005,d= 0.23). Notably, the effect sizes were larger for the experimental group. No differences were detected between groups at post-intervention.

Conclusion

BCI combined with MP and OT is a promising tool for promoting sensorimotor recovery of the upper limb and functional independence in subacute post-stroke survivors.
Case report: Spiller syndrome initially mimicking vestibular neuritis
Authors: Wang Huiyuan , Shi Tianming , Shang Yafei , Chen Xinyi , Xu Jie , Geng Yu
Published: January 2023

Spiller syndrome is a rare subtype of medial medullary infarction (MMI). Herein, we report on a patient with progressing stroke who presented with the initial features of acute peripheral vestibulopathy and MMI (Spiller syndrome), as confirmed by magnetic resonance imaging (MRI). A 42-year-old man experienced acute persistent vertigo with nausea, vomiting, and severe gait instability for 6 h before presenting to the emergency department. He exhibited spontaneous right-beating horizontal-torsional nystagmus that intensified on rightward gaze. The patient fell to the left side during the Romberg test. Cranial computed tomography (CT) performed immediately upon admission did not provide evidence for ischemia or hemorrhage of the brainstem and cerebellum; however, the symptoms underwent exacerbation 4 h after admission, manifesting as left-sided limb weakness and dysarthria, without dysphagia. Furthermore, bedside examination revealed difficulty in extending the tongue to the right, positive left Babinski's sign, and abnormal vibration and position sense in the paralyzed limb. Head impulse test recording revealed a normal gain in the vestibulo-ocular reflex, and numerous consistent covert corrective saccades were captured upon turning the head to the left side. Cranial MRI depicted an acute infarct confined to the right side of the medial medulla, which met the diagnostic criteria for Spiller syndrome. Our study underscores the importance of considering the possibility of a nucleus prepositus hypoglossi lesion even if the signs and symptoms support the diagnosis of peripheral lesions in patients with acute vestibular syndrome exhibiting vascular risk factors.
Analysis of the wall thickness of intracranial aneurysms: Can computational fluid dynamics detect the translucent areas of saccular intracranial aneurysms and predict the rupture risk preoperatively?
Authors: Fan Xin-xin , Geng Jie-wen , He Chuan , Hu Peng , Sun Li-yong , Zhang Hong-qi
Published: January 2023

Background and purpose

The translucent area on the surface of intracranial aneurysms (IAs) is associated with rupture risk. In the present study, the Polyflow module of the Ansys software was used to simulate and analyze the thickness of the aneurysm wall to detect whether it was “translucent” and to assess the rupture risk.

Methods

Forty-five patients with 48 IAs who underwent microsurgery were retrospectively reviewed. The medical records, radiographic data, and intraoperative images of the patients were collected. The image data were analyzed using computational fluid dynamics (CFD) simulations to explore the relationship between the simulated thickness of the aneurysm wall, the translucent area, and the rupture point of the real aneurysm's surface to predict the rupture risk and provide a certain reference basis for clinical treatment.

Results

The Polyflow simulation revealed that the location of the minimum extreme point of the simulated aneurysm wall thickness was consistent with the translucent area or rupture point on the surface of the real aneurysm. There was a downward trend in the correlation between the change rate (IS) in the wall area and volume during aneurysm growth and rupture. Ruptured aneurysms have a greater inhomogeneity coefficient Iδ than the unruptured ones. In the unruptured group, translucent aneurysms also had greater inhomogeneity coefficients Iδ and more significant thickness changes (multiple IBA) than non-translucent ones.

Conclusions

The Ansys software Polyflow module could detect whether the unruptured aneurysms were translucent and predict the rupture risk and rupture point.

Clinical trial registration

https://clinicaltrials.gov/, Identifier, NCT03133624.
Case report: Bilateral globus pallidus lesions and delayed progressive leukoencephalopathy in COVID-19: Effects of hypoxia alone or combination of hypoxia and inflammation?
Authors: Ballout Ahmad A. , Kolesnik Michael , Choi Yuna , Ayoub Marc S. , Harel Asaff , Najjar Souhel
Published: January 2023

Background

The globus pallidus is a highly mitochondria-rich metabolic structure that is particularly sensitive to metabolic disturbances and hypoxia. Symmetric lesions of globus pallidus and delayed diffuse leukoencephalopathy were documented in toxic–metabolic disorders, hypoxia, a neurodegenerative disorder, and mitochondrial encephalopathies. Similar changes are also reported in individuals with active COVID-19 infections with associated hypoxia or critical illness.

Case information

We describe a patient with post–COVID-19 infection who presented with rapid cognitive and neurological decline associated with similar neuroimaging structural changes but without toxic–metabolic changes or hypoxia. Despite multiple non-inflammatory cerebrospinal fluid studies, mechanisms involving post–COVID-19 inflammation and immune dysregulation are suspected, given the unexplained continued decline in the neurological status, lack of concurrent hypoxia or antecedent respiratory difficulties, and after a reasonable exclusion of alternative etiologies. Hypermetabolism of both anteromedial temporal structures and diffuse hypometabolism predominantly in the frontal region on PET scan provided indirect support for possible inflammatory mechanisms after reasonable exclusion of alternative etiologies, such as direct CNS infection, among others. The patient's neurological impairment improved substantially after treatment with pulse steroids, plasmapheresis, and rituximab.

Conclusion

To the best of our knowledge, this is the first report of post–COVID-19 with bilateral symmetric contrast-enhancing necrotic lesions of globus pallidus with delayed diffuse supratentorial leukoencephalopathy with microhemorrhages without concurrent hypoxia or reported preceding symptoms suggestive of hypoxia. We suspect that these inflammatory mechanisms might be triggered by prior COVID-19 exposure/infection. Furthermore, the role of the cross-talk between inflammation and clinically mild or silent hypoxia linked to prior COVID-19 infection cannot be excluded. Awareness of these post–COVID-19 neurological sequelae and their potential pathophysiology among those with no known antecedent significant hypoxia are important for early recognition and treatment.
Orexin dual receptor antagonists, zolpidem, zopiclone, eszopiclone, and cognitive research: A comprehensive dose-response meta-analysis
Authors: Zhou Mengzhen , Tang Jiyou , Li Shasha , Li Yaran , Zhao Mengke
Published: January 2023

Background

About one-third of adults have trouble sleeping, ranging from occasional difficulty to chronic insomnia, along with difficulty maintaining sleep. Many studies reported that the long-term use of hypnotics can cause brain dysfunction and damage cognition.

Objective

The objective of the study is to evaluate whether low, medium, and high doses of orexin dual receptor antagonists (DORA), zopiclone (ZOP), eszopiclone (ESZ), and zolpidem (ZST) can impair cognition.

Methods

From the beginning through September 20, 2022, PubMed, Embase, Scopus, the Cochrane Library, and Google Scholar were searched. Randomized controlled trials (RCTs) assessing the therapeutic effects of DORA, eszopiclone, and zopiclone for sleep and cognitive function were included. The primary outcomes were indices related to the cognitive profile, including memory, alertness, execution and control function, and attention and orientation. The secondary outcomes were indices related to sleep and adverse events. The standard mean difference (SMD) was generated for continuous variables. Certain data were captured from figures by GetData 2.26 and analyzed using RStudio 4.2.

Results

Finally, a total of 8,702 subjects were included in 29 studies. Compared with the placebo, the DSST (Digit Symbol Substitution Test) scores of low, medium, and high doses of DORA were SMD = 0.77; 95% CI: 0.33–1.20; SMD = 1.58; 95% CI: 1.11–2.05; and SMD = 0.85; 95% CI: 0.33–1.36, respectively. The DSST scores of zolpidem at low, medium, and high doses were SMD = −0.39; 95% CI: 0.85–0.07; SMD = −0.88, 95% CI: −2.34–0.58; and SMD = −0.12, 95% CI: −0.85–0.60, respectively. Zopiclone's DSST scale score was SMD = −0.18; 95% CI: −0.54–0.18. In addition, the total sleep time (TST) of low, medium, and high doses of DORA was SMD = 0.28, 95% CI: −0.15–0.70; SMD = 1.36, 95% CI: 0.87–1.86; and SMD = 2.59, 95% CI: 1.89–3.30, respectively. The TST of zolpidem with low, medium, and high doses was SMD = 1.01, 95% CI: 0.18–1.83; SMD = 1.94, 95% CI: 0.46–3.43; and SMD = 1.71, 95% CI: 0.86–2.56, respectively. The TST of low, medium, and high doses of eszopiclone was relatively SMD = 2.03, 95% CI: −0.21–4.27; SMD = 2.38, 95% CI: 1.35–3.42; and SMD = 1.71, 95% CI: 0.60–2.82. Zopiclone's TST was SMD = 2.47, 95% CI: 1.36–3.58.

Conclusion

We recommend DORA as the best intervention for insomnia because it is highly effective in inducing and maintaining sleep without impairing cognition. Although zolpidem has a more pronounced effect on maintaining sleep, it is best to reduce its use because of its side effects. Eszopiclone and zopiclone improved sleep quality, but their safety in cognition remains to be verified.
Personalized transcranial alternating current stimulation improves sleep quality: Initial findings
Authors: Ayanampudi V. , Kumar V. , Krishnan A. , Walker M. P. , Ivry R. B. , Knight R. T. , Gurumoorthy R.
Published: January 2023

Insufficient sleep is a major health issue. Inadequate sleep is associated with an array of poor health outcomes, including cardiovascular disease, diabetes, obesity, certain forms of cancer, Alzheimer’s disease, depression, anxiety, and suicidality. Given concerns with typical sedative hypnotic drugs for treating sleep difficulties, there is a compelling need for alternative interventions. Here, we report results of a non-invasive electrical brain stimulation approach to optimizing sleep involving transcranial alternating current stimulation (tACS). A total of 25 participants (mean age: 46.3, S.D. ± 12.4, 15 females) were recruited for a null-stimulation controlled (Control condition), within subjects, randomized crossed design, that included two variants of an active condition involving 15 min pre-sleep tACS stimulation. To evaluate the impact on sleep quality, the two active tACS stimulation conditions were designed to modulate sleep-dependent neural activity in the theta/alpha frequency bands, with both stimulation types applied to all subjects in separate sessions. The first tACS condition used a fixed stimulation pattern across all participants, a pattern composed of stimulation at 5 and 10 Hz. The second tACS condition used a personalized stimulation approach with the stimulation frequencies determined by each individual’s peak EEG frequencies in the 4–6 Hz and 9–11 Hz bands. Personalized tACS stimulation increased sleep quantity (duration) by 22 min compared to a Control condition (p = 0.04), and 19 min compared to Fixed tACS stimulation (p = 0.03). Fixed stimulation did not significantly increase sleep duration compared to Control (mean: 3 min; p = 0.75). For sleep onset, the Personalized tACS stimulation resulted in reducing the onset by 28% compared to the Fixed tACS stimulation (6 min faster, p = 0.02). For a Poor Sleep sub-group (n = 13) categorized with Clinical Insomnia and a high insomnia severity, Personalized tACS stimulation improved sleep duration by 33 min compared to Fixed stimulation (p = 0.02), and 30 min compared to Control condition (p < 0.1). Together, these results suggest that Personalized stimulation improves sleep quantity and time taken to fall asleep relative to Control and Fixed stimulation providing motivation for larger-scale trials for Personalized tACS as a sleep therapeutic, including for those with insomnia.
Perinatal Western-style diet alters serotonergic neurons in the macaque raphe nuclei
Authors: Dunn Geoffrey A. , Thompson Jacqueline R. , Mitchell A J , Papadakis Samantha , Selby Matthew , Fair Damien , Gustafsson Hanna C. , Sullivan Elinor L.
Published: January 2023

Introduction

The neurotransmitter serotonin is a key regulator of neurotransmission, mood, and behavior and is essential in neurodevelopment. Dysfunction in this important neurotransmitter system is connected to behavioral disorders such as depression and anxiety. We have previously shown that the developing serotonin system is sensitive to perinatal exposure to Western-style diet (WSD).

Methods

To advance our hypothesis that perinatal WSD has a long-term impact on the serotonergic system, we designed a fluorescent immunohistochemistry experiment using antibodies against tryptophan hydroxylase 2 (TPH2) and vesicular glutamate transporter 3 (VGLUT3) to probe protein expression in the raphe subnuclei in 13-month-old Japanese macaques (Macaca fuscata; n = 22). VGLUT3 has been shown to be coexpressed in TPH2+ cells in the dorsal raphe (DR) and median raphe nucleus (MnR) of rodent raphe nuclei and may provide information about the projection site of serotonergic fibers into the forebrain. We also sought to improve scientific understanding of the heterogeneity of the serotonin production center for the central nervous system, the midbrain raphe nuclei.

Results

In this immunohistochemical study, we provide the most detailed characterization of the developing primate raphe to date. We utilize multi-level modeling (MLM) to simultaneously probe the contribution of WSD, offspring sex, and raphe anatomical location, to raphe neuronal measurements. Our molecular and morphological characterization revealed that the 13-month-old macaque DR is remarkably similar to that of adult macaques and humans. We demonstrate that vesicular glutamate transporter 3 (VGLUT3), which rodent studies have recently shown can distinguish raphe populations with distinct projection targets and behavioral functions, likewise contributes to the heterogeneity of the primate raphe.

Discussion

This study provides evidence that perinatal WSD has a long-term impact on the density of serotonin-producing neurons, potentially limiting serotonin availability throughout the brain. Due to the critical involvement of serotonin in development and behavior, these findings provide important insight into the mechanisms by which maternal nutrition and metabolic state influence offspring behavioral outcomes. Finally, these findings could inform future research focused on designing therapeutic interventions to optimize neural development and decrease a child’s risk of developing a mental health disorder.