bluuebunny/crossref_metadata_2025 huggingface dataset:
Case report: Application of metagenomic next-generation sequencing in the diagnosis of visceral leishmaniasis and its treatment evaluation
Authors: Liang Qiuping , Liang Xiaogong , Hong Dengwei , Fang Yuan , Tang Lanlan , Mu Jiao , Tan Xiaoli , Chen Feng
Published: January 2023

Visceral leishmaniasis is a vector-borne infection by the Leishmania spp., a parasite. Although the overall incidence of visceral leishmaniasis is low, the disease still occurs frequently in some high-risk areas. In our study, two patients were admitted to the hospital with an unprovoked and recurrent high fever, and the condition was not improved after antibiotics administration. Meanwhile, bone marrow aspiration smears failed to find out any pathogen. Finally, Leishmania-specific nucleic acid sequences were successfully detected in the peripheral blood of two patients through metagenomic next-generation sequencing (mNGS), which was further confirmed by bone marrow smear microscopy and antibody tests. After targeted treatment for visceral leishmaniasis in the patients, mNGS reported a decrease in the reads number of Leishmania sequence. The results indicate the feasibility of mNGS in detecting Leishmania spp. in peripheral blood samples. Its therapeutic effect evaluation may be achieved through a comparative analysis of the number of reads before and after the treatment.
Analysis of ferroptosis-associated genes in Crohn’s disease based on bioinformatics
Authors: Ji Xingyu , Ma Su , Sun Xiaomei , Yu Dan , Song Ye , Li Rui
Published: January 2023

Background

Ferroptosis, a novel mode of apoptosis has recently been shown to be associated with fibrosis, tumor, cardiovascular, and other diseases. In this study, using bioinformatic analysis, we identified ferroptosis genes associated with Crohn’s disease (CD) and performed biological function analysis, identified potential drug targets, and provided new directions for the future treatment of CD.

Methods

Differential expression analysis was performed using the GSE186582 dataset from the Gene Expression Omnibus (GEO) database. Ferroptosis-associated genes were downloaded from the FerrDB database, and overlapping genes associated with CD and ferroptosis were extracted. Then, we performed functional enrichment analysis, constructed a protein-protein interaction network (PPI), identified the correlation between hub genes and immune infiltration, performed external validation using a second and third dataset (GSE102133, GSE95095), and identified potential therapeutic agents. Finally, we validated the protein expression levels of the identified hub genes by immunohistochemical staining in the colon tissues from CD and healthy participants.

Results

A total of 28 ferroptosis-associated genes associated with CD were identified in our analysis, which included 22 up-regulated and 6 down-regulated genes. Gene Ontology (GO) analysis showed that these genes are essential for the apical plasma membrane and amide transport, and Metascape analysis showed that these genes mainly act on IL-4 and IL-13 signaling pathways. Five hub genes, PTGS2, IL6, IL1B, NOS2, and IDO1, were identified by a protein interaction network, and external validation of these hub genes showed statistically significant differences in expression between the CD patients and normal participants (p < 0.05), and all AUC values were greater than 0.8. Further, we predicted the top 10 drugs used to treat CD. Immune infiltration results suggest that Hub gene is related to T cells, macrophages, dendritic cells, and other immune cells. Finally, the results of immunohistochemical experiments showed that the protein expression of the hub gene was higher in CD colon tissue than in normal subjects (p < 0.05).

Conclusion

Bioinformatics analysis showed that ferroptosis is closely related to the development of CD, and the prediction of potential drugs provides new targets for the treatment of CD. Moreover, five hub genes identified are potentially new and effective markers for the diagnosis of CD.
Cryptotanshinone attenuates LPS-induced acute lung injury by regulating metabolic reprogramming of macrophage
Authors: Ye Zesen , Wang Panxia , Feng Guodong , Wang Quan , Liu Cui , Lu Jing , Chen Jianwen , Liu Peiqing
Published: January 2023

Background

Acute lung injury (ALI) is a life-threatening inflammatory disease without effective therapeutic regimen. Macrophage polarization plays a key role in the initiation and resolution of pulmonary inflammation. Therefore, modulating macrophage phenotype is a potentially effective way for acute lung injury. Cryptotanshinone (CTS) is a lipophilic bioactive compound extracted from the root of Salvia miltiorrhiza with a variety of pharmacological effects, especially the anti-inflammatory role. In this study, we investigated the therapeutic and immunomodulatory effects of CTS on ALI.

Materials and methods

The rat model of ALI was established by intratracheal instillation of LPS (5 mg/kg) to evaluate the lung protective effect of CTS in vivo and to explore the regulation of CTS on the phenotype of lung macrophage polarization. LPS (1 μg/mL) was used to stimulate RAW264.7 macrophages in vitro to further explore the effect of CTS on the polarization and metabolic reprogramming of RAW264.7 macrophages and to clarify the potential mechanism of CTS anti-ALI.

Results

CTS significantly improved lung function, reduced pulmonary edema, effectively inhibited pulmonary inflammatory infiltration, and alleviated ALI. Both in vivo and in vitro results revealed that CTS inhibited the differentiation of macrophage into the M1 phenotype and promoted polarization into M2 phenotype during ALI. Further in vitro studies indicated that CTS significantly suppressed LPS-induced metabolic transition from aerobic oxidation to glycolysis in macrophages. Mechanistically, CTS blocked LPS-induced metabolic transformation of macrophages by activating AMPK.

Conclusion

These findings demonstrated that CTS regulates macrophage metabolism by activating AMPK, and then induced M1-type macrophages to transform into M2-type macrophages, thereby alleviating the inflammatory response of ALI, suggesting that CTS might be a potential anti-ALI agent.
Effects of growth stage on the fermentation quality, microbial community, and metabolomic properties of Italian ryegrass (Lolium multiflorum Lam.) silage
Authors: Fu Zhihui , Sun Lin , Wang Zhijun , Liu Jingyi , Hou Meiling , Lu Qiang , Hao Junfeng , Jia Yushan , Ge Gentu
Published: January 2023

Introduction

This study aimed to investigate the effects of different growth stages (booting period-SYK; initial flowering-SCK; full flowering-SSK) on the fermentation quality, microbial community, metabolic pathways and metabolomic characteristics of Italian ryegrass silage.

Methods

Single molecule real-time (SMRT) sequencing and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) were used to analyze bacterial communities and metabolites, respectively.

Results

After 60 d of fermentation, SYK had the lowest pH and the highest lactic acid content, which were significantly different from the other groups. The bacteria with the highest abundance in SYK, SCK and SSK groups were Lactiplantibacillus plantarum (63.98%), Weissella minor (28.82%) and Levilactobacillus brevis (64.81%), respectively. In addition, among the main differential metabolites in different growth stages, the number of amino acids was the most, and the corresponding metabolic pathways were mainly amino acid metabolic pathways. The biosynthesis of phenylalanine, tyrosine and tryptophan was significantly enriched (p<0.01) at booting stage and full flowering stage. Purine metabolism and ABC transporter pathway were significantly enriched at the initial flowering (p<0.001). Lactiplantibacillus plantarum had a negative correlation with xanthine and ganoderic acid F. Weissella minor had a positive correlation with D-Mannose and ganoderic acid F. Levilactobacillus brevis had a positive correlation with xanthine, and Latilactobacillus sakei had a positive correlation with cinnamic acid, D-Mannose, 2-Hydroxycinnamic acid and uridine.

Discussion

In conclusion, this study reveals the interaction mechanisms between ryegrass raw materials at different growth stages and epiphytic microorganisms during ensiling fermentation, providing new ideas for screening functional lactic acid bacteria, and laying a theoretical foundation for the production of safe and high-quality silage.
African swine fever virus ubiquitin-conjugating enzyme pI215L inhibits IFN-I signaling pathway through STAT2 degradation
Authors: Riera Elena , García-Belmonte Raquel , Madrid Ricardo , Pérez-Núñez Daniel , Revilla Yolanda
Published: January 2023

African swine fever virus (ASFV) is the causative agent of one of the most lethal diseases affecting domestic pig and wild boar, which is endangering the swine industry due to its rapid expansion. ASFV has developed different mechanisms to evade the host immune response, including inhibition of type I IFN (IFN-I) production and signaling, since IFN-I is a key element in the cellular antiviral response. Here, we report a novel mechanism of evasion of the IFN-I signaling pathway carried out by the ASFV ubiquitin-conjugating enzyme pI215L. Our data showed that pI215L inhibited IFN-stimulated response element (ISRE) activity and the consecutive mRNA induction of the IFN-stimulated genes ISG15 and IFIT1 through the ubiquitination and proteasomal degradation of STAT2. Additionally, by immunofluorescence, co-immunoprecipitation and nucleus-cytoplasm fractionation approaches, we have confirmed the interaction and colocalization of STAT2 and pI215L, in ectopic experiments and during ASFV infection. Moreover, expression of the catalytic mutant (I215L-C85A) did not inhibit the induction of ISG15 and IFIT1, nor the activity of ISRE. Furthermore, we confirmed that STAT2 degradation by pI215L is dependent on its catalytic activity, since expression of the pI215L-C85A mutant did not affect STAT2 levels, compared to the wild-type protein. Yet, our data reveal that the interaction of pI215L with STAT2 does not require the integrity of its catalytic domain since the pI215L-C85A mutant co-immunoprecipitates with STAT2. All these findings reveal, for the first time, the involvement of E2-ubiquitin-conjugating enzyme activity of pI215L in the immune response modulation.
Integrated analysis of the gut microbiome and metabolome in a mouse model of inflammation-induced colorectal tumors
Authors: Hong Yuntian , Chen Baoxiang , Zhai Xiang , Qian Qun , Gui Rui , Jiang Congqing
Published: January 2023

Colorectal cancer (CRC) is a common malignancy worldwide, and the gut microbiota and metabolites play an important role in its initiation and progression. In this study, we constructed a mouse model of inflammation-induced colorectal tumors, with fixed doses of azoxymethane/dextran sulfate sodium (AOM/DSS). We found that colorectal tumors only formed in some mice treated with certain concentrations of AOM/DSS (tumor group), whereas other mice did not develop tumors (non-tumor group). 16S rDNA amplicon sequencing and liquid chromatography-mass spectrometry (LC-MS)/MS analyses were performed to investigate the microbes and metabolites in the fecal samples. As a result, 1189 operational taxonomic units (OTUs) were obtained from the fecal samples, and the non-tumor group had a relatively higher OTU richness and diversity. Moreover, 53 different microbes were identified at the phylum and genus levels, including Proteobacteria, Cyanobacteria, and Prevotella. Furthermore, four bacterial taxa were obviously enriched in the non-tumor group, according to linear discriminant analysis scores (log10) > 4. The untargeted metabolomics analysis revealed significant differences between the fecal samples and metabolic phenotypes. Further, the heatmaps and volcano plots revealed 53 and 19 dysregulated metabolites between the groups, in positive and negative ion modes, respectively. Styrene degradation and amino sugar-nucleotide sugar metabolism pathways were significantly different in positive and negative ion modes, respectively. Moreover, a correlation analysis between the metabolome and microbiome was further conducted, which revealed the key microbiota and metabolites. In conclusion, we successfully established a tumor model using a certain dose of AOM/DSS and identified the differential intestinal microbiota and characteristic metabolites that might modulate tumorigenesis, thereby providing new concepts for the prevention and treatment of CRC.
Different living environments drive deterministic microbial community assemblages in the gut of Alpine musk deer (Moschus chrysogaster)
Authors: Zhang Zhirong , Ding Mengqi , Sun Yujiao , Khattak Romaan Hayat , Chen Junda , Teng Liwei , Liu Zhensheng
Published: January 2023

Substantial variation in the environment directly causes remodeling of the colonized gut microbiota, controlling community diversity, and functions in the host to tune-up their adaptive states. However, the mechanisms of microbial community assembly in response to environmental changes remain unclear, especially in endangered ruminants. In this study, we analyzed the microbial communities of 37 fecal samples collected from captive and wild Alpine musk deer (Moschus chrysogaster) to characterize the complexity and assembly processes using 16S rRNA gene sequencing. We found significantly different diversities and compositions of gut microbiota among both groups associated with different living environments. Heterogeneous selection was the predominant factor regulating the gut microbiota community under similar climatic conditions, indicating that microbial community assembly was largely driven by deterministic mechanisms. The species co-occurrence network showed complex and tight connections with a higher positive correlation in the wild environment. Moreover, the captive group exhibited significant differences in chemoheterotrophy and fermentation compared with the wild group, but the opposite was observed in animal parasites or symbionts, which might be closely related to diet, energy supply, and healthcare of animals. This study provides a framework basis and new insights into understanding gut microbiota in different environments.
Microbiome and metabolic features of tissues and feces reveal diagnostic biomarkers for colorectal cancer
Authors: Feng Jiahui , Gong Zhizhong , Sun Zhangran , Li Juan , Xu Na , Thorne Rick F. , Zhang Xu Dong , Liu Xiaoying , Liu Gang
Published: January 2023

Microbiome and their metabolites are increasingly being recognized for their role in colorectal cancer (CRC) carcinogenesis. Towards revealing new CRC biomarkers, we compared 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC–MS) metabolite analyses in 10 CRC (TCRC) and normal paired tissues (THC) along with 10 matched fecal samples (FCRC) and 10 healthy controls (FHC). The highest microbial phyla abundance from THC and TCRC were Firmicutes, while the dominant phyla from FHC and FCRC were Bacteroidetes, with 72 different microbial genera identified among four groups. No changes in Chao1 indices were detected between tissues or between fecal samples whereas non-metric multidimensional scaling (NMDS) analysis showed distinctive clusters among fecal samples but not tissues. LEfSe analyses indicated Caulobacterales and Brevundimonas were higher in THC than in TCRC, while Burkholderialese, Sutterellaceaed, Tannerellaceaea, and Bacteroidaceae were higher in FHC than in FCRC. Microbial association networks indicated some genera had substantially different correlations. Tissue and fecal analyses indicated lipids and lipid-like molecules were the most abundant metabolites detected in fecal samples. Moreover, partial least squares discriminant analysis (PLS-DA) based on metabolic profiles showed distinct clusters for CRC and normal samples with a total of 102 differential metabolites between THC and TCRC groups and 700 metabolites different between FHC and FCRC groups. However, only Myristic acid was detected amongst all four groups. Highly significant positive correlations were recorded between genus-level microbiome and metabolomics data in tissue and feces. And several metabolites were associated with paired microbes, suggesting a strong microbiota-metabolome coupling, indicating also that part of the CRC metabolomic signature was attributable to microbes. Suggesting utility as potential biomarkers, most such microbiome and metabolites showed directionally consistent changes in CRC patients. Nevertheless, further studies are needed to increase sample sizes towards verifying these findings.
ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis
Authors: Nikulin Sergey , Razumovskaya Alexandra , Poloznikov Andrey , Zakharova Galina , Alekseev Boris , Tonevitsky Alexander
Published: January 2023

Introduction: Relapse of breast cancer is one of the key obstacles to successful treatment. Previously we have shown that low expression of ELOVL5 and IGFBP6 genes in breast cancer tissue corresponded to poor prognosis. ELOVL5 participates directly in the elongation of polyunsaturated fatty acids (PUFAs) that are considered to play an important role in cancer cell metabolism. Thus, in this work we studied the changes in lipid metabolism in breast cancer cells with reduced expression of either ELOVL5 or IGFBP6 gene.

Methods: MDA-MB-231 cells with a stable knockdown of either ELOVL5 or IGFBP6 gene were used in this study. Transcriptomic and proteomic analysis as well as RT-PCR were utilized to assess gene expression. Content of individual fatty acids in the cells was measured with HPLC-MS. HPLC was used for analysis of the kinetics of PUFAs uptake. Cell viability was measured with MTS assay. Flow cytometry was used to measure activation of apoptosis. Fluorescent microscopy was utilized to assess accumulation of ROS and formation of lipid droplets. Glutathione peroxidase activity was measured with a colorimetric assay.

Results: We found that the knockdown of IGFBP6 gene led to significant changes in the profile of fatty acids in the cells and in the expression of many genes associated with lipid metabolism. As some PUFAs are known to inhibit proliferation and cause death of cancer cells, we also tested the response of the cells to single PUFAs and to combinations of docosahexaenoic acid (DHA, a n-3 PUFA) with standard chemotherapeutic drugs. Our data suggest that external PUFAs cause cell death by activation of ferroptosis, an iron-dependent mechanism of cell death with excessive lipid peroxidation. Moreover, both knockdowns increased cells’ sensitivity to ferroptosis, probably due to a significant decrease in the activity of the antioxidant enzyme GPX4. Addition of DHA to commonly used chemotherapeutic drugs enhanced their effect significantly, especially for the cells with low expression of IGFBP6 gene.

Discussion: The results of this study suggest that addition of PUFAs to the treatment regimen for the patients with low expression of IGFBP6 and ELOVL5 genes can be potentially beneficial and is worth testing in a clinically relevant setting.
Association between cognitive frailty and falls among older community dwellers in China: A Chinese longitudinal healthy longevity survey-based study
Authors: Chen Huihe , Huang Lanhui , Xiang Wei , Liu Yu , Xu Jian-Wen
Published: January 2023

Background

The combined effect of cognitive impairment (CoI) and frailty on falls is controversial. This study aimed to explore whether older adults with cognitive frailty (CF) were at a higher risk of falls than those with only CoI or frailty and to present a fall prediction model based on CF.

Methods

A total of 4,067 adults aged ≥ 60 years were included from the Chinese Longitudinal Healthy Longevity Survey through face-to-face interviews. Cognitive function and frailty were assessed using the mini-mental state examination scale and frailty index, respectively. Logistic regression was used to determine fall-associated risk factors and develop a fall prediction model. A nomogram was then plotted. The model performance was evaluated using the area under the curve (AUC), concordance index (C-index), and calibration curve. All analyses were performed using SPSS and R statistical packages.

Results

The prevalence of CF and falls were 1.4 and 19.4%, respectively. After adjusting for covariates, the odds ratio of CF, frailty only, and CoI only for falls were 2.27 (95% CI: 1.29–3.97), 1.41 (95% CI: 1.16–1.73), and 0.99 (95% CI: 0.43–2.29), respectively. CF, sex, age, hearing difficulty, depression, anxiety, disability in instrumental activities of daily living, and serious illness in the past 2 years were independently associated with falls. A prediction model based on these factors yielded an AUC of 0.646 and a C-index of 0.641.

Conclusion

Cognitive frailty (CF) exerted a cumulative effect on falls than did CoI or frailty alone. Joint assessments of cognitive function and frailty status may be beneficial for fall risk screening in community. A prediction model using CF as a factor could be helpful for this process.
Association between glaucoma and risk of stroke: A systematic review and meta-analysis
Authors: Wang Meng , Chen Ni , Sun Bai-chao , Guo Chun-Bao , Zhang Shuang , Huang Ming-Jie , Zhou Ben-Gang , Wang Xiang-yu , Huang Zheng-Biao
Published: January 2023

Background/objectives

Recently, several studies explored the association between glaucoma and the risk of stroke, but these results were inconsistent. Therefore, we conducted a meta-analysis to examine this possible association.

Methods

We conducted a systematic literature search of PubMed, Embase, and Web of Science from inception until February 28, 2022. Random-effects meta-analysis was conducted by generic inverse variance method. Sensitivity and subgroup analyses were performed. The review protocol has been registered with PROSPERO (CRD42022312797).

Results

Seven studies (involving 362,267 participants) have been published from 2004 to 2017 and included in the meta-analysis. These studies included four retrospective cohort studies, two cross-sectional studies, and one case–control study. Meta-analysis of these data has shown that glaucoma was associated with an increased risk of stroke (OR = 1.94, 95% CI = 1.45–2.59). Most of the subgroup analyses demonstrated similar results. These findings were stable in sensitivity analyses.

Conclusions

We found that glaucoma was associated with an increased risk of stroke. The result suggests that patients with glaucoma need to be assessed the risk of stroke to reduce the incidence of stroke. To better explore the nature of any association, prospective studies that consider the stroke subtypes, sample size, district, and other confounding factors are needed.
Elevated concentrations of macrophage migration inhibitory factor in serum and cerebral microdialysate are associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage
Authors: Neumaier Felix , Stoppe Christian , Stoykova Anzhela , Weiss Miriam , Veldeman Michael , Höllig Anke , Hamou Hussam Aldin , Temel Yasin , Conzen Catharina , Schmidt Tobias Philip , Dogan Rabia , Wiesmann Martin , Clusmann Hans , Schubert Gerrit Alexander , Haeren Roel Hubert Louis , Albanna Walid
Published: January 2023

Objective

Inflammation is increasingly recognized to be involved in the pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) and may increase the susceptibility to delayed cerebral ischemia (DCI). Macrophage migration inhibitory factor (MIF) has been shown to be elevated in serum and cerebrospinal fluid (CSF) after aSAH. Here, we determined MIF levels in serum, CSF and cerebral microdialysate (MD) at different time-points after aSAH and evaluated their clinical implications.

Methods

MIF levels were measured in serum, CSF and MD obtained from 30 aSAH patients during early (EPd1−4), critical (CPd5−15) and late (LPd16−21) phase after hemorrhage. For subgroup analyses, patients were stratified based on demographic and clinical data.

Results

MIF levels in serum increased during CPd5−15 and decreased again during LPd16−21, while CSF levels showed little changes over time. MD levels peaked during EPd1−4, decreased during CPd5−15 and increased again during LPd16−21. Subgroup analyses revealed significantly higher serum levels in patients with aneurysms located in the anterior vs. posterior circulation during CPd5−15 (17.3 [15.1–21.1] vs. 10.0 [8.4–11.5] ng/ml, p = 0.009) and in patients with DCI vs. no DCI during CPd5−15 (17.9 [15.1–22.7] vs. 11.9 [8.9–15.9] ng/ml, p = 0.026) and LPd16−21 (17.4 [11.7–27.9] vs. 11.3 [9.2–12.2] ng/ml, p = 0.021). In addition, MIF levels in MD during CPd5−15 were significantly higher in patients with DCI vs. no DCI (3.6 [1.8–10.7] vs. 0.2 [0.1–0.7] ng/ml, p = 0.026), while CSF levels during the whole observation period were similar in all subgroups.

Conclusion

Our findings in a small cohort of aSAH patients provide preliminary data on systemic, global cerebral and local cerebral MIF levels after aSAH and their clinical implications.

Clinical trial registration

ClinicalTrials.gov, identifier: NCT02142166.
The future of sensory substitution, addition, and expansion via haptic devices
Authors: Eagleman David M. , Perrotta Michael V.
Published: January 2023

Haptic devices use the sense of touch to transmit information to the nervous system. As an example, a sound-to-touch device processes auditory information and sends it to the brain via patterns of vibration on the skin for people who have lost hearing. We here summarize the current directions of such research and draw upon examples in industry and academia. Such devices can be used for sensory substitution (replacing a lost sense, such as hearing or vision), sensory expansion (widening an existing sensory experience, such as detecting electromagnetic radiation outside the visible light spectrum), and sensory addition (providing a novel sense, such as magnetoreception). We review the relevant literature, the current status, and possible directions for the future of sensory manipulation using non-invasive haptic devices.
Symptoms and patterns of symptom propagation in incipient ischemic stroke and migraine aura
Authors: Scutelnic Adrian , Bracher Jacqueline , Kreis Lukas A. , Beyeler Morin , Fischer Urs , Arnold Marcel , Mattle Heinrich P. , Jung Simon , Schankin Christoph J.
Published: January 2023

Background and objectives

Taking a detailed history of symptoms is important for differentiating incipient ischemic stroke and migraine aura. The aim of our study is to describe in detail symptom type and temporal pattern of symptom evolution (i.e., symptom succession and the time lapse between symptoms) and to identify differentiating clinical features in patients with ischemic stroke and migraine with aura.

Methods

Consecutive patients with ischemic stroke and migraine with aura were interviewed using a structured questionnaire. Stroke diagnosis was confirmed by imaging and migraine with aura was diagnosed according to the current criteria of the International Headache Society. Wake-up strokes and patients with severe cognitive deficits were excluded.

Results

In stroke patients and migraine patients, respectively, 50/78 (64%) vs. 123/326 (37%) had one, 18 (23%) vs. 127 (38%) had two, 5 (6%) vs. 69 (21%) had three, 2 (2%) vs. 4 (1%) had four, and 3 (3%) vs. 3 (1%) had five visual symptoms. In respect of sensory symptoms, 76/145 (52.4%) vs. 116/175 (66%) reported paresthesia and 92/145 (63.4%) vs. 132 (75%) numbness. Looking at the beginning, visual symptoms were the first symptom more often in migraine aura than in ischemic stroke (72.1 vs 18.8%, P < 0.001; PPV 86.8%). Sensory (29 vs 13.9%, P = 0.001; PPV 54.8%) and motor symptoms (20.5 vs 1.4%, P < 0.001; PPV 88.9%) were the first symptom more frequently in ischemic stroke. Of patients with consecutive symptoms, 39 of 201 (19%) compared to 34 of 117 (29%) (P = 0.02; PPV 46.6%) reported at least two simultaneous symptoms. A time lapse between symptoms of < 1 min (18.6 vs 6.3%, P < 0.001; PPV 57.1%) and > 360 min (15.8 vs 0%, χ2 = 39.61, P < 0.001; PPV 100%) was more frequent in stroke whereas a time lapse between 5 and 60 min was more frequent in migraine aura (41.1 vs 68.7%, χ2 = 23.52, P < 0.001; PPV 78.7%).

Conclusion

There is a significant overlap in the clinical presentation of stroke and migraine aura. In particular, a substantial proportion of patients in one group had symptoms that are traditionally attributed to the other group. This study highlights the similarities and differences between symptoms of ischemic stroke and migraine aura and challenges our reasoning in daily clinical practice.
Machine learning-based infection prediction model for newly diagnosed multiple myeloma patients
Authors: Peng Ting , Liu Leping , Liu Feiyang , Ding Liang , Liu Jing , Zhou Han , Liu Chong
Published: January 2023

Objective

To understand the infection characteristics and risk factors for infection by analyzing multicenter clinical data of newly diagnosed multiple myeloma (NDMM) patients.

Methods

This study reviewed 564 NDMM patients from 2 large tertiary hospitals from January 2018 to December 2021, of whom 395 comprised the training set and 169 comprised the validation set. Thirty-eight variables from first admission records were collected, including patient demographic characteristics, clinical scores and characteristics, laboratory indicators, complications, and medication history, and key variables were screened using the Lasso method. Multiple machine learning algorithms were compared, and the best performing algorithm was used to build a machine learning prediction model. The model performance was evaluated using the AUC, accuracy, and Youden’s index. Finally, the SHAP package was used to assess two cases and demonstrate the application of the model.

Results

In this study, 15 important key variables were selected, namely, age, ECOG, osteolytic disruption, VCD, neutrophils, lymphocytes, monocytes, hemoglobin, platelets, albumin, creatinine, lactate dehydrogenase, affected globulin, β2 microglobulin, and preventive medicine. The predictive performance of the XGBoost model was significantly better than that of the other models (AUROC: 0.8664), and it also performed well for the expected dataset (accuracy: 68.64%).

Conclusion

A machine learning algorithm was used to establish an infection prediction model for NDMM patients that was simple, convenient, validated, and performed well in reducing the incidence of infection and improving the prognosis of patients.
Combined neuromuscular electrical stimulation and transcutaneous spinal direct current stimulation increases motor cortical plasticity in healthy humans
Authors: Koseki Tadaki , Kudo Daisuke , Yoshida Kaito , Nito Mitsuhiro , Takano Keita , Jin Masafumi , Tanabe Shigeo , Sato Toshiaki , Katoh Hiroshi , Yamaguchi Tomofumi
Published: January 2023

Introduction

Neuromuscular electrical stimulation (NMES) induces neural plasticity of the central nervous system (CNS) and improves motor function in patients with CNS lesions. However, the extended stimulus duration of NMES reduces its clinical applicability. Transcutaneous spinal direct current stimulation (tsDCS), which increases afferent input, may enhance the effects and reduce the stimulus duration of NMES. This study investigated the excitability of the motor cortex, somatosensory cortex, and spinal motor neurons after the combined stimulation of NMES and tsDCS.

Methods

Among the 55 participants in this study, 24 were allocated to experiment 1, 15 to experiment 2, and 16 to experiment 3. They received intervention for 20 min on different days: (1) NMES combined with tsDCS (NMES + tsDCS), (2) NMES combined with sham tsDCS (NMES + sham tsDCS), and (3) sham NMES combined with tsDCS (sham NMES + tsDCS). NMES was delivered to the right common peroneal nerve at 25 Hz with the intensity at 120% of the motor threshold. For tsDCS, the cathodal electrode was positioned on the thoracic 10th–12th vertebral levels, and the anodal electrode was located on the right shoulder. The stimulus intensity was 2.5 mA. In experiment 1, motor evoked potentials (MEPs) and short-latency intracortical inhibition (SICI) were measured by transcranial magnetic stimulation up to 60 min after stimulation. The spinal motor neurons’ excitability was assessed by recording the posterior root muscle reflex (PRMR) induced via transcutaneous spinal cord stimulation in experiment 2, and the primary somatosensory cortex excitability was evaluated by recording the somatosensory evoked potentials (SEPs) in experiment 3 up to 15 min after stimulation.

Results

Compared to before the stimulation, NMES + tsDCS significantly increased MEP for 60 min or more, and significantly decreased SICI immediately after. Conversely contrast, the PRMR significantly decreased immediately after, and SEPs were unchanged.

Discussion

These results suggest that simultaneous afferent inputs from different stimulus positions critically induce primary motor cortex plasticity. The combined stimulation of NMES with tsDCS may facilitate the development of a new neurorehabilitation technique.
Selective stimulation of nociceptive small fibers during intraepidermal electrical stimulation: Experiment and computational analysis
Authors: Niimi Yuki , Gomez-Tames Jose , Wasaka Toshiaki , Hirata Akimasa
Published: January 2023

Electrical stimulation of skin nociceptors is gaining attention in pain research and peripheral neuropathy diagnosis. However, the optimal parameters for selective stimulation are still difficult to determine because they require simultaneous characterization of the electrical response of small fibers (Aδ- and C-fibers). In this study, we measured the in vivo electrical threshold responses of small fibers to train-pulse stimulation in humans for the first time. We also examined selective stimulation via a computational model, which combines electrical analysis, and terminal fiber and synaptic models, including the first cutaneous pain C-fiber model. Selective stimulation of small fibers is performed by injecting train-pulse stimulation via coaxial electrodes with an intraepidermal needle tip at varying pulse counts and frequencies. The activation Aδ- or C-fibers was discriminated from the differences in reaction time. Aδ-fiber elicited a pinpricking sensation with a mean reaction time of 0.522 s, and C-fiber elicited a tingling sensation or slight burning itch with a mean reaction time of 1.243 s. The implemented multiscale electrical model investigates synaptic effects while considering stimulation waveform characteristics. Experimental results showed that perception thresholds decreased with the number of consecutive pulses and frequency up to convergence (five pulses or 70 Hz) during the selective stimulation of Aδ- and C-fibers. Considering the synaptic properties, the optimal stimulus conditions for selective stimulation of Aδ- vs. C-fibers were train of at least four pulses and a frequency of 40–70 Hz at a pulse width of 1 ms. The experimental results were modeled with high fidelity by incorporating temporal synaptic effects into the computational model. Numerical analysis revealed terminal axon thickness to be the most important biophysical factor affecting threshold variability. The computational model can be used to estimate perception thresholds while understanding the mechanisms underlying the selective stimulation of small fibers. The parameters derived here are important in exploring selective stimulation between Aδ- and C-fibers for diagnosing neuropathies.
Coherence based graph convolution network for motor imagery-induced EEG after spinal cord injury
Authors: Li Han , Liu Ming , Yu Xin , Zhu JianQun , Wang Chongfeng , Chen Xinyi , Feng Chao , Leng Jiancai , Zhang Yang , Xu Fangzhou
Published: January 2023

Background

Spinal cord injury (SCI) may lead to impaired motor function, autonomic nervous system dysfunction, and other dysfunctions. Brain-computer Interface (BCI) system based on motor imagery (MI) can provide more scientific and effective treatment solutions for SCI patients.

Methods

According to the interaction between brain regions, a coherence-based graph convolutional network (C-GCN) method is proposed to extract the temporal-frequency-spatial features and functional connectivity information of EEG signals. The proposed algorithm constructs multi-channel EEG features based on coherence networks as graphical signals and then classifies MI tasks. Different from the traditional graphical convolutional neural network (GCN), the C-GCN method uses the coherence network of EEG signals to determine MI-related functional connections, which are used to represent the intrinsic connections between EEG channels in different rhythms and different MI tasks. EEG data of SCI patients and healthy subjects have been analyzed, where healthy subjects served as the control group.

Results

The experimental results show that the C-GCN method can achieve the best classification performance with certain reliability and stability, the highest classification accuracy is 96.85%.

Conclusion

The proposed framework can provide an effective theoretical basis for the rehabilitation treatment of SCI patients.
Interaction between habits as action sequences and goal-directed behavior under time pressure
Authors: Frölich Sascha , Esmeyer Marlon , Endrass Tanja , Smolka Michael N. , Kiebel Stefan J.
Published: January 2023

Human behavior consists in large parts of action sequences that are often repeated in mostly the same way. Through extensive repetition, sequential responses become automatic or habitual, but our environment often confronts us with events to which we have to react flexibly and in a goal-directed manner. To assess how implicitly learned action sequences interfere with goal-directed control, we developed a novel behavioral paradigm in which we combined action sequence learning through repetition with a goal-directed task component. So-called dual-target trials require the goal-directed selection of the response with the highest reward probability in a fast succession of trials with short response deadlines. Importantly, the response primed by the learned action sequence is sometimes different from that required by the goal-directed task. As expected, we found that participants learned the action sequence through repetition, as evidenced by reduced reaction times (RT) and error rates (ER), while still acting in a goal-directed manner in dual-target trials. Specifically, we found that the learned action sequence biased choices in the goal-directed task toward the sequential response, and this effect was more pronounced the better individuals had learned the sequence. Our novel task may help shed light on the acquisition of automatic behavioral patterns and habits through extensive repetition, allows to assess positive features of habitual behavior (e.g., increased response speed and reduced error rates), and importantly also the interaction of habitual and goal-directed behaviors under time pressure.
Mechanisms controlling the trafficking, localization, and abundance of presynaptic Ca2+ channels
Authors: Cunningham Karen L. , Littleton J. Troy
Published: January 2023

Voltage-gated Ca2+ channels (VGCCs) mediate Ca2+ influx to trigger neurotransmitter release at specialized presynaptic sites termed active zones (AZs). The abundance of VGCCs at AZs regulates neurotransmitter release probability (Pr), a key presynaptic determinant of synaptic strength. Given this functional significance, defining the processes that cooperate to establish AZ VGCC abundance is critical for understanding how these mechanisms set synaptic strength and how they might be regulated to control presynaptic plasticity. VGCC abundance at AZs involves multiple steps, including channel biosynthesis (transcription, translation, and trafficking through the endomembrane system), forward axonal trafficking and delivery to synaptic terminals, incorporation and retention at presynaptic sites, and protein recycling. Here we discuss mechanisms that control VGCC abundance at synapses, highlighting findings from invertebrate and vertebrate models.
Spinal meningiomas, from biology to management - A literature review
Authors: Serratrice Nicolas , Lameche Imène , Attieh Christian , Chalah Moussa A , Faddoul Joe , Tarabay Bilal , Bou-Nassif Rabih , Ali Youssef , Mattar Joseph G , Nataf François , Ayache Samar S , Abi Lahoud Georges N
Published: January 2023

Meningiomas arise from arachnoidal cap cells of the meninges, constituting the most common type of central nervous system tumors, and are considered benign tumors in most cases. Their incidence increases with age, and they mainly affect females, constituting 25-46% of primary spinal tumors. Spinal meningiomas could be detected incidentally or be unraveled by various neurological symptoms (e.g., back pain, sphincter dysfunction, sensorimotor deficits). The gold standard diagnostic modality for spinal meningiomas is Magnetic resonance imaging (MRI) which permits their classification into four categories based on their radiological appearance. According to the World Health Organization (WHO) classification, the majority of spinal meningiomas are grade 1. Nevertheless, they can be of higher grade (grades 2 and 3) with atypical or malignant histology and a more aggressive course. To date, surgery is the best treatment where the big majority of meningiomas can be cured. Advances in surgical techniques (ultrasonic dissection, microsurgery, intraoperative monitoring) increase the complete resection rate. Operated patients have a satisfactory prognosis, even in those with poor preoperative neurological status. Adjuvant therapy has a growing role in treating spinal meningiomas, mainly in the case of subtotal resection and tumor recurrence. The current paper reviews the fundamental epidemiological and clinical aspects of spinal meningiomas, their histological and genetic characteristics, and their management, including the various surgical novelties and techniques.
Identification of a tumor immune-inflammation signature predicting prognosis and immune status in breast cancer
Authors: Liu Yajing , Ouyang Wenhao , Huang Hong , Tan Yujie , Zhang Zebang , Yu Yunfang , Yao Herui
Published: January 2023

Background

Breast cancer has become the malignancy with the highest mortality rate in female patients worldwide. The limited efficacy of immunotherapy as a breast cancer treatment has fueled the development of research on the tumor immune microenvironment.

Methods

In this study, data on breast cancer patients were collected from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Differential gene expression analysis, univariate Cox regression analysis, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were performed to select overall survival (OS)-related, tumor tissue highly expressed, and immune- and inflammation-related genes. A tumor immune-inflammation signature (TIIS) consisting of 18 genes was finally screened out in the LASSO Cox regression model. Model performance was assessed by time-dependent receiver operating characteristic (ROC) curves. In addition, the CIBERSORT algorithm and abundant expression of immune checkpoints were utilized to clarify the correlation between the risk signature and immune landscape in breast cancer. Furthermore, the association of IL27 with the immune signature was analyzed in pan-cancer and the effect of IL27 on the migration of breast cancer cells was investigated since the regression coefficient of IL27 was the highest.

Results

A TIIS based on 18 genes was constructed via LASSO Cox regression analysis. In the TCGA-BRCA training cohort, 10-year AUC reached 0.89, and prediction performance of this signature was also validated in the METABRIC set. The high-risk group was significantly correlated with less infiltration of tumor-killing immune cells and the lower expression level of the immune checkpoint. Furthermore, we recommended some small-molecule drugs as novel targeted drugs for new breast cancer types. Finally, the relationship between IL27, a significant prognostic immune and inflammation cytokine, and immune status was analyzed in pan-cancer. Expression of IL27 was significantly correlated with immune regulatory gene expression and immune cell infiltration in pan-cancer. Furthermore, IL27 treatment improved breast cancer cell migration.

Conclusion

The TIIS represents a promising prognostic tool for estimating OS in patients with breast cancer and is correlated with immune status.
Chidamide-based 3-drug combination regimen reverses molecular relapse post transplantation in AML1-ETO–positive acute myeloid leukemia
Authors: Xi Yang , Chenglong Li , Rong Zhang , Wen Wang , Yu Wang , Jiao Chen , Juan Huang , Feifei Che , Rong Xiao , Tao Jiang , Hui Li , Xiaobing Huang
Published: January 2023

Objective: We aimed to explore a new method to reverse early relapse in patients with AML1-ETO–positive acute myeloid cell transplantation.

Methods: A chidamide-based 3-drug combination regimen was used in our center to treat patients with AML1-ETO–positive AML post transplantation but negative flow cytometry results. A retrospective analysis was performed of the survival rate and possible influencing factors of patients with relapse treated with this regimen in our center from January 2018 to January 2022.

Results: The overall response rate was 95.8% (23/24), and the median number of treatment courses was 4 (range, 3–12 courses). The total molecular complete response (MCR) was 79.1% (19/24) after all treatments, and the molecular complete response was 37.5% (9/24) after one cycle of treatment but reached 58.3% (14/24) after four cycles; overall, the proportion of MCR increased gradually with the increase in treatment cycles. The projected 5-year overall survival rate was 73.9%. The projected 5-year leukemia-free survival rate was 64.8%, and the projected 1-year cumulative relapse rate was 35.5%. The incidence of grade II–IV graft-versus-host diseases (GVHD) was 29.2% (7/24), and that of grade III–IV GVHD was 20.8% (5/24), which could be effectively controlled by glucocorticoid therapy combined with calcineurin inhibitors The total incidence of chronic GVHD was 29.2% (7/24), and all cases were localized chronic GVHD. The total infection rate was 33.3% (8/24), mainly involving bacterial and fungal infections, and the incidence of life-threatening infections was 4.17% (1/24). The treatment-related mortality rate was 0%; and the total mortality rate was 20.8% (5/24). Nausea and vomiting, thrombocytopenia, and neutropenia were common adverse reactions, all of which were Common Terminology Criteria for Adverse Events grade 2–3 events and reversible after drug withdrawal. In terms of immunity, Th1 cell counts gradually increased, Th17 cell counts gradually decreased, and the Th1/Th17 ratio gradually increased after treatment. The CD8+ T lymphocyte count increased gradually, while the CD4+ T lymphocyte count did not change significantly.

Conclusion: Our chidamide-based 3-drug combination regimen led to a high remission rate and tolerable adverse reactions in patients with AML1-ETO–positive post-transplant relapse, and most patients can achieve long-term survival with this regimen.
Open questions in human lung organoid research
Authors: Hughes Tessa , Dijkstra Krijn K. , Rawlins Emma L. , Hynds Robert E.
Published: January 2023

Organoids have become a prominent model system in pulmonary research. The ability to establish organoid cultures directly from patient tissue has expanded the repertoire of physiologically relevant preclinical model systems. In addition to their derivation from adult lung stem/progenitor cells, lung organoids can be derived from fetal tissue or induced pluripotent stem cells to fill a critical gap in modelling pulmonary development in vitro. Recent years have seen important progress in the characterisation and refinement of organoid culture systems. Here, we address several open questions in the field, including how closely organoids recapitulate the tissue of origin, how well organoids recapitulate patient cohorts, and how well organoids capture diversity within a patient. We advocate deeper characterisation of models using single cell technologies, generation of more diverse organoid biobanks and further standardisation of culture media.