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BackgroundThis study aimed to examine the evolving trends in the global burden of low back pain (LBP) from 1990 to 2021 and predicted disease burden until 2035.Materials and methodsLBP-related data were obtained from the Global Health Data Exchange (GHDx) query tool. All estimates and their 95% uncertainty intervals (UIs) were generated using DisMod-MR 2.1, a Bayesian meta-regression tool in Global Burden of Disease, Injury, and Risk Factor Study (GBD) 2021. Data processing and visualization were conducted using The R Programming Language software version 4.3.2 and Joinpoint 4.7.ResultsIn 2021, approximately 628.8 million people worldwide were affected by LBP, with approximately 266.9 million new incident cases and age-standardized incidence rate (ASIR) of 3176.6 per 100,000. Compared with 1990, although the ASIR and age-standardized disability-adjusted life years rate (ASDALYsR) decreased, absolute numbers increased significantly. Projections for 2035 reveal a continued decline in ASIR and ASDALYsR for LBP. The LBP burden varied by the sociodemographic index quintile and GBD region, with the highest ASIR and ASDALYsR observed in Central Europe and the greatest decrease in East Asia. Globally, women bear a higher burden of LBP than men, with middle-aged populations experiencing the heaviest burden. Occupational ergonomic factors, high body mass index, and smoking remain the primary risk factors for LBP, with occupational ergonomic factors contributing the most to the overall burden.ConclusionDespite a projected decline in incidence, the global burden of LBP persists, exhibiting significant regional and gender disparities. To mitigate its future burden, precise and effective prevention and control strategies targeting high-risk factors are imperative.

BackgroundHypertension (HT) is a common chronic disease in older adults. It not only leads to dizziness and other symptoms affecting balance in older adults with HT but also affects the hemodynamics of the cerebral cortex. At present, potential neural mechanisms of balance control in older adults with HT are still unclear. Therefore, this study aimed to explore the differences in the center of pressure (COP) and cerebral cortex activation between older adults with HT and normotension (NT) during standing balance tasks. This study May provide guidance for the early detection of the risk of falls among older adults with HT and the development of clinical rehabilitation strategies.MethodsIn this cross-sectional study, 30 older adults with NT (NT group) and 27 older adults with HT (HT group) were subjected to three conditions: task 1, standing with eyes open on a stable surface; task 2, standing with eyes closed on a stable surface; and task 3, standing with eyes open on the surface of the foam pad. Cortical hemodynamic reactions were measured using functional near-infrared spectroscopy, and COP parameters were measured using a force plate.ResultsThe mean velocity of the COP in the medial–lateral direction in the NT group was significantly higher than that in the HT group (F = 5.955, p = 0.018) during task 3. When proprioception was disturbed, the activation of the left premotor cortex and supplementary motor cortex in the HT group was significantly lower than that in the NT group (F = 14.381, p

IntroductionSpiking neural networks (SNNs), inspired by biological neural networks, have received a surge of interest due to its temporal encoding. Biological neural networks are driven by multiple plasticities, including spike timing-dependent plasticity (STDP), structural plasticity, and homeostatic plasticity, making network connection patterns and weights to change continuously during the lifecycle. However, it is unclear how these plasticities interact to shape neural networks and affect neural signal processing.MethodHere, we propose a reward-modulated self-organization recurrent network with structural plasticity (RSRN-SP) to investigate this issue. Specifically, RSRN-SP uses spikes to encode information, and incorporate multiple plasticities including reward-modulated spike timing-dependent plasticity (R-STDP), homeostatic plasticity, and structural plasticity. On the one hand, combined with homeostatic plasticity, R-STDP is presented to guide the updating of synaptic weights. On the other hand, structural plasticity is utilized to simulate the growth and pruning of synaptic connections.Results and discussionExtensive experiments for sequential learning tasks are conducted to demonstrate the representational ability of the RSRN-SP, including counting task, motion prediction, and motion generation. Furthermore, the simulations also indicate that the characteristics arose from the RSRN-SP are consistent with biological observations.

BackgroundA Suicide Screening Questionnaire-Observer Rating (SSQ-OR) has been used to assess risk of suicide among individuals and to help clinicians identify and rescue individuals attempting suicide. To prevent the risk of suicide in China, a Chinese language SSQ-OR (CL-SSQ-OR) needs to be introduced.ObjectiveTo test the validity and reliability of a CL-SSQ-OR.MethodA total of 250 individuals were enrolled in this study. Each completed a CL-SSQ-OR assessment, Patient Health Questionnaire-9, and the Beck Scale for Suicide Ideation. Confirmatory factor analysis (CFA) was adopted to determine structural validity. Spearman correlation coefficients were adopted to determine criterion validity. An internal correlation coefficient (ICC) was used to test inter-consistency and Cronbach’s α coefficient was used to test split-half reliability.ResultsCFA was conducted with use of the maximum variance method to evaluate the item results. All of the items received scores >0.40. In addition, good model fit indices were observed for the two-factor structure RMSEA = 0.046, TLI = 0.965, CFI = 0.977. The items’ factor loading of the CL-SSQ-OR in the first factor ranged from 0.443 to 0.878. The items’ factor loading of the CL-SSQ-OR in the second factor ranged from 0.400 to 0.810. The ICC of the total CL-SSQ-OR was 0.855. Cronbach’s α was 0.873.ConclusionThe CL-SSQ-OR described here demonstrates ideal psychometric properties and is found to be a suitable tool for screening Chinese children/adolescents who are at risk of suicide.

BackgroundPhthalates (PAEs) are important synthetic substances in plastics, attracting much attention due to their potential effects on the cardiovascular system.MethodsIn this study, urine and blood samples from 39 individuals were collected in Tianjin, China. Phthalates and phthalate metabolites (mPAEs) were analyzed using gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography-mass spectrometry (HPLC-MS), respectively. The polymerase chain reaction (PCR) products from bisulfite-treated mitochondrial DNA (mtDNA) samples were analyzed using pyrosequencing technology.ResultsThe detection frequencies for 9 PAEs varied from 2.56 to 92.31%, and those for 10 mPAEs varied from 30.77 to 100%. The estimated daily intakes (EDIs) and cumulative risk of PAEs were calculated based on the experimental statistics of urinary PAEs and mPAEs. For PAEs, the HIRfD (hazard index corresponding to reference doses) values of 10.26% of participants and the HITDI (hazard index corresponding to tolerable daily intake) values of 30.77% of participants were estimated to exceed 1, suggesting a relatively high exposure risk. The mtDNA methylation levels in the MT-ATP8 and MT-ND5 were observed to be lower than in the MT-ATP6. Mono-ethyl phthalate (MEP) and MT-ATP8 were positively correlated with triglyceride levels (p < 0.05). Based on the association of PAEs, mtDNA methylation, and triglycerides, the mediating role of mtDNA methylation between PAEs and cardiovascular diseases (CVDs) was analyzed in this study, but no mediated effect was observed.ConclusionThe effects of PAE exposure on cardiovascular diseases (CVDs) should be investigated further.

ObjectiveThe characteristic morphological parameters (bony posterior fossa volume (bony-PFV), posterior fossa crowdness, cerebellar tonsillar hernia, and syringomyelia) and CSF dynamics parameters at the craniocervical junction (CVJ) in Chiari malformation type I (CMI) were measured. The potential association between these characteristic morphologies and CSF dynamics at CVJ was analyzed.MethodsA total of 46 cases of control subjects and 48 patients with CMI underwent computed tomography and phase-contrast magnetic resonance imaging. Seven morphovolumetric measures and four CSF dynamics at CVJ measures were performed. The CMI cohort was further divided into “syringomyelia” and “non-syringomyelia” subgroups. All the measured parameters were analyzed by the Pearson correlation.ResultsCompared with the control, the posterior cranial fossa (PCF) area, bony-PFV, and CSF net flow were significantly smaller (P < 0.001) in the CMI group. Otherwise, the PCF crowdedness index (PCF CI, P < 0.001) and the peak velocity of CSF (P < 0.05) were significantly larger in the CMI cohort. The mean velocity (MV) was faster in patients with CMI with syringomyelia (P < 0.05). In the correlation analysis, the degree of cerebellar tonsillar hernia was correlated with PCF CI (R = 0.319, P < 0.05), MV (R = −0.303, P < 0.05), and the net flow of CSF (R = −0.300, P < 0.05). The Vaquero index was well correlated with the bony-PFV (R= −0.384, P < 0.05), MV (R = 0.326, P < 0.05), and the net flow of CSF (R = 0.505, P < 0.05).ConclusionThe bony-PFV in patients with CMI was smaller, and the MV was faster in CMI with syringomyelia. Cerebellar subtonsillar hernia and syringomyelia are independent indicators for evaluating CMI. Subcerebellar tonsillar hernia was associated with PCF crowdedness, MV, and the net flow of CSF at CVJ, while syringomyelia was associated with bony-PFV, MV, and the net flow of CSF at the CVJ. Thus, the bony-PFV, PCF crowdedness, and the degree of CSF patency should also be one of the indicators of CMI evaluation.

In recent decades, multiple primary lung cancer (MPLC) has been increasingly prevalent in clinical practice. However, many details about MPLC have not been completely settled, such as understanding the driving force, clinical management, pathological mechanisms, and genomic architectures of this disease. From the perspective of diagnosis and treatment, distinguishing MPLC from lung cancer intrapulmonary metastasis (IPM) has been a clinical hotpot for years. Besides, compared to patients with single lung lesion, the treatment for MPLC patients is more individualized, and non-operative therapies, such as ablation and stereotactic ablative radiotherapy (SABR), are prevailing. The emergence of next-generation sequencing has fueled a wave of research about the molecular features of MPLC and advanced the NCCN guidelines. In this review, we generalized the latest updates on MPLC from definition, etiology and epidemiology, clinical management, and genomic updates. We summarized the different perspectives and aimed to offer novel insights into the management of MPLC.

Liquid organic hydrogen storage with N-ethylcarbazole (NEC) as a carrier is a very promising method. The use of precious metal hydrogenation catalysts restricts the development in industrial grade. Efficient and low-cost hydrogen storage catalysts are essential for its application. In this work, a Ni-Mo alloy catalyst supported by commercial activated carbon was synthesized by impregnation method, and the Ni-Mo ratio and preparation conditions were optimized. The catalyst was characterized by XRD, XPS, H2-TPR, SEM, and TEM. The results showed that the doping of Mo could dramatically promote the catalytic hydrogenation of N-ethylcarbazole by the Ni-based catalyst. More than 5.75 wt% hydrogenation could be achieved in 4 h using the Ni-Mo catalyst, and the selectivity of the fully hydrogenated product 12H-NEC could be effectively improved. This result reduces the cost of hydrogenation catalysts by more than 90% and makes liquid organic hydrogen storage a scaled possibility.

Background: N-Alpha-Acetyltransferase 50 (NAA50) has acetyltransferase activity and is important for chromosome segregation. However, the function and mechanism of NAA50 expression in cancer development was still unclear. Here, we systematically researched the function and mechanism of NAA50 in pan-cancer, and further verified the results of NAA50 in lung adenocarcinoma (LUAD).Methods: In this study, using the online databases TIMER2.0, SangerBox3.0, HPA, UCSC, GEPIA, cBioPortal, UALCAN, TISIDB, CancerSEA and LinkedOmics, we focused on the relevance between NAA50 and oncogenesis, progression, methylation, immune infiltration, function and prognosis. In addition, the proliferation of cells was detected by CCK-8 and Edu assay. Finally, we analyzed the relationship between the expression of NAA50 and cell cycle related proteins.Results: Pan-cancer analysis indicated that NAA50 was overexpressed in most cancers. And there was a significant correlation between NAA50 expression and the prognosis of cancer patients. In the meantime, NAA50 gene changes occur in a variety of tumors. Compared with normal tissues, the methylation level of NAA50 promoter increased in most cancer tissues. In addition, the results exhibited that in most cancers, NAA50 was significantly positively correlated with bone myeloid-derived suppressor cell (MDSC) infiltration and negatively correlated with T cell NK infiltration. Moreover, functional enrichment indicated that NAA50 regulates cell cycle and proliferation in LUAD. In vitro experiments testified that knockout of NAA50 could significantly inhibit the proliferation of LUAD.Conclusion: NAA50 may be a potential biomarker and oncogene of pan-cancer, especially LUAD, which may promote the occurrence and development of tumors through different mechanisms. Furthermore, NAA50 was bound up with to immune cell infiltration in pan-cancer, meaning NAA50 may be an important therapeutic target for human cancers.

The circadian clock is an internal time-keeping mechanism that synchronizes the physiological adaptation of an organism to its surroundings based on day and night transition in a period of 24 h, suggesting the circadian clock provides fitness by adjusting environmental constrains. The circadian clock is driven by positive and negative elements that regulate transcriptionally and post-transcriptionally. Alternative splicing (AS) is a crucial transcriptional regulator capable of generating large numbers of mRNA transcripts from limited numbers of genes, leading to proteome diversity, which is involved in circadian to deal with abiotic stresses. Over the past decade, AS and circadian control have been suggested to coordinately regulate plant performance under fluctuating environmental conditions. However, only a few reports have reported the regulatory mechanism of this complex crosstalk. Based on the emerging evidence, this review elaborates on the existing links between circadian and AS in response to abiotic stresses, suggesting an uncovered regulatory network among circadian, AS, and abiotic stresses. Therefore, the rhythmically expressed splicing factors and core clock oscillators fill the role of temporal regulators participating in improving plant growth, development, and increasing plant tolerance against abiotic stresses.

Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development.

A geometric equation of borehole deformation under stress was deduced based on the basic theory of elasticity. Subsequently, we established the quantitative relationship between the in situ stress and geometrical parameters of borehole deformation. Furthermore, we proposed an in situ stress prediction model based on borehole deformation. Additionally, numerical simulations of borehole morphology in different lithologies under in situ stress were conducted to analyze the deformation effect. Logging parameters that are sensitive to the shear wave time difference, such as longitudinal wave time difference, density, and natural gamma radiation, were selected for training using an artificial neural network (ANN) to predict the shear wave time difference. The results demonstrated that 1) combining the theoretical derivation and numerical simulation, the borehole geometry under stress was quasi-elliptic, and 2) compared with the existing shear wave time difference curve, the predicted geometry by the ANN was consistent with the actual geometry. Consequently, compared with the tested data from acoustic emission, the overall error of the in situ stress predicted using the new method was less than 9.2%. Moreover, the accuracy of the coal seam was the highest, wherein the average errors of the maximum and minimum horizontal principal stresses were 2.01 and 2.56%, respectively, which confirms the feasibility of the proposed method.

The technological innovation of horizontal drilling and high-volume hydraulic fracturing has promoted the development of unconventional natural gas (UNG) production worldwide, and hence has aroused public concern about the air pollution it may bring about. In this study, we have provided (1) an overview of the study on air pollutants from UNG emissions in the USA, focusing on both the air pollutant characterization and their related observation technologies/platforms; and (2) the potential air quality measurements of UNG development emerging in China. This study will provide useful information for Chinese environmental researchers and the local governments to deal with related air quality issues.

Maize is an important food crop and its fungal disease has become a limiting factor to improve the yield and quality of maize. In the control of plant pathogens, commercial fungicides have no obvious effect on corn diseases due to the emergence of drug resistance. Therefore, it is of great significance to develop new fungicides with novel structure, high efficiency, and low toxicity to control maize diseases. In this paper, a series of 1,3,4-oxadiazole derivatives were designed and synthesized from benzoyl hydrazine and aromatic aldehydes through condensation and oxidation cyclization reaction. The antifungal activity of oxadiazole derivatives against three maize disease pathogens, such as Rhizoctonia solani (R. solani), Gibberella zeae (G. zeae), and Exserohilum turcicum (E. turcicum), were evaluated by mycelium growth rate method in vitro. The results indicated that most of the synthesized derivatives exhibited positive antifungal activities. Especially against E. turcicum, several compounds demonstrated significant antifungal activities and their EC50 values were lower than positive control carbendazim. The EC50 values of compounds 4k, 5e, and 5k were 50.48, 47.56, 32.25 μg/ml, respectively, and the carbendazim was 102.83 μg/ml. The effects of active compounds on E. turcicum microstructure were observed by scanning electron microscopy (SEM). The results showed that compounds 4k, 5e, and 5k could induce the hyphae of E. turcicum to shrink and collapse obviously. In order to elucidate the preliminary mechanism of oxadiazole derivatives, the target compounds 5e and 5k were docked with the theoretical active site of succinate dehydrogenase (SDH). Compounds 5e and 5k could bind to amino acid residues through hydrophobic contact and hydrogen bonds, which explained the possible mechanism of binding between the inhibitor and target protein. In addition, the compounds with antifungal activities had almost no cytotoxicity to MCF-7. This study showed that 1,3,4-oxadiazole derivatives were worthy for further attention as potential antifungal agents for the control of maize diseases.

Programmed cell death (PCD) is a process that regulates the homeostasis of cells in the body, and it plays an important role in tumor immunity. However, the expression profile and clinical characteristics of PCD-related genes remain unclear. In this study, we comprehensively analysed the PCD genes with the tumor microenvironment (TME), drug sensitivity, immunothearapy response, and evaluated their prognostic value through systematic bioinformatics methods.We identified 125 PCD-related regulatory factors, which were expressed differently in lung adenocarcinoma (LUAD) and normal lung tissues. 32 PCD related prognostic genes associated with LUAD were identified by univariate Cox analysis. 23 PCD-related gene signature was constructed, and all LUAD patients in the Cancer Genome Atlas (TCGA) dataset were stratified as low-risk or high-risk groups according to the risk score. This signature had a powerful prognostic value, which was validated in three independent data sets and clinical subtypes. Additionally, it has unique properties in TME. Further analysis showed that different risk groups have different immune cell infiltration, immune inflammation profile, immune pathways, and immune subtypes. In addition, the low-risk group had a better immunotherapy response with higher levels of multiple immune checkpoints and lower Tumor immune dysfunction and exclusion (TIDE) score, while the high-risk group was sensitive to multiple chemotherapeutic drugs because of its lower IC50. In short, this is the first model to predict the prognosis and immunological status of LUAD patients based on PCD-related genes. It may be used as a predictor of immunotherapy response to achieve customized treatment of LUAD.

Understanding the structure–function relationship in a neuronal network is one of the major challenges in neuroscience research. Despite increasing researches at circuit connectivity and neural network structure, their structure-based biological interpretability remains unclear. Based on the attractor theory, here we develop an analytical framework that links neural circuit structures and their functions together through fixed point attractor in Caenorhabditis elegans. In this framework, we successfully established the structural condition for the emergence of multiple fixed points in C. elegans connectome. Then we construct a finite state machine to explain how functions related to bistable phenomena at the neural activity and behavioral levels are encoded. By applying the proposed framework to the command circuit in C. elegans, we provide a circuit level interpretation for the forward-reverse switching behaviors. Interestingly, network properties of the command circuit and first layer amphid interneuron circuit can also be inferred from their functions in this framework. Our research indicates the reliability of the fixed point attractor bridging circuit structure and functions, suggesting its potential applicability to more complex neuronal circuits in other species.

Depressive disorders are a severe psychiatric and social problem that affect more than 4% of the global population. Depressive disorders have explicit hereditary characteristics; however, the precise driving genetic force behind these disorders has not yet been clearly illustrated. In the present study, we recruited a three-generation Chinese pedigree in which 5 of 17 members had long-term depression. We conducted whole-exome sequencing to identify the genetic mutation profiles of the family, and a list of susceptible genetic variations that were highly associated with depression onset was revealed via multiple omics analysis. In particular, a non-synonymous single nucleotide variation in the oxoglutarate dehydrogenase-like (OGDHL) gene, rs2293239 (p.Asn725Ser), was identified as one of the major driving genetic forces for depression onset in the family. This variant causes an important conformational change in the transketolase domain of OGDHL, thus reducing its binding affinity with the cofactor thiamine pyrophosphate and eventually resulting in the abnormal accumulation of glutamate in the brain. Brain imaging analysis further linked the rs2293239 variant with an enlarged amygdala and cerebellum in depressive family members. In summary, the present study enhances the current genetic understanding of depressive disorders. It also provides new options for prioritizing better clinical therapeutic regimens, as well as identifying a new protein target for the design of highly specific drugs to treat depressive disorders.

The role and mechanism of transmembrane proteins (TMEMs) in tumorigenesis remain unclear. Based on 4 independent cohorts containing 1,208 cases, we identified 3 TMEMs (TMEM273, TMEM164, and TMEM125), which were used to construct a risk model to predict the prognosis of LUAD. The two patterns based on the risk score exhibited a high degree of consistency with the characteristics of immune cell infiltration and epigenetic distribution. Patients with a low-risk score, characterized by an increased activation of immunity, H3K4me3 modification, tumor cell apoptosis, chemokine secretion, and TMB, had better disease-free survival (DFS) and overall survival (OS). Obvious immunosuppression, increased epithelial–mesenchymal transition, a low H3K4me3 level, shortened cell cycle, and accelerated cell division manifested in high-risk patients, with poorer DFS and OS. The model showed a better prognostic value than the tumor immune dysfunction and exclusion score. Correlation analysis told us that patients with high scores were suitable for treatment with CD276 inhibitors for their higher levels of CD276 expression. The risk score had a strong negative correlation with HAVCR2 and ICOS among patients with EGFR-WT, KRAS-WT, STK11-WT, or TP53-MUT, and patients with these mutation types with low scores were suitable for treatment with HAVCR2 or ICOS inhibitors. This work comprehensively analyzed the role and mechanism of TMEMs in LUAD and revealed the characteristics of histone methylation modification. The TMEM-based signature gave us deep insight into immune cell infiltration profiles and provided an individualized immunotherapy strategy.

Background: In the treatment of patients with bipolar disorder (BP), antidepressant-induced mania is usually observed. The rate of phase switching (from depressive to manic) in these patients exceeds 22%. The exploration of brain activity patterns during an antidepressant-induced manic phase may aid the development of strategies to reduce the phase-switching rate. The use of a murine model to explore brain activity patterns in depressive and manic phases can help us to understandthe pathological features of BP. The novel object recognition preference ratio is used to assess cognitive ability in such models.Objective: To investigate brain Ca2+ activity and behavioral expression in the depressive and manic phases in the same murine model, to aid understanding of brain activity patterns in phase switching in BP.Methods: In vivo two-photon imaging was used to observe brain activity alterations in a murine model in which induce depressive-like and manic-like behaviors were induced sequentially. The immobility time was used to assess depressive-like symptoms and the total distance traveled was used to assess manic-like symptoms.Results: In vivo two-photon imaging revealed significantly reduced brain Ca2+ activity in temporal cortex pyramidal neurons in the depressive phase in mice exposed to chronic unpredictable mild stress compared with naïve controls. The brain Ca2+ activity correlated negatively with the novel object recognition preference ratio within the immobility time. Significantly increased brain Ca2+ activity was observed in the ketamine-induced manic phase. However, this activity did not correlate with the total distance traveled. The novel object recognition preference ratio correlated negatively with the total distance traveled in the manic phase.

BackgroundThe early-stage lung adenocarcinoma (LUAD) rate has increased with heightened public awareness and lung cancer screening implementation. Lipid metabolism abnormalities are associated with lung cancer initiation and progression. However, the comprehensive features and clinical significance of the immunometabolism landscape and lipid metabolism-related genes (LMRGs) in cancer recurrence for early-stage LUAD remain obscure.MethodsLMRGs were extracted from Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Samples from The Cancer Genome Atlas (TCGA) were used as training cohort, and samples from four Gene Expression Omnibus (GEO) datasets were used as validation cohorts. The LUAD recurrence-associated LMRG molecular pattern and signature was constructed through unsupervised consensus clustering, time-dependent receiver operating characteristic (ROC), and least absolute shrinkage and selection operator (LASSO) analyses. Kaplan-Meier, ROC, and multivariate Cox regression analyses and prognostic meta-analysis were used to test the suitability and stability of the signature. We used Gene Ontology (GO), KEGG pathway, immune cell infiltration, chemotherapy response analyses, gene set variation analysis (GSVA), and GSEA to explore molecular mechanisms and immune landscapes related to the signature and the potential of the signature to predict immunotherapy or chemotherapy response.ResultsFirst, two LMRG molecular patterns were established, which showed diverse prognoses and immune infiltration statuses. Then, a 12-gene signature was identified, and a risk model was built. The signature remained an independent prognostic parameter in multivariate Cox regression and prognostic meta-analysis. In addition, this signature stratified patients into high- and low-risk groups with significantly different recurrence rates and was well validated in different clinical subgroups and several independent validation cohorts. The results of GO and KEGG analyses and GSEA showed that there were differences in multiple lipid metabolism, immune response, and drug metabolism pathways between the high- and low-risk groups. Further analyses revealed that the signature-based risk model was related to distinct immune cell proportions, immune checkpoint parameters, and immunotherapy and chemotherapy response, consistent with the GO, KEGG, and GSEA results.ConclusionsThis is the first lipid metabolism-based signature for predicting recurrence, and it could provide vital guidance to achieve optimized antitumor for immunotherapy or chemotherapy for early-stage LUAD.

Background: Cardio-renal profiles are available from cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs).Methods: A comprehensive systematic review of Embase, Medline, Web of Knowledge, and CENTRAL databases was conducted. Randomized controlled cardiovascular outcome trials of type 2 diabetes mellitus (T2DM) patients administered GLP-1 RAs were included. The following primary outcomes were examined: cardiovascular death, major adverse cardiovascular events (MACE), myocardial infarction, stroke, mortality, heart failure, hypoglycemia, pancreatitis, and thyroid carcinoma. Secondary outcomes included: composite kidney outcome, worsening kidney function, macroalbuminuria, and retinopathy.Results: Seven trials involving 56,004 patients and eight interventions were identified. Albiglutide was associated with fewer MACE and myocardial infarction events compared with lixisenatide. Lixisenatide was related to a greater number of stroke events and cardiovascular deaths compared to once-weekly semaglutide and oral semaglutide, respectively. Improved mortality was associated with oral semaglutide compared with once-weekly semaglutide, albiglutide, dulaglutide, exenatide, or lixisenatide. Risks of heart failure, thyroid carcinoma, and pancreatitis were similar among all the treatments. Weighting of the nine primary outcomes identified oral semaglutide as first among the eight treatments examined. Among three of the secondary outcomes, once-weekly semaglutide ranked first. Better composite kidney outcome was observed with once-weekly semaglutide than with dulaglutide or exenatide; once-weekly semaglutide improved macroalbuminuria compared with exenatide or lixisenatide; and albiglutide, exenatide, and placebo was associated with fewer cases of retinopathy compared with once-weekly semaglutide. Meanwhile, kidney function was less likely to worsen with dulaglutide than with lixisenatide or placebo.Conclusion: Semaglutide should be considered when GLP-1 RAs are indicated for T2DM patients.

BackgroundImmunotherapy has been proven effective among several human cancer types, including Squamous cell lung carcinoma (SqCLC). ERAP2 plays a pivotal role in peptide trimming of many immunological processes. However, the prognostic role of ERAP2 and its relationship with immune cell infiltration in SqCLC remains unclear.MethodsThe differential expression of ERAP2 was identified via GEO and TCGA databases. We calculated the impact of ERAP2 on clinical prognosis using the Kaplan-Meier plotter. TIMER was applied to evaluate the abundance of immune cells infiltration and immune markers. SqCLC tissue microarrays containing 190 patients were constructed, and we performed immunohistochemical staining for ERAP2, CD8, CD47, CD68, and PD-L1 to validate our findings in public data.ResultsIn the GEO SqCLC database, ERAP2 was upregulated in patients with better survival (p=0.001). ERAP2 expression in SqCLC was significantly lower than that of matched normal samples (p

Objective: Post-stroke depression (PSD) is one of the most common neuropsychiatric symptoms with high prevalence, however, the mechanism of the brain network in PSD and the relationship between the structural and functional network remain unclear. This research applies graph theory to structural networks and explores the relationship between structural and functional networks.Methods: Forty-five patients with acute ischemic stroke were divided into the PSD group and post-stroke without depression (non-PSD) group respectively and underwent the magnetic resonance imaging scans. Network construction and Module analysis were used to explore the structural connectivity-functional connectivity (SC-FC) coupling of multi-scale brain networks in patients with PSD.Results: Compared with non-PSD, the structural network in PSD was related to the reduction of clustering and the increase of path length, but the degree of modularity was lower.Conclusions: The SC-FC coupling may serve as a biomarker for PSD. The similarity in SC and FC is associated with cognitive dysfunction, retardation, and desperation. Our findings highlighted the distinction in brain structural-functional networks in PSD.Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03256305, NCT03256305.

Metabolic reprogramming is a hallmark of malignancy. Understanding the characteristics of metabolic reprogramming in esophageal squamous cell carcinoma (ESCC) helps uncover novel targets for cancer progression. In this study, 880 metabolism-related genes were identified from microarray data and then filtered to divide patients into two subgroups using consensus clustering, which exhibits significantly different overall survival. After a differential analysis between two subtypes, 3 genes were screened out to construct a two subtypes decision model on the training cohort (GSE53624), defined as high-risk and low-risk subtypes. These risk models were then verified in two public databases (GSE53622 and TCGA-ESCC), an independent cohort of 49 ESCC patients by RT-qPCR and an external cohort of 95 ESCC patients by immunohistochemistry analysis (IHC). Furthermore, the immune cell infiltration of regulatory T cells (Tregs) and plasma cells showed a significant difference between the high and low-risk subtypes in the IHC experiment with 119 ESCC patients. In conclusion, our study indicated that three metabolism-related prognostic genes could stratify patients into subgroups and were associated with immune infiltration, clinical features and clinical outcomes.

Background: Few studies attempt to investigate the impact of histology on the outcome of nonsmall-cell lung cancer (NSCLC) patients. In this study, we aim to determine whether the type of histology influenced the outcome of stage IA NSCLC patients with tumor size (TS) ≤20 mm.Methods: The data of the population in our study was collected from the Surveillance, Epidemiology, and End Results (SEER) program, which is supported by the National Cancer Institute of the United States. The primary outcome was overall survival (OS). Cox-regression proportional hazards models were performed to identify prognostic factors for OS. The secondary outcome was lung cancer-specific mortality (LCSM). A competing risk model was used to identify risk factors associated with LCSM.Results: A total of 4,424 eligible patients (T1a-bN0M0) who received sublobar resection [wedge resection (WR) and segmentectomy] were identified and included in the study for further analysis. For patients with TS ≤ 10 mm, multivariate Cox-regression analyses for OS showed that lung squamous cell carcinoma (LUSC) yielded poorer OS compared with lung adenocarcinoma (LUAD), and no difference was observed between LUSC and LUAD for LCSM in competing risk models. For patients with TS > 10 and ≤20 mm, multivariate analyses revealed that LUSC patients experienced poorer OS compared with that of LUAD; the univariate competing risk analysis indicated SCC pathology predicted an increased risk of death from lung cancer, whereas no difference is observed in the multivariate competing analysis. In addition, segmentectomy was associated with longer OS in patients with >10 and ≤20 mm but not in patients with ≤10 mm compared with WR.Conclusion: Our study demonstrated that squamous pathology was associated with the worse OS but not LCSM for patients with ≤20 mm compared with adenocarcinoma. Moreover, segmentectomy when compared to wedge resection appears to be associated with a better prognosis in patients with neoplasm >10 mm, but not in the case of nodule ≤10 mm.

Roots provide multiple key functions for plants, including anchorage and capturing of water and nutrients. Evolutionarily, roots represent a crucial innovation that enabled plants to migrate from aquatic to terrestrial environment and to grow in height. Based on fossil evidence, roots evolved at least twice independently, once in the lycophyte clade and once in the euphyllophyte (ferns and seed plants) clade. In lycophytes, roots originated in a stepwise manner. Despite their pivotal position in root evolution, it remains unclear how root development is controlled in lycophytes. Getting more insight into lycophyte root development might shed light on how genetic players controlling the root meristem and root developmental processes have evolved. Unfortunately, genetic studies in lycophytes are lagging behind, lacking advanced biotechnological tools, partially caused by the limited economic value of this clade. The technology of RNA sequencing (RNA-seq) at least enabled transcriptome studies, which could enhance the understanding or discovery of genes involved in the root development of this sister group of euphyllophytes. Here, we provide an overview of the current knowledge on root evolution followed by a survey of root developmental events and how these are genetically and hormonally controlled, starting from insights obtained in the model seed plant Arabidopsis and where possible making a comparison with lycophyte root development. Second, we suggest possible key genetic regulators in root development of lycophytes mainly based on their expression profiles in Selaginella moellendorffii and phylogenetics. Finally, we point out challenges and possible future directions for research on root evolution.

Background: Flexor spasticity of the upper limb is common in poststroke patients and seriously affects the recovery of upper limb function. However, there are no standard management protocols for this condition. Radial extracorporeal shock wave therapy (rESWT) is widely used for various diseases, some studies reported the effects of ESWT on reducing spasticity, but the mechanism of ESWT to reduce spasticity by affecting the excitability of stretch reflex or non-neural rheological components in spastic muscles or both is not yet clear. A large randomized controlled trial with comprehensive evaluation indicators is still needed. The study is to observe the effect of rESWT on flexor spasticity of the upper limb after stroke and explore its mechanism.Methods: A prospective, randomized, double-blind controlled trial is to be performed. One hundred participants will be recruited from the Inpatient Department of Zhujiang Hospital. Eligible patients will be randomly allocated to either receive three sessions of active rESWT (group A) or sham-placebo rESWT (group B) with 3-day intervals between each session. Assessment will be performed at baseline and at 24 h after each rESWT (t1, t2, and t3). The primary assessment outcome will be the Modified Ashworth Scale, and other assessments include surface electromyography, MyotonPRO digital muscle function evaluation, and infrared thermal imaging. All data will be analyzed using intention-to-treat principles. Multiple imputation by chained equations will be used to address missing data caused by loss to follow-up and nonresponses. Per protocol, analyses will also be performed on the participants who complete other assessments. Statistical analysis will be performed using SPSS software (version 20.0) and the significance level set at p < 0.05.Discussion: This trial aims to analyze the application of rESWT for the management of spasticity after stroke via appropriate assessments. We hypothesized that after receiving active rESWT, patients would show greater improvement of upper limb muscles compared with patients within the sham-placebo group. The rESWT would be an alternative to traditional methods, and the results of this study may provide support for the further study of potential mechanisms.Clinical Trial Registration:www.chictr.org.cn, identifier: ChiCTR1800016144.

Interleukins (ILs) and interleukin receptors (ILRs) play important role in the antitumor immune response. However, the expression signature and clinical characteristics of the IL(R) family in lung adenocarcinoma (LUAD) remains unclear. The main purpose of this study was to explore the expression profile of IL(R) family genes and construct an IL(R)-based prognostic signature in LUAD. Five public datasets of 1,312 patients with LUAD were enrolled in this study. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and samples from the other four cohorts extracted from Gene Expression Omnibus (GEO) database were used as the validation set. Additionally, the profile of IL(R) family signature was explored, and the association between this signature and immunotherapy response was also analyzed. Meanwhile, the prognostic value was compared between this IL(R)-based signature and different immunotherapy markers. A signature based on five identified IL(R)s (IL7R, IL5RA, IL20RB, IL11, IL22RA1) was constructed using the TCGA dataset through univariate/multivariable Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) Cox analysis. These cases with LUAD were stratified into high- and low-risk group according to the risk score. This signature showed a strong prognostic ability, which was verified by the five independent cohorts and clinical subtypes. The IL(R)-based models presented unique characteristics in terms of immune cell infiltration and immune inflammation profile in tumor microenvironment (TME). Biological pathway analysis confirmed that high-risk patients showed significant T- and B-cell immunosuppression and rapid tumor cell proliferation. More importantly, we researched the relationship between this IL(R)-based signature and immune checkpoints, tumor mutation burden (TMB), tumor purity and ploidy, and tumor immune dysfunction and exclusion (TIDE) score, which confirmed that this signature gave the best prognostic value. We first provided a robust prognostic IL(R)-based signature, which had the potential as a predictor for immunotherapy response to realize individualized treatment of LUAD.

Objective: To investigate the efficacy and safety of a novel lower-limb exoskeletal robot, BEAR-H1 (Shenzhen Milebot Robot Technology), in the locomotor function of subacute stroke patients.Methods: The present study was approved by the ethical committee of the First Affiliated Hospital of Nanjing Medical University (No. 2019-MD-43), and registration was recorded on the Chinese Clinical Trial Registry with a unique identifier: ChiCTR2100044475. A total of 130 patients within 6 months of stroke were randomly divided into two groups: the robot group and the control group. The control group received routine training for walking, while in the robot group, BEAR-H1 lower-limb exoskeletal robot was used for locomotor training. Both groups received two sessions daily, 5 days a week for 4 weeks consecutively. Each session lasted 30 min. Before treatment, after treatment for 2 weeks, and 4 weeks, the patients were assessed based on the 6-minute walking test (6MWT), functional ambulation scale (FAC), Fugl-Meyer assessment lower-limb subscale (FMA-LE), and Vicon gait analysis.Results: After a 4-week intervention, the results of 6MWT, FMA-LE, FAC, cadence, and gait cycle in the two groups significantly improved (P < 0.05), but there was no significant difference between the two groups (P > 0.05). The ratio of stance phase to that of swing phase, swing phase symmetry ratio (SPSR), and step length symmetry ratio (SLSR) was not significantly improved after 4 weeks of training in both the groups. Further analyses revealed that the robot group exhibited potential benefits, as the point estimates of 6MWT and Δ6MWT (post-pre) at 4 weeks were higher than those in the control group. Additionally, within-group comparison showed that patients in the robot group had a significant improvement in 6MWT earlier than their counterparts in the control group.Conclusions: The rehabilitation robot in this study could improve the locomotor function of stroke patients; however, its effect was no better than conventional locomotor training.

As an important component, 1,000 kernel weight (TKW) plays a significant role in the formation of yield traits of wheat. Kernel size is significantly positively correlated to TKW. Although numerous loci for kernel size in wheat have been reported, our knowledge on loci for kernel area (KA) and kernel circumference (KC) remains limited. In the present study, a recombinant inbred lines (RIL) population containing 371 lines genotyped using the Wheat55K SNP array was used to map quantitative trait loci (QTLs) controlling the KA and KC in multiple environments. A total of 54 and 44 QTLs were mapped by using the biparental population or multienvironment trial module of the inclusive composite interval mapping method, respectively. Twenty-two QTLs were considered major QTLs. BLAST analysis showed that major and stable QTLs QKc.sau-6A.1 (23.12–31.64 cM on 6A) for KC and QKa.sau-6A.2 (66.00–66.57 cM on 6A) for KA were likely novel QTLs, which explained 22.25 and 20.34% of the phenotypic variation on average in the 3 year experiments, respectively. Two Kompetitive allele-specific PCR (KASP) markers, KASP-AX-109894590 and KASP-AX-109380327, were developed and tightly linked to QKc.sau-6A.1 and QKa.sau-6A.2, respectively, and the genetic effects of the different genotypes in the RIL population were successfully confirmed. Furthermore, in the interval where QKa.sau-6A.2 was located on Chinese Spring and T. Turgidum ssp. dicoccoides reference genomes, only 11 genes were found. In addition, digenic epistatic QTLs also showed a significant influence on KC and KA. Altogether, the results revealed the genetic basis of KA and KC and will be useful for the marker-assisted selection of lines with different kernel sizes, laying the foundation for the fine mapping and cloning of the gene(s) underlying the stable QTLs detected in this study.

This study aimed to investigate the safety and efficacy of high-dose vitamin B6 (vB6) as an adjunct treatment for antipsychotic-induced hyperprolactinemia (AIHP) in male patients with treatment-resistant schizophrenia (TRS). In this randomized double-blinded controlled study, patients were randomized (1:1) into a control group given aripiprazole (ARI; 10 mg/day; n = 100) or an intervention group given vB6 (300 mg/12 h for 16 weeks; n = 100). Prolactin levels, psychotic symptoms [Positive and Negative Syndrome Scale (PANSS)], cognitive function [MATRICS Consensus Cognitive Battery (MCCB)], liver function, kidney function, growth hormone level, micronutrient levels, blood lipids, and adverse secondary effects (ASEs)[Treatment Emergent Symptom Scale (TESS) and Barnes-Akathisia scale] were monitored. After a 16-week treatment period, the vB6 group showed a 68.1% reduction in serum prolactin levels (from 95.52 ± 6.30 μg/L to 30.43 ± 18.65 μg/L) while the ARI group showed only a 37.4% reduction (from 89.07 ± 3.59 μg/L to 55.78 ± 7.39 μg/L). During weeks 1–4, both treatments reduced prolactin similarly. Subsequently, the ARI effect plateaued, while the vB6 effect remained robust. The vB6 group showed better alleviation of psychotic symptoms and cognitive impairment. No serious ASEs were observed; ASEs were more frequent in the ARI group. AIHP reduction efficacy of vB6 was associated with baseline prolactin and triglyceride levels, total vB6 dosage, and education level. In conclusion, compared with the ARI group, TRS patients given vB6 showed better attenuation of AIHP, lower ASE scores, and greater improvements in clinical symptoms and cognitive impairments. These results support further consideration of vB6 as a putative treatment for AIHP.Trial Registration: ChiCTR1800014755

Bladder urothelial carcinoma (BC) is a fatal invasive malignancy and the most common malignancy of the urinary system. In the current study, we investigated the function and mechanisms of Neuropilin-1 (NRP1), the co-receptor for vascular endothelial growth factor, in BC pathogenesis and progression. The expression of NRP1 was evaluated using data extracted from GEO and HPA databases and examined in BC cell lines. The effect on proliferation, apoptosis, angiogenesis, migration, and invasion of BC cells were validated after NRP1 knockdown. After identifying differentially expressed genes (DEGs) induced by NRP1 silencing, GO/KEGG and IPA® bioinformatics analyses were performed and specific predicted pathways and targets were confirmed in vitro. Additionally, the co-expressed genes and ceRNA network were predicted using data downloaded from CCLE and TCGA databases, respectively. High expression of NRP1 was observed in BC tissues and cells. NRP1 knockdown promoted apoptosis and suppressed proliferation, angiogenesis, migration, and invasion of BC cells. Additionally, after NRP1 silencing the activity of MAPK signaling and molecular mechanisms of cancer pathways were predicted by KEGG and IPA® pathway analysis and validated using western blot in BC cells. NRP1 knockdown also affected various biological functions, including antiviral response, immune response, cell cycle, proliferation and migration of cells, and neovascularisation. Furthermore, the main upstream molecule of the DEGs induced by NRP1 knockdown may be NUPR1, and NRP1 was also the downstream target of NUPR1 and essential for regulation of FOXP3 expression to activate neovascularisation. DCBLD2 was positively regulated by NRP1, and PPAR signaling was significantly associated with low NRP1 expression. We also found that NRP1 was a predicted target of miR-204, miR-143, miR-145, and miR-195 in BC development. Our data provide evidence for the biological function and molecular aetiology of NRP1 in BC and for the first time demonstrated an association between NRP1 and NUPR1, FOXP3, and DCBLD2. Specifically, downregulation of NRP1 contributes to BC progression, which is associated with activation of MAPK signaling and molecular mechanisms involved in cancer pathways. Therefore, NRP1 may serve as a target for new therapeutic strategies to treat BC and other cancers.

With the increasingly early stage lung squamous cell carcinoma (LUSC) being discovered, there is an urgent need for a comprehensive analysis of the prognostic characteristics of early stage LUSC. Here, we developed an immune-related gene signature for outcome prediction of early stage LUSC based on three independent cohorts. Differentially expressed genes (DEGs) were identified using CIBERSORT and ESTMATE algorithm. Then, a 17-immune-related gene (RPRM, APOH, SSX1, MSGN1, HPR, ISM2, FGA, LBP, HAS1, CSF2, RETN, CCL2, CCL21, MMP19, PTGIS, F13A1, C1QTNF1) signature was identified using univariate Cox regression, LASSO regression and stepwise multivariable Cox analysis based on the verified DEGs from 401 cases in The Cancer Genome Atlas (TCGA) database. Subsequently, a cohort of GSE74777 containing 107 cases downloaded from Gene Expression Omnibus (GEO) database and an independent data set consisting of 36 frozen tissues collected from National Cancer Center were used to validate the predictive value of the signature. Seventeen immune-related genes were identified from TCGA cohort, which were further used to establish a classification system to construct cases into high- and low-risk groups in terms of overall survival. This classifier was still an independent prognostic factor in multivariate analysis. In addition, another two independent cohorts and different clinical subgroups validated the significant predictive value of the signature. Further mechanism research found early stage LUSC patients with high risk had special immune cell infiltration characteristics and gene mutation profiles. In conclusion, we characterized the tumor microenvironment and established a highly predictive model for evaluating the prognosis of early stage LUSC, which may provide a lead for effective immunotherapeutic options tailored for each subtype.

Lung adenocarcinoma is one of the most malignant diseases worldwide. The immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have changed the paradigm of lung cancer treatment; however, there are still patients who are resistant. Further exploration of the immune infiltration status of lung adenocarcinoma (LUAD) is necessary for better clinical management. In our study, the CIBERSORT method was used to calculate the infiltration status of 22 immune cells in LUAD patients from The Cancer Genome Atlas (TCGA). We clustered LUAD based on immune infiltration status by consensus clustering. The differentially expressed genes (DEGs) between cold and hot tumor group were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed. Last, we constructed a Cox regression model. We found that the infiltration of M0 macrophage cells and follicular helper T cells predicted an unfavorable overall survival of patients. Consensus clustering of 22 immune cells identified 5 clusters with different patterns of immune cells infiltration, stromal cells infiltration, and tumor purity. Based on the immune scores, we classified these five clusters into hot and cold tumors, which are different in transcription profiles. Hot tumors are enriched in cytokine–cytokine receptor interaction, while cold tumors are enriched in metabolic pathways. Based on the hub genes and prognostic-related genes, we developed a Cox regression model to predict the overall survival of patients with LUAD and validated in other three datasets. In conclusion, we developed an immune-related signature that can predict the prognosis of patients, which might facilitate the clinical application of immunotherapy in LUAD.

Accumulating studies have confirmed the crucial role of long non-coding RNAs (ncRNAs) as favorable biomarkers for cancer diagnosis, therapy, and prognosis prediction. In our recent study, we established a robust model which is based on multi-gene signature to predict the therapeutic efficacy and prognosis in glioblastoma (GBM), based on Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. lncRNA-seq data of GBM from TCGA and CGGA datasets were used to identify differentially expressed genes (DEGs) compared to normal brain tissues. The DEGs were then used for survival analysis by univariate and multivariate COX regression. Then we established a risk score model, depending on the gene signature of multiple survival-associated DEGs. Subsequently, Kaplan-Meier analysis was used for estimating the prognostic and predictive role of the model. Gene set enrichment analysis (GSEA) was applied to investigate the potential pathways associated to high-risk score by the R package “cluster profile” and Wiki-pathway. And five survival associated lncRNAs of GBM were identified: LNC01545, WDR11-AS1, NDUFA6-DT, FRY-AS1, TBX5-AS1. Then the risk score model was established and shows a desirable function for predicting overall survival (OS) in the GBM patients, which means the high-risk score significantly correlated with lower OS both in TCGA and CGGA cohort. GSEA showed that the high-risk score was enriched with PI3K-Akt, VEGFA-VEGFR2, TGF-beta, Notch, T-Cell pathways. Collectively, the five-lncRNAs signature-derived risk score presented satisfactory efficacies in predicting the therapeutic efficacy and prognosis in GBM and will be significant for guiding therapeutic strategies and research direction for GBM.

As extracellular vesicles, exosomes are released from most cells to perform cell–cell communication. Recent studies have shown that exosomes could be released into tumor microenvironment and blood to promote tumor progression through packaging and transmitting various bioactive molecules, such as cholesterol, proteins, lipids, miRNAs, mRNAs, and long non-coding RNAs (lncRNAs) to distant cells. LncRNAs have emerged as a major class of non-coding transcripts. A lot of LncRNAs have been discovered during the past few years of research on genomics. They have been proven to participate in various biological functions and disease processes through multiple mechanisms. In this review, we analyzed the role of exosome-derived lncRNAs in lung carcinogenesis and metastasis. We also highlight opportunities for the clinical potential of exosomes with specific lncRNAs as biomarkers and therapeutic intervention in lung cancer.

Esophageal microbiota plays important roles in esophageal cancer. Esophagectomy, as the most important therapeutic way, contributes to changes of esophageal microbiome. However, there are few studies examining the esophageal microbiome and the metabolic changes before and after esophagectomy. The present study characterized the esophageal microbiome of 17 patients with esophageal squamous cell carcinoma (ESCC), 11 patients with esophagogastric junction (EGJ) cancer, 15 patients at 9–12 months after radical esophagectomy and 16 healthy controls (HC). 16S ribosomal RNA gene sequencing was used to evaluate the microbiome and predict the metabolic pathways. Our results showed that the microbial diversity was significantly lower in ESCC, EGJ and post-ESCC groups than that in the HC group. The abundance of Fusobacteria was higher (7.01 vs. 1.12%, P = 0.039) and the abundance of Actinobacteria (1.61 vs. 4.04%) was lower in the ESCC group than that in the HC group. We found significant differences in the abundance of Bacteroidetes (20.45 vs. 9.86%, P = 0.026), Fusobacteria (7.01 vs. 1.66%, P = 0.030) between ESCC and post-ESCC groups. The results of microbial composition analysis and PICRUSt demonstrated significant differences between ESCC and HC groups. The β diversity and PICRUSt suggested that the microbial composition and metabolic pathways were similar to HC group after esophagectomy. The monitoring of the esophagus microbiota may be an essential method to predict the recurrence of tumor.

Background: Lobectomy with mediastinal lymph node dissection has always been recognized as the standardized treatment for early-stage non-small-cell lung cancer. However, the feasibility of segmentectomy performed in stage IB non-small-cell lung cancer (NSCLC) patients remains controversial. The present study aims to investigate whether the outcome of stage IB NSCLC patients undergoing segmentectomy was comparable to those who underwent lobectomy.Method: We retrospectively collected data of 11,010 patients with primary stage IB non-small-cell lung cancer from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and lung cancer-specific survival (LCSS) were assessed among patients who were performed lobectomy or segmentectomy. To further assess the impact of the surgical procedures on patients with different tumor sizes, subgroups stratified by tumor size were analyzed.Results: A total of 11,010 patients who were pathologically confirmed to be stage IB were included, of whom 10,453 received lobectomy and 557 received segmentectomy. Both univariate and multivariate Cox regression analyses showed that the patients receiving lobectomy had better OS [hazards ratio (HR) = 1.197, 95% confidence interval (CI) (1.066, 1.343), P < 0.001] than those receiving segmentectomy. However, multivariate analysis showed that there was no significant difference in LCSS between lobectomy and segmentectomy [HR = 1.172, 95% CI (0.963, 1.427), P = 0.114]. Meanwhile, subgroup analyses showed that lobectomy rather than segmentectomy was associated with better OS [HR = 1.278, 95% CI (1.075, 1.520) P = 0.006] and LCSS [HR = 1.118, 95% CI (1.005, 1.280), P = 0.047] for patients with a tumor size (TS) of ≤ 40 and >30 mm, while for patients with a TS of ≤ 30 mm, lobectomy yielded similar OS [TS ≤ 20 mm: HR = 1.068, 95% CI (0.853, 1.336), P = 0.566; TS > 20 mm and ≤ 30 mm: HR = 1.195, 95% CI (0.961, 1.487), P = 0.109] and LCSS [TS ≤ 20 mm: HR = 1.029, 95% CI: (0.682, 1.552), P = 0.893; TS > 20 and ≤ 30 mm: HR = 1.144, 95% CI (0.795, 1.645), P = 0.469] to that of segmentectomy.Conclusion: Segmentectomy achieved equivalent OS and LCSS in stage IB NSCLC patients with TS ≤ 30 mm compared with lobectomy. Lobectomy showed better OS and LCSS than segmentectomy for patients with a TS of >30 and ≤ 40 mm. Segmentectomy may be acceptable in patients with an older age and a smaller TS.

Objective: To investigate the clinical features, treatment methods, and outcomes of fulminant myocarditis (FM) in children.Methods: The clinical data of 23 children with FM hospitalized in the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Provincial Children's Hospital from January 2011 to September 2019 were retrospectively analyzed.Results: Among the 23 patients analyzed, 10 were male and 13 were female. The patients aged from 6 months to 14 years old (6.5 ± 3.4 years), and 18 patients were over 3 years old. There were 14 cases with respiratory symptoms, 16 cases with gastrointestinal symptoms, 15 cases with neurological symptoms, and 19 cases with hypoperfusion manifestations. Creatine kinase MB (CK-MB) and cardiac troponin I (CTnI) levels were increased in 19 and 21 cases, respectively. Electrocardiography (ECG) showed ST-T changes in 18 cases and atrioventricular blocks (AVB) in 15 cases. Echocardiography (ECHO) showed cardiac chamber enlargement (CCE) in eight cases, left ventricular systolic dysfunction in five cases, decrease in left ventricular ejection fraction (LVEF) in four cases, reduction in wall motion in two cases, and pericardial effusion in seven cases. Intravenous immunoglobulin (IVIG) and glucocorticoids were administered to 19 and 20 patients, respectively. Fourteen patients were treated with temporary pacemakers, one patient received extracorporeal membrane oxygenation (ECMO), one patient received continuous renal replacement therapy (CRRT), and one patient received ECMO combined with CRRT. Twenty patients improved at discharge, and three patients died.Conclusion: Preschool and school-age children showing hypoperfusion symptoms, such as paleness, cold, clammy limbs, and capillary refill time (CRT) extension, accompanied by vomiting, abdominal pain, dizziness, convulsions, and other symptoms, should be carefully examined for FM. CK-MB, CTnI, ECG, and echocardiogram need to be performed at the earliest opportunity. In the early stages of FM, vital signs should be actively monitored, high-dose IVIG and glucocorticoids should be administered, and life support technologies such as temporary pacemakers, ECMO, and CRRT should be used to increase the survival rate of children with FM as needed.

We present Clustering and Lineage Inference in Single-Cell Transcriptional Analysis (CALISTA), a numerically efficient and highly scalable toolbox for an end-to-end analysis of single-cell transcriptomic profiles. CALISTA includes four essential single-cell analyses for cell differentiation studies, including single-cell clustering, reconstruction of cell lineage specification, transition gene identification, and cell pseudotime ordering, which can be applied individually or in a pipeline. In these analyses, we employ a likelihood-based approach where single-cell mRNA counts are described by a probabilistic distribution function associated with stochastic gene transcriptional bursts and random technical dropout events. We illustrate the efficacy of CALISTA using single-cell gene expression datasets from different single-cell transcriptional profiling technologies and from a few hundreds to tens of thousands of cells. CALISTA is freely available on https://www.cabselab.com/calista.

The human brain is thought to be an extremely complex but efficient computing engine, processing vast amounts of information from a changing world. The decline in the synaptic density of neuronal networks is one of the most important characteristics of brain development, which is closely related to synaptic pruning, synaptic growth, synaptic plasticity, and energy metabolism. However, because of technical limitations in observing large-scale neuronal networks dynamically connected through synapses, how neuronal networks are organized and evolve as their synaptic density declines remains unclear. Here, by establishing a biologically reasonable neuronal network model, we show that despite a decline in the synaptic density, the connectivity, and efficiency of neuronal networks can be improved. Importantly, by analyzing the degree distribution, we also find that both the scale-free characteristic of neuronal networks and the emergence of hub neurons rely on the spatial distance between neurons. These findings may promote our understanding of neuronal networks in the brain and have guiding significance for the design of neuronal network models.

Liraglutide (Lir) is a glucagon-like peptide-1 receptor agonist that lowers blood sugar and reduces myocardial infarct size by improving endothelial cell function. However, its mechanism has not yet been clarified. Unfolded protein response (UPR) plays an important role in the pathogenesis of myocardial ischemia-reperfusion injury. It determines the survival of cells. Endoplasmic reticulum position protein homologue 2 (CNPY2) is a novel initiator of UPR that also participates in angiogenesis. To this extent, the current study further explored whether Lir regulates angiogenesis through CNPY2. In our article, a hypoxia/reoxygenation (H/R) injury model of human umbilical vein endothelial cells (HUVECs) was established and the effect of Lir on HUVECs was first evaluated by the Cell Counting Kit-8. Endothelial tube formation was used to analyze the ability of Lir to induce angiogenesis. Subsequently, the effect of Lir on the concentrations of hypoxia-inducible factor 1α (HIF1α), vascular endothelial growth factor (VEGF), and CNPY2 was detected by enzyme-linked immunosorbent assay. To assess whether Lir regulates angiogenesis through the CNPY2-initiated UPR pathway, the expression of UPR-related pathway proteins (CNPY2, GRP78, PERK, and ATF4) and angiogenic proteins (HIF1α and VEGF) was detected by reverse transcription-polymerase chain reaction and Western blot. The results confirmed that Lir significantly increased the expression of HIF1α and VEGF as well as the expression of CNPY2-PERK pathway proteins in HUVECs after H/R injury. To further validate the experimental results, we introduced the PERK inhibitor GSK2606414. GSK2606414 was able to significantly decrease both the mRNA and protein expression of ATF4, HIF1α, and VEGF in vascular endothelial cells after H/R injury. The effect of Lir was also inhibited using GSK2606414. Therefore, our study suggested that the CNPY2-PERK pathway was involved in the mechanism of VEGF expression after H/R injury in HUVECs. Lir increased the expression of VEGF through the CNPY2-PERK pathway, which may promote endothelial cell angiogenesis and protect HUVEC from H/R damage.

Angiosperms develop intensively branched root systems that are accommodated with the high capacity to produce plenty of new lateral roots throughout their life-span. Root branching can be dynamically regulated in response to edaphic conditions and provides the plants with a soil-mining potential. This highly specialized branching capacity has most likely been key in the colonization success of the present flowering plants on our planet. The initiation, formation and outgrowth of branching roots in Angiosperms are dominated by the plant hormone auxin. Upon auxin treatment root branching through the formation of lateral roots can easily be induced. In this study, we questioned whether this strong branching-inducing action of auxin is part of a conserved mechanism that was already active in the earliest diverging lineage of vascular plants with roots. In Selaginella, an extant representative species of this early clade of root forming plants, components of the canonical auxin signaling pathway are retrieved in its genome. Although we observed a clear physiological response and an indirect effect on root branching, we were not able to directly induce root branching in this species by application of different auxins. We conclude that the structural and developmental difference of the Selaginella root, which branches via bifurcation of the root meristem, or the absence of an auxin-mediated root development program, is most likely causative for the absence of an auxin-induced branching mechanism.

Neuronal networks in the brain are the structural basis of human cognitive function, and the plasticity of neuronal networks is thought to be the principal neural mechanism underlying learning and memory. Dominated by the Hebbian theory, researchers have devoted extensive effort to studying the changes in synaptic connections between neurons. However, understanding the network topology of all synaptic connections has been neglected over the past decades. Furthermore, increasing studies indicate that synaptic activities are tightly coupled with metabolic energy, and metabolic energy is a unifying principle governing neuronal activities. Therefore, the network topology of all synaptic connections may also be governed by metabolic energy. Here, by implementing a computational model, we investigate the general synaptic organization rules for neurons and neuronal networks from the perspective of energy metabolism. We find that to maintain the energy balance of individual neurons in the proposed model, the number of synaptic connections is inversely proportional to the average of the synaptic weights. This strategy may be adopted by neurons to ensure that the ability of neurons to transmit signals matches their own energy metabolism. In addition, we find that the density of neuronal networks is also an important factor in the energy balance of neuronal networks. An abnormal increase or decrease in the network density could lead to failure of energy metabolism in the neuronal network. These rules may change our view of neuronal networks in the brain and have guiding significance for the design of neuronal network models.

As a sophisticated computing unit, the pyramidal neuron requires sufficient metabolic energy to fuel its powerful computational capabilities. However, the majority of previous works focus on nonlinear integration and energy consumption in individual pyramidal neurons but seldom on the effects of metabolic energy on synaptic transmission and dendritic integration. Here, we developed biologically plausible models to simulate the synaptic transmission and dendritic integration of pyramidal neurons, exploring the relations between synaptic transmission and metabolic energy and between dendritic integration and metabolic energy. We find that synaptic energy not only drives synaptic vesicle cycle, but also participates in the regulation of this cycle. Release probability of synapses adapts to synaptic energy levels by regulating the speed of synaptic vesicle cycle. Besides, we also find that to match neural energy levels, only a part of the synapses receive presynaptic signals during a given period so that neurons have a low action potential frequency. That is, the number of simultaneously active synapses over a period of time should be adapted to neural energy levels.

ObjectiveTo determine whether robot-assisted gait training (RAGT) is more effective in improving mobility, endurance, gait performance, and balance in patients with multiple sclerosis (MS) compared with conventional walking rehabilitation treatment (CWT).Data sourcesSources included the Cochrane Library, PubMed, Embase, and Science Direct databases.Review methodAll possible articles were retrieved by two independent investigators and relevant articles were gathered. Studies on adult patients (older than 19 years old) suffering from MS were included, regardless the subtype of MS diagnosis. Finally, we identified seven studies that comprised 205 patients with MS.ResultsWe identified seven studies comprising 205 patients with MS in our meta-analysis. The pooled mean difference (MD) for the six-minute walk test (6MWT) was 14.25 [95% confidence interval (CI) 3.19 to 25.32, Z = 2.53, P = 0.01, I2 = 54%], which indicates that RAGT is superior to CWT on improving endurance. No significant improvement on using RAGT was found regarding the Berg Balance Scale (MD = −0.59, 95% CI: −2.7 to 1.52, Z = 0.55, P = 0.58, I2 = 51%), 10-meter walk test [standard mean difference (SMD) = 0.03, 95% CI: −0.26 to 0.31, Z = 0.18, P = 0.86, I2 = 48%] timed up and go (TUG) test (MD = −1.04, 95% CI: −8.68 to 6.60, Z = 0.27, P = 0.79), or stride length (SMD = 0.36, 95% CI: −0.13 to 0.85, Z = 0.73, P = 0.15).ConclusionWe can conclude that RAGT can bring more benefits on improving 6MWT among MS patients, but it is not enough to make a clinically significance conclusion. Considering the limitation of our study, it takes reservations about recommending all MS patients to take RAGT as primary rehabilitation intervention. Unless patients with progressive MS can take conventional rehabilitation in early time, RAGT would be a suitable substitute.