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Optogenetics is a rapidly developing field combining optics and genetics, with promising applications in neuroscience and beyond. However, there is currently a lack of bibliometric analyses examining publications in this area. Publications on optogenetics were gathered from the Web of Science Core Collection Database. A quantitative analysis was conducted to gain insights into the annual scientific output, and distribution of authors, journals, subject categories, countries, and institutions. Additionally, qualitative analysis, such as co-occurrence network analysis, thematic analysis, and theme evolution, were performed to identify the main areas and trends of optogenetics articles. A total of 6,824 publications were included for analysis. The number of articles has rapidly grown since 2010, with an annual growth rate of 52.82%. Deisseroth K, Boyden ES, and Hegemann P were the most prolific contributors to the field. The United States contributed the most articles (3,051 articles), followed by China (623 articles). A majority of optogenetics-related articles are published in high-quality journals, including NATURE, SCIENCE, and CELL. These articles mainly belong to four subjects: neurosciences, biochemistry and molecular biology, neuroimaging, and materials science. Co-occurrence keyword network analysis identified three clusters: optogenetic components and techniques, optogenetics and neural circuitry, optogenetics and disease. The results suggest that optogenetics research is flourishing, focusing on optogenetic techniques and their applications in neural circuitry exploration and disease intervention. Optogenetics is expected to remain a hot topic in various fields in the future.

[This corrects the article DOI: 10.3389/fnins.2023.1221316.].

Background To assess the inter-observer and intra-observer reliability of the magnetic resonance urography (MRU)—upper urinary tract dilation (UUTD) grading system. Methods A total of 40 patients with a diagnosis of NB were enrolled in this study. The images were assembled in an electronic presentation randomly. The presentations were reviewed and graded by 4 junior and 4 senior urologists. One week later, the images were randomized again and reassessed. The inter-observer reliability was estimated by Kendall’s coefficient of concordance and intra-class correlation coefficient (ICC), and the intra-observer reliability was estimated by weighted Cohen’s kappa. Results The inter-observer reliability strength was excellent for all urologists, with the ICC value of 0.939 (0.908–0.963) and Kendall’s W value of 0.967. The highest agreement was shown in Grade 4 at 92.50%, and the lowest in Grade 2 at 82.14%. All disagreements were within one grade of difference. Moreover, the Intra-observer reliability was excellent, with the weighted kappa value ranging from 0.904 to 0.954. Conclusions The inter-observer and intra-observer reliability of this novel MRU-UUTD grading system is confirmed, providing adequate evidence for broader clinical application.

Objective To determine the efficacy of novel wearable transcutaneous tibial nerve stimulation (TTNS) device on bladder reflex in cats compared to implantable tibial nerve stimulation (ITNS). Materials and methods Two self-adhesive electrodes of the TTNS device were placed at the left leg, and ITNS was applied to stimulate the tibial nerve of the right leg, respectively. The intensity threshold (T) was defined as inducing observable toe movement. Multiple cystometrograms (CMGs) with normal saline (NS) infusion were performed to determine the inhibitory effects of TTNS and ITNS on the micturition reflex. Results TTNS at 4 times T (4 T), 6 times T (6 T), and the maximum output current intensity 24 mA significantly increased the bladder capacity (BC) compared to the control level (8.70 ± 2.46 ml) (all p  < 0.05); however, there was no statistical significance among the three intensities. At the same time, ITNS at 2 times T (2 T), 4 T, 6 T, and the current intension 24 mA could significantly increase the BC compared to the control level (all p  < 0.05). Likewise, no significant difference was observed among the four intensities ( p  > 0.05). The T values of TTNS were higher than those of ITNS ( p  = 0.02). The inhibitory effects of TTNS and ITNS revealed no significant difference at their respective 2 T, 4 T, 6 T, and 24 mA. Neither TTNS nor ITNS changed the contraction duration and amplitude (all p  > 0.05). Conclusions TTNS was effective in increasing BC. The non-invasive neuromodulation technique could achieve a similar effect as ITNS.

This study aimed at exploring the effects of saphenous nerve stimulation (SNS) on treating both overactive bladder (OAB) and underactive bladder (UAB). In 6 α-chloralose anesthetized cats, bipolar nerve cuff electrodes were implanted on the saphenous nerve and pudendal nerve. UAB was induced by pudendal nerve stimulation (PNS) at 5Hz, 2 threshold (T) and OAB was induced by infusion of 0.25% acetic acid (AA). Multiple cystometrograms (CMGs) were performed to investigate the effects of SNS on pathological bladder at 1Hz and 20Hz, respectively. Application of PNS (5Hz, 2T) induced UAB by significantly increasing the bladder capacity (BC) to 156.3%±9.8% of control level, while combination of PNS and SNS (1Hz, 2T) applied during CMGs normalized the bladder underactivity by significantly reducing the BC to 93.6%±9.5% (P =0.026). Moreover, the BC was reduced to 64.1%±5.4% of control after infusion of AA, and SNS at 20Hz, 6T significantly increased the BC back to 93.4%±6.3% (P =0.005). No post-stimulation effect of SNS was detected at both 1Hz and 20Hz. However, there were no significant changes of contraction amplitude and duration during stimulation. In this study, we confirmed the frequency-dependence of SNS in regulating pathological bladder in cats. It provided experimental evidence for treating both OAB and UAB using SNS in clinic.

Metastatic colorectal cancer (mCRC) patients have poor overall survival despite using irinotecan- or oxaliplatin-based chemotherapy combined with anti-EGFR (epidermal growth factor receptor) drugs, especially those with the oncogene mutation of KRAS. Metformin has been reported as a potentially novel antitumor agent in many experiments, but its therapeutic activity is discrepant and controversial so far. Inspiringly, the median survival time for KRAS-mutation mCRC patients with diabetes on metformin is 37.8 mo longer than those treated with other hypoglycemic drugs in combination with standard systemic therapy. In contrast, metformin could not improve the survival of mCRC patients with wild-type KRAS. Interestingly, metformin is preferentially accumulated in KRAS-mutation mCRC cells, but not wild-type ones, in both primary cell cultures and patient-derived xenografts, which is in agreement with its tremendous effect in KRAS-mutation mCRC. Mechanistically, the mutated KRAS oncoprotein hypermethylates and silences the expression of multidrug and toxic compound extrusion 1 (MATE1), a specific pump that expels metformin from the tumor cells by upregulating DNA methyltransferase 1 (DNMT1). Our findings provide evidence that KRAS-mutation mCRC patients benefit from metformin treatment and targeting MATE1 may provide a strategy to improve the anticancer response of metformin.

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare and distinct subtype of primary lung cancer characterized by Epstein-Barr virus (EBV) infection. Herein, we reported the mutational landscape of pulmonary LELC using whole-exome sequencing, targeted deep sequencing and single-nucleotide polymorphism arrays. We identify a low degree of somatic mutation but widespread existence of copy number variations. We reveal predominant signature 2 mutations and frequent loss of type I interferon genes that are involved in the host-virus counteraction. Integrated analysis shows enrichment of genetic lesions affecting several critical pathways, including NF-κB, JAK/STAT, and cell cycle. Notably, multi-dimensional comparison unveils that pulmonary LELC resemble NPC but are clearly different from other lung cancers, natural killer/T-cell lymphoma or EBV-related gastric cancer in terms of genetic features. In all, our study illustrates a distinct genomic landscape of pulmonary LELC and provides a road map to facilitate genome-guided personalized treatment. The rare lung cancer subtype pulmonary lymphoepithelioma-like carcinoma is linked to Epstein-Barr virus infection. Here, the authors provide a mutational landscape for this cancer, showing a low burden of somatic mutations and high prevalence of copy number variations.

A massive intronic hexanucleotide repeat (GGGGCC) expansion in C9ORF72 is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryogenic electron microscopy (cryo-EM) structure of the human C9ORF72–SMCR8–WDR41 complex at a resolution of 3.2 Å. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72–SMCR8–WDR41. Notably, the C-terminal tail of C9ORF72 and the DENN domain of SMCR8 play critical roles in the dimerization of the two protomers of the C9ORF72–SMCR8–WDR41 complex. In the protomer, C9ORF72 and WDR41 are joined by SMCR8 without direct interaction. WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix. Interestingly, the prominent structural feature of C9ORF72–SMCR8 resembles that of the FLNC–FNIP2 complex, the GTPase activating protein (GAP) of RagC/D. Structural comparison and sequence alignment revealed that Arg147 of SMCR8 is conserved and corresponds to the arginine finger of FLCN, and biochemical analysis indicated that the Arg147 of SMCR8 is critical to the stimulatory effect of the C9ORF72–SMCR8 complex on Rab8a and Rab11a. Our study not only illustrates the basis of C9ORF72–SMCR8–WDR41 complex assembly but also reveals the GAP activity of the C9ORF72–SMCR8 complex.

Background Gut microbiota and the tumor microenvironment are thought to be critical factors that modulate the processes of liver diseases, including hepatocellular carcinoma (HCC). Interleukin-25 (IL-25) promotes type 2 immunity via alternative activation of macrophages, and is closely associated with inflammation-related diseases, even malignancies. However, it is not clear which role IL-25 plays in the development of HCC, and whether gut microbiota are involved. Methods IL-25 was detected by ELISA, Western blotting (WB), and immunohistochemistry. Chemokines were measured by RT-qPCR and WB. After co-culture with IL-25-stimulated macrophages, the cell growth, migration, invasion and EMT marker of HCC cell lines (MHCC97L and HepG2) were evaluated by Brdu proliferation, Transwell assays and WB. An antibody neutralization assay of chemokine CXCL10 was performed to confirm its role in HCC development. Furthermore, the effects of IL-25 in HCC were investigated in vivo. Dysbiosis of gut microflora was induced by antibiotics (vancomycin, cefoperazone or combination of ampicillin, neomycin, metronidazole, and vancomycin). We used feces suspension to treat colonic epithelial NCM460 cells, and detected IL-25 and tuft cell marker DCLK1 using WB and immunofluorescence staining. Results We found that the level of IL-25 was significantly elevated in HCC patients, and was negatively correlated with survival rate after hepatectomy. However, IL-25 did not directly promote the development of HCC cells. Then, we observed the significant positive correlation between IL-25 level and M2 percentage (CD206/CD68) in HCC tumors. In vitro and in vivo, IL-25 induced alternative activation of macrophages promoted HCC cell migration, invasion and tumorigenesis, increased the expression of vimentin, Snail and phospho-ERK, and decreased the expression of E-cadherin in HCC cells. After IL-25 treatment, chemokine CXCL10 was increased in macrophages. Neutralizing CXCL10 in macrophage-conditioned medium reversed the IL-25-mediated effect on HCC cells. Vancomycin-induced dysbiosis promoted the growth of orthotopic HCC homograft. Surprisedly, we found the hyperplasia of colonic epithelial tuft cells, from which more IL-25 was secreted . Conclusions IL-25 promotes the progression of HCC through inducing alternative activation and CXCL10 secretion of macrophages in tumor microenvironment, and IL-25 secretion may partly result from hyperplastic epithelial tuft cells in colon, induced by gut microbiota dysbiosis.

Understanding of intratumor heterogeneity (ITH) among different non-small cell lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA) profile could represent these ITH is still an open question. We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if the tumor has less trunk mutations. We found EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD ( P  = 0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P  = 0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P  = 0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P  = 0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%, P  = 4.53e-6) among all NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to reflect ITH.