Celine, a long interspersed nuclear element retrotransposon, colonizes in the centromeres of poplar chromosomes.

Centromeres in most multicellular eukaryotes are composed of long arrays of repetitive DNA sequences. Interestingly, several transposable elements, including the well-known long terminal repeat (LTR) retrotransposon CRM (centromeric retrotransposon of maize), were found to be enriched in functional centromeres marked by the centromeric histone H3 (CENH3). Here we report a centromeric long interspersed nuclear element (LINE), Celine, in Populus species. Celine has colonized preferentially in the CENH3-associated chromatin of every poplar chromosome, with 84% of the Celine elements localized in the CENH3-binding domains. By contrast, only 51% of the CRM elements were bound to CENH3 domains in Populus trichocarpa. These results suggest different centromere targeting mechanisms employed by Celine and CRM elements. Nevertheless, the high target specificity seems to be detrimental to further amplification of the Celine elements, leading to a shorter life span and patchy distribution among plant species compared to the CRM elements. Using a phylogenetically guided approach we were able to identify Celine-like LINE elements in tea plant (Camellia sinensis) and green ash tree (Fraxinus pennsylvanica). The centromeric localization of these Celine-like LINEs was confirmed in both species. We demonstrate that the centromere targeting property of Celine-like LINEs is of primitive origin and has been conserved among distantly related plant species.

Cisplatin induces acute kidney injury by downregulating miR-30e-5p that targets Galnt3 to activate the AMPK signaling pathway.

Cisplatin nephrotoxicity is an etiological factor for acute kidney injury (AKI). MicroRNA (miRNA) expression is dysregulated in cisplatin-induced AKI (cAKI) although the underlying mechanisms are unclear. A cAKI model was established by intraperitoneally injecting cisplatin, and key miRNAs were screened using high-throughput miRNA sequencing. The functions of key miRNAs were determined using the cell viability, live/dead, reactive oxygen species (ROS), and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays. Additionally, the macrophage membrane was wrapped around a metal-organic framework (MOF) loaded with miRNA agomir to develop a novel composite material, macrophage/MOF/miRNA agomir nanoparticles (MMA NPs). High-throughput miRNA sequencing revealed that miR-30e-5p is a key miRNA that is downregulated in cAKI. The results of in vitro experiments demonstrated that miR-30e-5p overexpression partially suppressed the cisplatin-induced or lipopolysaccharide (LPS)-induced downregulation of cell viability, proliferation, upregulation of ROS production, and cell death. Meanwhile, the results of in vivo and in vitro experiments demonstrated that MMA NPs alleviated cAKI by exerting anti-inflammatory effects. Mechanistically, cisplatin downregulates the expression of miR-30e-5p, and the downregulated miR-30e-5p can target Galnt3 to activate the adenosine 5'-monophosphate activated protein kinase (AMPK) signaling pathway, which promotes the progression of AKI. Our study found that miR-30e-5p is a key downregulated miRNA in cAKI. The downregulated miR-30e-5p promotes AKI progression by targeting Galnt3 to activate the AMPK signaling pathway. The newly developed MMA NPs were found to have protective effects on cAKI, suggesting a potential novel strategy for preventing cAKI.

Expression of FOXA1 Is Associated with the Tumor-Infiltrating M2 Macrophage, Cytotoxic T Lymphocyte, and Effect of Chemotherapy in Bladder Cancer.

PURPOSE: Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s, but the response rate is <50%. Studies have shown that the efficiency of chemotherapy differs among molecular subtypes of bladder cancer. In this study, we aimed to correlate FOXA1, a marker for differentiation of the basal and luminal subtypes, with tumor immune cell infiltration and the effect of chemotherapy in bladder cancer. MATERIALS AND METHODS: Eighty-three patients with bladder cancer treated with chemotherapy were reviewed. Clinicopathological variables for each case were recorded. FOXA1, M2 tumor-associated macrophage (TAM), dendritic cell (DC), and cytotoxic T lymphocyte (CTL) were examined by immunohistochemistry. The relationship between FOXA1, immune cell infiltration, and clinical response to chemotherapy was assessed. RESULTS: The overall objective response rate was 34%. The objective response rate for tumors with lower FOXA1 expression was 58% and for tumors with higher FOXA1 expression was 12%. Tumors with infiltrated M2 TAM proportion <3% had a higher objective response rate compared with infiltrated M2 TAM proportion >3% tumors (46% vs. 21%, p = 0.02). Tumors with infiltrated CTL proportion >5% had a higher objective response rate compared with infiltrated CTL proportion <5% tumors (50% vs. 17%, p = 0.002). DCs showed no significant differences. We found that the objective response rate for tumors with lower FOXA1 expression, proportion <3% M2 TAM infiltration, and proportion >5% CTL infiltration is 82%. Lower FOXA1 expression was associated with low M2 TAM infiltration and high CTL infiltration. CONCLUSIONS: Thus, we showed that in patients with bladder cancer who received chemotherapy, the higher clinical response rate is associated with low FOXA1 expression, low M2 TAM infiltration, and high CTL infiltration.

Giant two-photon absorption in MXene quantum dots.

Looking for materials with compelling nonlinear optical (NLO) response is of great importance for next-generation nonlinear nanophotonics. We demonstrate an escalated two-photon absorption (TPA) in ultrasmall niobium carbide quantum dots (Nb2C QDs) that is induced by a two-even-parity states transition. The TPA response of Nb2C QDs was observed in the near-infrared band of 1064-1550 nm. Surprisingly, at 1064 nm, Nb2C QDs shows an enhanced TPA response than other wavelengths with a nonlinear absorption coefficient up to a value of 0.52 ± 0.05 cm/GW. Additionally, the nonlinear optical response of Nb2C changes to saturable absorption when the incident wavelength is between 400-800 nm wavelength. Density functional theory (DFT) validates that TPA, induced by two even-parity states transition, breaks the forbidden single-photon transition, enabling a tremendous TPA response in Nb2C QDs at 1064 nm. It offers the possibility of manipulating the NLO response of Nb2C via morphology or surface termination.

Saturable absorption and self-defocusing response of 2D monoelemental germanium nanosheets in broadband spectra.

Germanium has caused a research boom in recent years due to its high carrier mobility and good stability. Although germanium has been proven to have application potential in photodetectors and other fields, its nonlinear optical properties are rarely reported. Herein, we prepared 2D germanium nanosheets by liquid phase-exfoliation (LPE) method and studied its third-order nonlinear optical response. It is found that the germanium nanosheets exhibit a broadband nonlinear optical response such as it has a large nonlinear absorption coefficient αNL ≈ -0.87 cm GW-1 and a negative nonlinear refractive index n2 ≈ -6.30 × 10-13 cm2 W-1 at 1064 nm wavelength. The experimental results show the excellent nonlinear optical performance of germanium nanosheets and indicate that 2D germanium nanosheets have promising potential in a wide range of photonics device applications.

Observation of spatial self-phase modulation induced via two competing mechanisms.

Two spatial self-phase modulation (SSPM) patterns were observed in suspensions of Bi2TeSe2 nanosheets. Two mechanisms were found to produce SSPM with different occurrence times and power dependence. The Type I (narrow) rings are attributed to the coherent third-order nonlinear optical Kerr effect, which induces self-diffraction in 2D materials, and the Type II (wide) rings are assigned to the contribution of a thermal effect. The nonlinear refractive index of Bi2TeSe2 is found to be 2.30×10-5cm2W-1 at 700 nm. The findings described here provide an explanation for the formation of rings in 2D systems due to SSPM.

Inhibition of inflammation using diacerein markedly improved renal function in endotoxemic acute kidney injured mice.

BACKGROUND: Inflammation is an important pathogenic component of endotoxemia-induced acute kidney injury (AKI), finally resulting in renal failure. Diacerein is an interleukin-1ß (IL-1ß) inhibitor used for osteoarthritis treatment by exerting anti-inflammatory effects. This study aims to investigate the effects of diacerein on endotoxemia-induced AKI. METHODS: Male C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS, 10 mg/kg) for 24 h prior to diacerein treatment (15 mg/kg/day) for another 48 h. Mice were examined by histological, molecular and biochemical approaches. RESULTS: LPS administration showed a time-dependent increase of IL-1ß expression and secretion in kidney tissues. Diacerein treatment normalized urine volume and osmolarity, reduced blood urea nitrogen (BUN), fractional excretion of sodium (FENa), serum creatinine and osmolarity, and protected renal function in an endotoxemic AKI mice model. In the histopathologic study, diacerein also improved renal tubular damage such as necrosis of the tubular segment. Moreover, diacerein inhibited LPS-induced increase of inflammatory cytokines, such as IL-1ß, tumor necrosis factor-α, monocyte chemoattractant protein-1 and nitric oxide synthase 2. In addition, LPS administration markedly decreased aquaporin 1 (AQP1), AQP2, AQP3, Na,K-ATPase α1, apical type 3 Na/H exchanger and Na-K-2Cl cotransporter expression in the kidney, which was reversed by diacerein treatment. We also found that diacerein or IL-1ß inhibition prevented the secretion of inflammatory cytokines and the decrease of AQP and sodium transporter expression induced by LPS in HK-2 cells. CONCLUSION: Our study demonstrates for the first time that diacerein improves renal function efficiently in endotoxemic AKI mice by suppressing inflammation and altering tubular water and sodium handing. These results suggest that diacerein may be a novel therapeutic agent for the treatment of endotoxemic AKI.

hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR.

Prostate cancer is one of the leading causes of death in men worldwide. Differentially expressed microRNAs (miRNAs) are associated with metastatic prostate cancer. However, their potential roles for affecting prostate cancer initiation and progression remain largely unknown. Here, we examined the aberrant expression profiles of miRNAs in human metastatic prostate cancer tissues. We further validated our miRNA expression data using two large, independent clinical prostate cancer datasets from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA). Our data support a model in which hsa-miR-135-1 acts as a potential tumor suppressor in metastatic prostate cancer. First, its downregulation was positively correlated with late TNM stage, high Gleason score, and adverse prognosis. Second, cell growth, cell cycle progression, cell migration and invasion, and xenograft tumor formation were dramatically inhibited by miR-135a overexpression. Third, in the microarray gene expression data analysis using Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, Ingenuity Pathway Analysis (IPA), and Oncomine concept analysis, we showed that miR-135a targets multiple oncogenic pathways including epidermal growth factor receptor (EGFR), which we verified using functional experimental assays. These results help advance our understanding of the function of miRNAs in metastatic prostate cancer and provide a basis for further clinical investigation.

[Expression of long noncoding RNA LINC01358 in prostate cancer and its effect on the proliferation and migration of prostate cancer cells].

OBJECTIVE: To explore the expression of long noncoding RNA (lncRNA) LINC01358 in prostate cancer (PCa) and its effect on the proliferation and migration of PCa cells. METHODS: The lncRNA array was used to screen differentially expressed lncRNAs in PCa and the corresponding carcinoma-adjacent normal tissues from 3 patients. The expressions of LINC01358 in the primary PCa, metastatic PCa, and carcinoma-adjacent tissues were compared using the PCa dataset of the Memorial Sloan Kettering Cancer Center (MSKCC). The data obtained were validated by determining the expression of LINC01358 in the PCa and carcinoma-adjacent tissues of another 10 patients by quantitative real time PCR (qRT-PCR). The effects of lncRNA LINC01358 on the proliferation of DU145 cells and migration of PCa cells were detected by MTT and Transwell assay, respectively. RESULTS: Totally, 79 differentially expressed lncRNAs in the lncRNA array, 36 highly and the other 43 lowly expressed in the PCa tissue. LINC01358 was up-regulated in the cancerous tissue. According to the MSKCC data, the LINC01358 expression was markedly higher in metastatic PCa (5.81±0.19, n = 19) and primary PCa (5.47±0.04, n = 131) than in the PCa-adjacent tissue (5.15±0.07, n = 29) and significantly correlated with postoperative biochemical relapse of the malignancy (P<0.05). qRT-PCR indicated a remarkably higher expression of LINC01358 in the PCa than in the carcinoma-adjacent tissue (6.02±1.12 vs 3.21±0.21, P<0.05). Transfection of the DU145 cells with siRNA significantly decreased the level of LINC01358 and inhibited the proliferation and migration of the PCa cells. CONCLUSIONS: LINC01358 is highly expressed in the PCa tissue and knockdown of LINC01358 may inhibit the proliferation and migration of PCa cells. LncRNA LINC01358 may be involved in the development and progression of PCa and become an index for the early diagnosis as well as a new target for the gene therapy of the malignancy.

Safety and Postoperative Outcomes of Regional versus Global Ischemia for Partial Nephrectomy: A Systematic Review and Meta-Analysis.

OBJECTIVE: To analyze current evidence comparing the safety and outcomes of regional and global ischemia for partial nephrectomy (PN). MATERIALS AND METHODS: A systematic search of the PubMed and Web of Science databases was conducted in May 2014 to identify studies comparing the safety and outcomes of regional and global ischemia for PN. A systematic review and meta-analysis was also performed. RESULTS: Six retrospective observational studies were selected for the analysis, including 363 patients who underwent PN (162 regional ischemia and 201 global ischemia cases). Operation times were not statistically different [weighted mean difference (WMD) = 20.35 min, 95% CI: -0.28-40.97, p = 0.05], but estimated blood loss was significantly higher in the regional ischemia group (WMD = 52.04 ml, 95% CI: 14.30-89.78, p = 0.007) than in the global ischemia group. Complication rates [odds ratio (OR) = 1.16; 95% CI: 0.63-2.15, p = 0.63] and blood transfusion rates (OR = 1.85; 95% CI: 0.86-4.01, p = 0.12) of the two groups were not significantly different. The regional ischemia group showed better postoperative renal function (WMD = 4.23 ml/min, 95% CI: 2.61-5.85, p < 0.00001) than the global ischemia group, and all cases in the regional ischemia group showed negative margins. CONCLUSIONS: Regional ischemia is as safe to perform as global ischemia, and the former leads to better postoperative renal functions than the latter. These findings support the application of regional ischemia for PN.

Association between hsa-miR-34b/c rs4938723 T > C promoter polymorphism and cancer risk: a meta-analysis based on 6,036 cases and 6,204 controls.

OBJECTIVE: Emerging evidence shows that microRNAs (miRNAs) function as tumor suppressors or oncogenes in human carcinogenesis. A single nucleotide polymorphism (SNP) located in the pri-miRNA promoter may affect the processing and expression of mature miRNA. However, previous studies showed conflicting results regarding the association of hsa-miR-34b/c rs4938723 T > C promoter polymorphism with cancer. Therefore, we conducted a meta-analysis to determine the association of polymorphism with cancer risk. METHODS: A computerized search of PubMed, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) for publications on hsa-miR-34b/c rs4938723 T > C promoter polymorphism and cancer risk was performed and the genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Test of heterogeneity, cumulative meta-analysis, sensitivity analysis and assessment of bias were performed in our meta-analysis by STATA software 12.0. RESULTS: There was no significant association between hsa-miR-34b/c rs4938723 polymorphism and overall cancer risk in the comparison models. Moreover, subgroup analysis revealed that the variant CT (OR =1.19, 95% CI: 1.03-1.37) and CC/CT (OR =1.18, 95% CI: 1.03-2.35) genotypes were associated with an increased risk of hepatocellular carcinoma (HCC) compared with wild-type TT genotype. However, a decreased risk of colorectal cancer (CRC) was found in the genetic model of CC/TT (OR =0.66, 95% CI: 0.47-0.92) and CC/CTTT (OR =0.67, 95% CI: 0.49-0.93). CONCLUSIONS: The results suggest that hsa-miR-34b/c rs4938723 polymorphism may play an opposite role in different types of cancer based on current studies, which is the main origin of heterogeneity in this meta-analysis. Further large-scale studies and functional studies between this polymorphism and cancer risk are warranted.

Knockdown of Glycolysis-Related LINC01070 Inhibits the Progression of Breast Cancer.

Accumulative evidence confirms that glycolysis and long non-coding RNAs (lncRNAs) are closely associated with tumor development. The aim of this study was to construct a novel prognostic model based on glycolysis-related lncRNAs (GRLs) in breast cancer patients. By performing Pearson correlation analysis and Lasso regression analysis on differentially expressed genes and lncRNAs associated with glycolysis in the Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) datasets, we identified nine GRLs and constructed associated prognostic risk signature. Kaplan-Meier survival analysis and univariate and multivariate Cox analysis showed that patients in the low-risk group had a better prognosis. The receiver operator characteristics (ROC) curves showed that the area under the curve (AUC) of the prognostic risk signature predicting patients' overall survival at 1-, 3- and 5- years was 0.78, 0.71, and 0.71, respectively. Moreover, the validation curves also showed that the signature had better diagnostic efficacy and clinical predictive power. Furthermore, clone formation assay, EdU assay, and Transwell assay showed that knockdown of LINC01070 inhibited breast cancer progression. We developed a prognostic risk-associated GRLs signature that can accurately predict the breast cancer patient's prognostic status, and LINC01070 can be used as a potential biomarker for the prognosis of breast cancer patients.

Two-Dimensional Molybdenum Boride (MBene) Mo4/3B2Tx with Broadband and Termination-Dependent Ultrafast Nonlinear Optical Response.

Two-dimensional molybdenum borides (MBenes) comprise a new class of 2D transition metal borides that exhibit potential photonics applications. Recently, the synthesis of individual single-layer Mo4/3B2Tx (T = O, F, OH) MBene sheets has been realized, which attracted considerable attention in optoelectronics. However, there is still a lack of understanding and regulation of the photophysical processes of Mo4/3B2Tx MBene. Here, we demonstrate that Mo4/3B2Tx MBene exhibits a surface termination-dependent electronic structure, carrier dynamics, and nonlinear optical response over a wide wavelength range (500-1550 nm). As prepared 2D Mo4/3B2F2 MBene possesses a semimetal material property that exhibits a shorter intraband scattering process (<100 ps) and a considerable nonlinear optical response at a broadband cover optical communication C band at 1550 nm. These thrilling results are confirmed theoretically and experimentally. The analysis of these results adds to the regulating and understanding of the basic photophysical processes, which is anticipated to be beneficial for the further design of MBene-based photonics and nanoelectronics devices.

Interfacial Charge Transfer for Enhancing Nonlinear Saturable Absorption in WS2/graphene Heterostructure.

Interlayer charge-transfer (CT) in 2D atomically thin vertical stacks heterostructures offers an unparalleled new approach to regulation of device performance in optoelectronic and photonics applications. Despite the fact that the saturable absorption (SA) in 2D heterostructures involves highly efficient optical modulation in the space and time domain, the lack of explicit SA regulation mechanism at the nanoscale prevents this feature from realizing nanophotonic modulation. Here, the enhancement of SA response via CT in WS2/graphene vertical heterostructure is proposed and the related mechanism is demonstrated through simulations and experiments. Leveraging this mechanism, CT-induced SA enhancement can be expanded to a wide range of nonlinear optical modulation applications for 2D materials. The results suggest that CT between 2D heterostructures enables efficient nonlinear optical response regulation.

The complex roles of microRNAs in the metastasis of renal cell carcinoma.

Renal cell carcinoma (RCC) accounts for approximately 3% of cancers in adults as well as the most common neoplasm of the adult kidney with the highest mortality rate at over 40%. Metastasis is the most significant process affecting the clinical management of RCC patients. It occurs in multiple sequential steps. However, the molecular pathways underlying each step still remain obscure. Recent researches have shown that microRNAs (miRNAs) function as regulators in metastasis of RCC. In this article, we review the role of miRNAs in metastasis of RCC, including: specific miRNA signatures of metastatic RCC, metastasis-associated targets and pathways of miRNAs in RCC, miRNAs participate in epithelial-mesenchymal transition (EMT), miRNA DNA methylation signature in RCC metastasis and so on. MiRNAs are potential to serve as powerful biomarkers of RCC metastasis and novel therapeutic targets in RCC treatment.

Necroptosis-related genes are associated with prognostic features of kidney renal clear cell carcinoma.

INTRODUCTION: Renal clear cell carcinoma is a common type of cancer in the adult urological system. It has a high mortality rate, with 30% of patients developing metastasis and 60% dying within 1-2 years of diagnosis. Recent advancements in tumor immunology and necroptosis have provided new insights into kidney cancer therapy. Therefore, it is crucial to identify potential targets for combining immunotherapy with necroptosis. MATERIALS AND METHODS: Using the GSE168845 dataset and necroptosis-related genes, we identified genes that are differentially expressed in relation to necroptosis. We analyzed the prognostic value of these genes through differential expression analysis, prognostic analysis, and Cox regression analysis. The expression levels of the MYCN and CDKN2A genes were verified using the GSE53757 dataset. We also examined the association between the differentially expressed genes and clinicopathological features, as well as overall survival in our cohorts. In addition, we constructed a lasso Cox regression model to assess the correlation between these genes and immune score, ICP, and OCLR score. We conducted qRT-PCR to detect the expression of MYCN, CDKN2A, and ZBP1 in different samples of kidney renal clear cell carcinoma (KIRC). The expression levels of these genes were verified in a normal kidney cell line (HK-2 cells) and two KIRC cell lines (786-O, ACHN). The protein levels of MYCN and CDKN2A were detected using immunohistochemistry (IHC). SiRNA was used to silence the expression of MYCN and CDKN2A in the ACHN cell line, and wound healing assays were performed to measure cell migration. RESULTS: MYCN, CDKN2A, and ZBP1 were identified as necroptosis-related genes with independent prognostic value, leading to the development of a risk prognostic model. The expression of the CDKN2A gene was significantly higher in KIRC tissues compared to normal tissues, while the expression of the MYCN gene was significantly lower in KIRC tissues. The expression of MYCN and CDKN2A was associated with tumor stage, metastasis, and overall survival in our cohort. Furthermore, MYCN, CDKN2A, and ZBP1 were significantly correlated with immune score, ICP, and OCLR score. The expression levels of CDKN2A and ZBP1 were higher in KIRC cells compared to normal kidney cells, while the expression of MYCN was lower in KIRC cells. The protein expression of MYCN and CDKN2A was also higher in KIRC tissues, as confirmed by IHC. The results of the wound healing assay indicated that silencing CDKN2A inhibited cell migration, while silencing MYCN enhanced cell migration. CONCLUSIONS: MYCN and CDKN2A are potential targets and valuable prognostic biomarkers for combining immunotherapy with necroptosis in kidney renal clear cell carcinoma. CDKN2A promotes the migration of renal cancer cells, while MYCN inhibits their migration.

Secukinumab alleviates cognitive impairment by attenuating oxidative stress and neuronal apoptosis via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis.

BACKGROUND: Septic-associated encephalopathy (SAE) is a critical manifestation of sepsis that leads to long-term cognitive impairment. Interleukin (IL)-17A has been shown to mediate neuronal apoptosis in central nervous system diseases, while oxidative stress has been found to have a detrimental effect in SAE. However, the relationship between IL-17A and oxidative stress in SAE remains unclear. This study aimed to investigate the effects of secukinumab on alleviating cognitive impairment in a rat model of sepsis, as well as examine its underlying molecular mechanism of action. METHODS: A total of 282 male 8-week-old Sprague-Dawley rats were randomly subjected to cecal ligation and puncture (CLP) or sham treatment followed by volume resuscitation immediately after surgery. Secukinumab was administered intranasally 1 h post-CLP. Rats were given the p-ERK activator ceramide C6 intracerebroventricularly (i.c.v) 24 h before CLP surgery. Recombinant rIL-17A was administered i.c.v. at 0 h in naive rats, followed by intraperitoneal injection of the AKT inhibitor GDC0068 1 h post-rIL-17A injection. Clinical scores, body weight, and survival rate were assessed. In addition, immunofluorescence staining, neurobehavioral tests, Nissl staining, and western blotting were performed. Cognitive function was assessed 15-20 days post-CLP using the Morris water maze test. RESULTS: IL-17A and IL-17RA protein expression levels in the rat hippocampus increased and peaked 24 h post-CLP. Furthermore, IL-17RA was found to be expressed in neurons. The survival rate after CLP was 50%. Following CLP, an increased clinical score and significant decrease in body weight were observed. However, treatment with secukinumab led to a decrease in the clinical score of rats 24 h post-CLP. CLP resulted in spatial and memory impairment and anxiety-like behaviors in rats, while secukinumab treatment significantly alleviated cognitive impairment compared to the CLP group (p < 0.05). In addition, oxidative stress and neuronal apoptosis were found to be increased in the CLP group, while secukinumab significantly reduced oxidative stress and neuronal apoptosis in the hippocampus following CLP. Furthermore, secukinumab treatment led to a significant decrease in the protein expression levels of p-AKT, p-ERK1/2, Romo1, and Bax, together with increased Bcl-2 protein expression. Finally, treatment with ceramide C6 and GDC0068 abolished the neuroprotective effects of secukinumab post-CLP. CONCLUSION: Our results demonstrated that secukinumab attenuated oxidative stress and neuronal apoptosis and partially ameliorated cognitive impairment via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis. Thus, secukinumab may be a potential therapeutic strategy for septic patients.

Ultra-high throughput mapping of genetic design space.

Massively parallel genetic screens have been used to map sequence-to-function relationships for a variety of genetic elements. However, because these approaches only interrogate short sequences, it remains challenging to perform high throughput (HT) assays on constructs containing combinations of sequence elements arranged across multi-kb length scales. Overcoming this barrier could accelerate synthetic biology; by screening diverse gene circuit designs, "composition-to-function" mappings could be created that reveal genetic part composability rules and enable rapid identification of behavior-optimized variants. Here, we introduce CLASSIC, a generalizable genetic screening platform that combines long- and short-read next-generation sequencing (NGS) modalities to quantitatively assess pooled libraries of DNA constructs of arbitrary length. We show that CLASSIC can measure expression profiles of >10 5 drug-inducible gene circuit designs (ranging from 6-9 kb) in a single experiment in human cells. Using statistical inference and machine learning (ML) approaches, we demonstrate that data obtained with CLASSIC enables predictive modeling of an entire circuit design landscape, offering critical insight into underlying design principles. Our work shows that by expanding the throughput and understanding gained with each design-build-test-learn (DBTL) cycle, CLASSIC dramatically augments the pace and scale of synthetic biology and establishes an experimental basis for data-driven design of complex genetic systems.

Enhanced biological antimony removal from water by combining elemental sulfur autotrophic reduction and disproportionation.

Antimony (Sb), a toxic metalloid, has serious negative effects on human health and its pollution has become a global environmental problem. Bio-reduction of Sb(V) is an effective Sb-removal approach. This work, for the first time, demonstrates the feasibility of autotrophic Sb(V) bio-reduction and removal coupled to anaerobic oxidation of elemental sulfur (S0). In the S0-based biological system, Sb(V) was reduced to Sb(III) via autotrophic bacteria by using S0 as electron donor. Meanwhile, S0 disproportionation reaction occurred under anaerobic condition, generating sulfide and SO42- in the bio-systems. Subsequently, Sb(III) reacted with sulfide and formed Sb(III)-S precipitate, achieving an effective total Sb removal. The precipitate was identified as Sb2S3 by SEM-EDS, XPS, XRD and Raman spectrum analyses. In addition, it was found that co-existing nitrate inhibited the Sb removal, as nitrate is the favored electron acceptor over Sb(V). In contrast, the bio-reduction of co-existing SO42- enhanced sulfide generation, followed by promoting Sb(V) reduction and precipitation. Illumina high-throughput sequencing analysis revealed that Metallibacterium, Citrobacter and Thiobacillus might be responsible for Sb(V) reduction and S0 disproportionation. This study provides a promising approach for the remediation of Sb(V)-contaminated water.