The role of E2F2 in cancer progression and its value as a therapeutic target.

The E2F family of transcription factors plays a crucial role in the regulation of cell cycle progression and cell proliferation. Accumulative evidence indicates that aberrant expression or activation of E2F2 is a common phenomenon in malignances. E2F2 has emerged as a key player in the development and progression of various types of tumors. A wealth of research has substantiated that E2F2 could contribute to the enhancement of tumor cell proliferation, angiogenesis, and invasiveness. Moreover, E2F2 exerts its influence on a myriad of cellular processes by engaging with a spectrum of auxiliary factors and downstream targets, including apoptosis and DNA repair. The dysregulation of E2F2 in the context of carcinogenesis may be attributable to a multitude of mechanisms, which encompass modifications in upstream regulatory elements or epigenetic alterations. This review explores the function of E2F2 in cancer progression and both established and emerging therapeutic strategies aiming at targeting this oncogenic pathway, while also providing a strong basis for further research on the biological function and clinical applications of E2F2.

Bmp4 in Zebrafish Enhances Antiviral Innate Immunity through p38 MAPK (Mitogen-Activated Protein Kinases) Pathway.

Bone morphogenetic proteins (BMPs) are a group of structurally and functionally related signaling molecules that comprise a subfamily, belonging to the TGF-ß superfamily. Most BMPs play roles in the regulation of embryonic development, stem cell differentiation, tumor growth and some cardiovascular and cerebrovascular diseases. Although evidence is emerging for the antiviral immunity of a few BMPs, more BMPs are needed to determine whether this function is universal. Here, we identified the zebrafish bmp4 ortholog, whose expression is up-regulated through challenge with grass carp reovirus (GCRV) or its mimic poly(I:C). The overexpression of bmp4 in epithelioma papulosum cyprini (EPC) cells significantly decreased the viral titer of GCRV-infected cells. Moreover, compared to wild-type zebrafish, viral load and mortality were significantly increased in both larvae and adults of bmp4-/- mutant zebrafish infected with GCRV virus. We further demonstrated that Bmp4 promotes the phosphorylation of Tbk1 and Irf3 through the p38 MAPK pathway, thereby inducing the production of type I IFNs in response to virus infection. These data suggest that Bmp4 plays an important role in the host defense against virus infection. Our study expands the understanding of BMP protein functions and opens up new targets for the control of viral infection.

Peripheral complete blood cell count indices and serum lipid levels in polypoidal choroidal vasculopathy.

CLINICAL RELEVANCE: Systemic inflammation factors (e.g. white blood cells and neutrophils), high level of triglyceride and high neutrophil-to-lymphocyte ratio have significant associations with the risk of polypoidal choroidal vasculopathy (PCV). BACKGROUND: This study aimed to investigate associations of complete blood cell count-derived indicators and serum lipid levels with PCV. METHODS: Forty-eight patients with PCV and 54 age- and gender-matched control group participants were included in the study. Records of demographic characteristics and the results of ophthalmic examinations and haematologic parameters for the participants were collected retrospectively. Blood cell count-derived indicators and serum lipid levels were calculated and were compared between the two groups. RESULTS: The PCV group had higher white blood cell, neutrophils, triglyceride, and neutrophil-to-lymphocyte ratio levels and lower mean corpuscular volume level, compared with the control group (P = 0.002, P < 0.001, P = 0.003, P = 0.002, and P = 0.027, respectively). White blood cell, neutrophil, triglyceride, and neutrophil-to-lymphocyte ratio were independent risk factors for PCV (odds ratio [OR] = 1.668, 2.324, 2.846, and 2.543, respectively; P = 0.003, P = 0.001, P = 0.005, and P = 0.004, respectively). Mean corpuscular volume was an independent protective factor against PCV (OR = 0.902; P = 0.031). Receiver operating characteristic curve analysis revealed that the area under the curve values for white blood cell, neutrophil, triglyceride, neutrophil-to-lymphocyte ratio, and mean corpuscular volume was 0.656, 0.687, 0.660, 0.659, and 0.633, respectively (P< 0.05, respectively). The combined area under the curve value was 0.772 (P < 0.001). CONCLUSIONS: White blood cells, neutrophils, triglycerides, and the neutrophil-to-lymphocyte ratio were the risk factors for PCV. Mean corpuscular volume was a protective factor against PCV. These results suggested that the combination of white blood cells, neutrophils, triglyceride, neutrophil-to-lymphocyte ratio, and mean corpuscular volume can be used to predict PCV.

Raman spectroscopy reveals phenotype switches in breast cancer metastasis.

The accurate analytical characterization of metastatic phenotype at primary tumor diagnosis and its evolution with time are critical for controlling metastatic progression of cancer. Here, we report a label-free optical strategy using Raman spectroscopy and machine learning to identify distinct metastatic phenotypes observed in tumors formed by isogenic murine breast cancer cell lines of progressively increasing metastatic propensities. Methods: We employed the 4T1 isogenic panel of murine breast cancer cells to grow tumors of varying metastatic potential and acquired label-free spectra using a fiber probe-based portable Raman spectroscopy system. We used MCR-ALS and random forests classifiers to identify putative spectral markers and predict metastatic phenotype of tumors based on their optical spectra. We also used tumors derived from 4T1 cells silenced for the expression of TWIST, FOXC2 and CXCR3 genes to assess their metastatic phenotype based on their Raman spectra. Results: The MCR-ALS spectral decomposition showed consistent differences in the contribution of components that resembled collagen and lipids between the non-metastatic 67NR tumors and the metastatic tumors formed by FARN, 4T07, and 4T1 cells. Our Raman spectra-based random forest analysis provided evidence that machine learning models built on spectral data can allow the accurate identification of metastatic phenotype of independent test tumors. By silencing genes critical for metastasis in highly metastatic cell lines, we showed that the random forest classifiers provided predictions consistent with the observed phenotypic switch of the resultant tumors towards lower metastatic potential. Furthermore, the spectral assessment of lipid and collagen content of these tumors was consistent with the observed phenotypic switch. Conclusion: Overall, our findings indicate that Raman spectroscopy may offer a novel strategy to evaluate metastatic risk during primary tumor biopsies in clinical patients.

Enhanced Nerve Regeneration by Bionic Conductive Nerve Scaffold Under Electrical Stimulation.

Repair of peripheral nerve defect (PND) with a poor prognosis is hard to deal with. Neural conduit applied to nerve defect at present could not achieve the effect of autologous nerve transplantation. We prepared bionic conductive neural scaffolds to provide a new strategy for the treatment of PNDs. The highly aligned poly (L-lactic acid) (PLLA) fiber mats and the multi-microchannel conductive scaffolds were combined into bionic conductive nerve scaffolds, which were implanted into rats with sciatic nerve defects. The experimental animals were divided into the scaffold group (S), scaffold with electrical stimulation (ES) group (S&E), and autologous nerve transplantation group (AT). The regenerative effect of bionic conductive nerve scaffolds was analyzed. Compared with aligned PLLA fiber mats (APFMs), highly aligned fiber mats had a higher fiber orientation and did not change the tensile strength, Young's modulus, degradation rate, elongation at break of the fiber membrane, and biocompatibility. The bionic conductive nerve scaffolds were well matched with the rat sciatic nerve. The evaluations of the sciatic nerve in Group S&E were close to those in Group AT and better than those in Group S. Immunohistochemical results showed that the expression levels of neurofilament heavy polypeptide (NF-H) and protein S100-B (S100-ß) in Group S&E were higher than those in Group S, and the expression levels of low-density lipoprotein receptor-related protein 4 (LRP4), mitogen-activated protein kinase (MAPK) p38, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase kinase (MEK) in Group AT were higher than those in Group S. Bionic conductive nerve scaffolds combined with ES could enhance peripheral nerve regeneration and achieve satisfactory nerve regeneration close to autologous nerve grafts. ERK, p38 MAPK, MEK, and LRP4 may be involved in peripheral nerve regeneration under ES.

Label-Free Vibrational and Quantitative Phase Microscopy Reveals Remarkable Pathogen-Induced Morphomolecular Divergence in Tumor-Derived Cells.

Delineating the molecular and morphological changes that cancer cells undergo in response to extracellular stimuli is crucial for identifying factors that promote tumor progression. Label-free optical imaging offers a potentially promising route for retrieving such single-cell information by generating detailed visualization of the morphology and determining alterations in biomolecular composition. The potential of such nonperturbative morphomolecular microscopy for analyzing microbiota-cancer cell interactions has been surprisingly underappreciated, despite the growing evidence of the critical role of dysbiosis in malignant transformations. Here, using a model system of breast cancer cells, we show that label-free Raman microspectroscopy and quantitative phase microscopy can detect biomolecular and morphological changes in single cells exposed to Bacteroides fragilis toxin (BFT), a toxin secreted by enterotoxigenicB. fragilis. Remarkably, using machine learning to elucidate subtle, but consistent, cellular differences, we found that the morphomolecular differences between BFT-exposed and control breast cancer cells became more accentuated after in vivo passage, corroborating our findings that a short-term BFT exposure imparts a long-term effect on cancer cells and promotes a more invasive phenotype. Complementing more classical labeling techniques, our label-free platform offers a global detection approach with measurements representative of the overall cellular phenotype, paving the way for further investigations into the multifaceted interactions between the cancer cell and the microbiota.

Metabolomic strategies and biochemical analysis of the effect of processed Rehmanniae radix extract on a blood-deficient rat model.

BACKGROUND: Rehmanniae Radix (RR), an herb with numerous pharmacological effects, is widely used in traditional Chinese medicine for the treatment of blood deficiency syndrome, either alone or in combination with other herbs. However, the mechanism by which processed Rehmanniae Radix (PRR) improves blood enrichment efficacy has not been clearly defined. METHODS: Ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass (UPLC-Q-TOF/MS) and biochemical methods were combined to explore the hematopoietic functional mechanisms of PRR on blood deficiency in a rat model, as well as the potential active ingredient for blood enrichment efficacy. The pharmacological effects of PRR were evaluated on a rat blood deficiency model induced by cyclophosphamide in combination with 1-acetyl-2-phenylhydrazine. The blood routine index, including white blood cell (WBC), red blood cell (RBC), and platelet (PLT) counts, as well as hemoglobin (HGB) level, and the changing metabolite profile based on urine and serum were assessed. Nontargeted metabolomic studies, combined with biochemical analyses, were employed to clarify pharmacological mechanisms. RESULTS: PRR significantly increased the blood routine index levels and reversed the levels of SOD, GSH, and ATP. The PRR group was similar to the control group, as determined from the metabolic profile. All of the 60 biomarkers, representing the typical metabolic characteristics of the blood-deficient rat model, mainly involved energy metabolism dysfunction, the peripheral circulation system, and oxidative damage in the body. This improvement may be attributed to changes in polysaccharide and sixteen non-polysaccharide compounds in PRR, which were caused by processing RR with rice wine. CONCLUSIONS: The strategies of integrated metabolomic and biochemical analyses were combined, revealing the biological function and effective mechanism of PRR.

Unequal impact of the COVID-19 pandemic on paediatric cancer care: a population-based cohort study in China.

BACKGROUND: The COVID-19 pandemic has had widespread adverse collateral effects on health care delivery for non-COVID-19 disease conditions. Paediatric oncology care is reliant on prompt testing and diagnosis and on timely and coordinated multimodal treatment, all of which have been impacted by the pandemic. This study aimed to quantify the initial and enduring effects of the COVID-19 pandemic on the utilization of paediatric cancer care and to examine whether the pandemic differentially impacted specific demographic groups. METHOD: We performed an interrupted time series analysis using negative binomial regression to estimate the change in the monthly admissions for paediatric cancer patients (Age 0-17) associated with the COVID-19 pandemic and subsequent lockdown policies. We obtained data from deidentified individual electronic medical records of paediatric cancer inpatients admitted between January 1, 2015 and May 31, 2021 to a tertiary hospital that provides general and specialized healthcare services to an estimated population of 8.4 million in Jining China. Relative risk (RR) estimates representing monthly admissions compared with expected admissions had the pandemic not occurred were derived. The number of inpatient admissions lost due to the pandemic were estimated. FINDINGS: The overall denominator for the paediatric population was 1 858 209 individuals in January 2015, which increased to 2 043 803 by May 2021. In total, there were 4 901 admissions for paediatric cancer during the study period, including 1 479 (30%) since February 2020 when the lockdown was implemented. A 33% reduction (95% CI: -43% to -22%) in admissions was observed in February 2020, with the largest relative reduction (-48%, 95% CI: -64% to -24%) among first-time admissions and admissions for patients from rural districts (-46%, 95% CI: -55% to -36%). Admissions quickly rebounded in March 2020 when many government-imposed mobility restrictions were lifted, and continued to resume gradually over time since April 2020, leading to a full recovery as of November 2020. However, the recovery for first-time admissions, and among female patients, younger patients (<5 years) and patients from rural districts was slower over time and incomplete (first-time admissions and rural patients) as of January 2021. INTERPRETATION: The COVID-19 pandemic has had substantial impact on the timely utilization of paediatric oncology services in China, particularly in the early stage of the first wave. Importantly, some population groups were disproportionately affected and the recovery of admissions among those subgroups has been slow and incomplete, warranting targeted approaches to address potentially exacerbated gender and socio-economic inequalities in access to healthcare resources.

Vibrational spectroscopy for decoding cancer microbiota interactions: Current evidence and future perspective.

The role of human microbiota in cancer initiation and progression is recognized in recent years. In order to investigate the interactions between cancer cells and microbes, a systematic analysis using various emerging techniques is required. Owing to the label-free, non-invasive and molecular fingerprinting characteristics, vibrational spectroscopy is uniquely suited to decode and understand the relationship and interactions between cancer and the microbiota at the molecular level. In this review, we first provide a quick overview of the fundamentals of vibrational spectroscopic techniques, namely Raman and infrared spectroscopy. Next, we discuss the emerging evidence underscoring utilities of these spectroscopic techniques to study cancer or microbes separately, and share our perspective on how vibrational spectroscopy can be employed at the intersection of the two fields. Finally, we envision the potential opportunities in exploiting vibrational spectroscopy not only in basic cancer-microbiome research but also in its clinical translation, and discuss the challenges in the bench to bedside translation.

Relationship between elevated microRNAs and growth factors levels in the vitreous of patients with proliferative diabetic retinopathy.

AIM: The aim of this study was to identify differentially expressed microRNAs (miRNAs) in the vitreous of patients with proliferative diabetic retinopathy (PDR) and correlate some of them with growth factors. METHODS: Vitreous samples were collected from 5 PDR eyes and 5 control eyes, and then miRNAs were assayed with next-generation sequencing (NGS). Three differentially expressed miRNAs were validated in vitreous of another cohort using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). RESULTS: Transforming growth factor ß (TGF-ß) and vascular endothelial growth factor (VEGF) signaling pathway were excavated out through bioinformatic analysis of deregulated miRNAs. The expression of hsa-miR-24-3p, hsa-miR-197-3p and hsa-miR-3184-3p, VEGF-A and TGF-ß were confirmed to be significantly higher in the vitreous of PDR eyes than controls(P < 0.05). Furthermore, Pearson's correlation analysis showed significantly positive correlations between these elevated miRNAs and growth factors (P < 0.05). CONCLUSIONS: Elevated vitreous levels of hsa-miR-24-3p, hsa-miR-197-3p, hsa-miR-3184-3p in PDR patients may play roles in pathophysiology of PDR, the target mRNAs of which significantly enriched in VEGF and TGF-ß signaling pathways. Positive correlations between elevated vitreous levels of the three miRNAs and VEGF-A, TGF-ß in PDR patients could provide a novel research direction for PDR.

Bmp8a is an essential positive regulator of antiviral immunity in zebrafish.

Bone morphogenetic protein (BMP) is a kind of classical multi-functional growth factor that plays a vital role in the formation and maintenance of bone, cartilage, muscle, blood vessels, and the regulation of adipogenesis and thermogenesis. However, understanding of the role of BMPs in antiviral immunity is still limited. Here we demonstrate that Bmp8a is a newly-identified positive regulator for antiviral immune responses. The bmp8a-/- zebrafish, when infected with viruses, show reduced antiviral immunity and increased viral load and mortality. We also show for the first time that Bmp8a interacts with Alk6a, which promotes the phosphorylation of Tbk1 and Irf3 through p38 MAPK pathway, and induces the production of type I interferons (IFNs) in response to viral infection. Our study uncovers a previously unrecognized role of Bmp8a in regulation of antiviral immune responses and provides a target for controlling viral infection.

Management of high-energy tibial shaft fractures using the hexapod circular external fixator.

BACKGROUND: The hexapod external fixator (HEF) is increasingly used for high-energy tibial shaft fracture care as more general orthopedic surgeons are gaining expertise of this versatile device. The purpose of this study was to evaluate the clinical effectiveness of the HEF for definitive management in patients with high-energy tibial shaft fractures. METHODS: The study was conducted on 34 patients with tibial shaft fractures who were admitted or referred to our institution and consented to HEF treatment from Jan 2016 to June 2019, including 27 males and 7 females with a mean age of 39 years (range 18 to 65 years). Patients' clinical and radiological data, and the final clinical outcomes at a minimum of 12 months follow-up were collected and retrospectively analyzed. All complications were documented according to Paley's classification. The clinical outcomes were evaluated using the Association for the Study and Application of the Method of Ilizarov criteria (ASAMI) at the last clinical visit. RESULTS: All patients remained in the HEF for a mean of 26 weeks (range 15 to 52 weeks) and acquired complete bone union. The satisfactory alignment was achieved in all patients, and all the patients were able to perform daily activities with no difficulty at the last clinical visit. Complications included pin tract infection (44%), delayed union (6%), nonunion (3%), and joint stiffness (3%). The ASAMI bony result was excellent in 31 patients and good in 3. The ASAMI functional result was excellent in 27 patients, good in 6, and fair in 1. CONCLUSIONS: Definitive management using the hexapod external fixator is an alternative and effective method for high-energy tibial shaft fractures, including technical advantages of early trauma-control, the versatility of achieving excellent alignment, and the continuity of device until bone union.

Prognostic factors in patients who underwent surgery for common peroneal nerve injury: a nest case-control study.

BACKGROUND: Common peroneal nerve (CPN) injury is one of the most common nerve injuries in the lower extremities and the motor functional recovery of injured common peroneal nerve (CPN) was often unsatisfactory, the mechanism of which is still controversial. The purpose of this retrospective study was to determine the prognostic factors in patients who underwent surgery for CPN injury and provide a tool for clinicians to assess the patients' prognosis. METHODS: This is a retrospective cohort study of all patients who underwent neural exploration for injured CPN from 2009 to 2019. A total of 387 patients with postoperative follow-up more than 12 months were included in the final analysis. We used univariate logistics regression analyses to explore explanatory variables which were associated with recovery of neurological function. By applying multivariable logistic regression analysis, we determined variables incorporated into clinical prediction model, developed a nomogram by the selected variables, and then assessed discrimination of the model by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: The case group included 67 patients and the control group 320 patients. Multivariate logistic regression analysis showed that area (urban vs rural, OR = 3.35), occupation("blue trouser" worker vs "white-trouser" worker, OR = 4.39), diabetes (OR = 11.68), cardiovascular disease (OR = 51.35), knee joint dislocation (OR = 14.91), proximal fibula fracture (OR = 3.32), tibial plateau fracture (OR = 9.21), vascular injury (OR = 5.37) and hip arthroplasty (OR = 75.96) injury increased the risk of poor motor functional recovery of injured CPN, while high preoperative muscle strength (OR = 0.18) and postoperative knee joint immobilization (OR = 0.11) decreased this risk of injured CPN. AUC of the nomogram was 0.904 and 95% CI was 0.863-0.946. CONCLUSIONS: Area, occupation, diabetes, cardiovascular disease, knee joint dislocation, proximal fibula fracture, tibial plateau fracture, vascular injury and hip arthroplasty injury are independent risk factors of motor functional recovery of injured CPN, while high preoperative muscle strength and postoperative knee joint immobilization are protective factors of motor functional recovery of injured CPN. The prediction nomogram can provide a tool for clinicians to assess the prognosis of injured CPN.

Prevalence and Correlation of Metabolic Syndrome: A Cross-Sectional Study of Nearly 10 Million Multi-Ethnic Chinese Adults.

PURPOSE: This study aimed to examine the prevalence and correlates of metabolic syndrome (MetS) in multi-ethnic populations of Northwest China based on Large-scale provincial health checking data. PATIENTS AND METHODS: A total of 9,745,640 Chinese aged ≥18 years in Xinjiang, the largest autonomous region of multi-ethnic in China, were enrolled from Feb. to Sep. 2019. MetS was defined by modified Adult Treatment Panel (ATP III) criteria. RESULTS: The overall prevalence of MetS was 20.85% [Sex: 20.06% female, 21.56% male; Age: 39.22% 60-years and above, 26.32% 40- to 59-years and 9.56% 18- to 39-years; Ethnicity: 28.19% Hui followed by Han (26.39%), Uyghur (18.56%), Other (18.61%), Kazak (17.98%), Mongolian (17.87%), Kyrgyz (14.44%)]. People living in cities and towns (23.03%) or North (24.78%) had higher prevalence of MetS than rural (19.94%) and South (17.66%). Although the prevalence of hypertension, smoking, drinking and lack of physical activity were higher in Kyrgyz, Mongolian and Kazak than those of other ethnic groups, the risk of MetS was lower. CONCLUSION: The results indicated that a high prevalence of MetS in Hui and Han groups and people living in cities and towns. Living in North Xinjiang and elder population tend to have higher prevalence of MetS. The prevention and management of MetS in these populations should be prioritized.

Cancer cells display increased migration and deformability in pace with metastatic progression.

In this study, we explored the relation between metastatic states vs the capacity of confined migration, amoeboid transition, and cellular stiffness. We compared across an isogenic panel of human breast cancer cells derived from MDA-MB-231 cells. It was observed that cells after lung metastasis have the fastest migration and lowest stiffness, with a significantly higher capacity to transition into an amoeboid mode. Our findings illustrate that metastasis is a selective process favoring motile and softer cells. Moreover, the observation that circulating tumor cells resemble the parental cell line, but not lung-metastatic cells, suggests that cells with higher deformability and motility are likely selected during extravasation and colonization.

Preparation of Multiwall Carbon Nanotubes Embedded Electroconductive Multi-Microchannel Scaffolds for Neuron Growth under Electrical Stimulation.

OBJECTIVES: To prepare the conductive MWCNT (multiwall carbon nanotube)-agarose scaffolds with multi-microchannel for neuron growth under electrical stimulation. METHODS: The scaffolds were produced by gradient freeze and lyophilization methods. The synthesized materials were characterized by SEM and near-infrared spectroscopy, and their microstructure, swelling-deswelling, conductivity, biocompatibility, and shape memory behavior were measured. A three-dimensional culture model by implanting cells into scaffolds was built, and the behaviors of RSC96 cells on scaffolds under electrical stimulation were evaluated. RESULTS: The addition of MWCNT did not affect the pore composition ratio and shape memory of agarose scaffolds, but 0.025% wt MWCNT in scaffolds improved the swelling ratio and water retention at the swelling equilibrium state. Though MWCNTs in high concentration had slight effect on proliferation of RSC96 cells and PC12 cells, there was no difference that the expressions of neurofilament of RSC96 cells on scaffolds with MWCNTs of different concentration. RSC96 cells arranged better along the longitudinal axis of scaffolds and showed better adhesion on both 0.025% MWCNT-agarose scaffolds and 0.05% MWCNT-agarose scaffolds compared to other scaffolds. CONCLUSIONS: Agarose scaffolds with MWCNTs possessed promising applicable prospect in peripheral nerve defects.

Acetylcholinesterase-catalyzed silver deposition for ultrasensitive electrochemical biosensing of organophosphorus pesticides.

Herein, an electrochemical biosensing platform with acetylcholinesterase (AChE)-catalyzed silver deposition was developed for the ultrasensitive detection of organophosphorus pesticides (OPs). The biosensing mechanism is based on the fact that AChE can catalyze the rapid hydrolysis of indoxyl acetate to form hydroxyindole, which in turn reduces silver ions to metallic silver, resulting in the deposition of silver on the gold electrode. Upon sweeping positive voltages on the gold electrode using linear sweep voltammetry (LSV), the deposited silver on the gold electrode surface undergoes a rapid electrochemical oxidation reaction. Due to its lower oxidation potential under facile conditions with a relatively sharp peak, a small amount of deposited silver generated from AChE-catalysis could result in a significant change in the LSV response. In the presence of OPs, the AChE-catalyzed hydrolysis of indoxyl acetate is blocked, and then the silver deposition on the gold electrode declines, leading to a remarkable decrease in the LSV response and, thus producing a large signal output for the ultrasensitive detection of chlorpyrifos, a proof-of-concept OP in this work. The change in the LSV peak current intensity is linearly correlated with the logarithmic value of the chlorpyrifos concentration ranging from 10 pM to 10 nM with a low detection limit of 4.0 pM. To the best of our knowledge, this is the first example of a biosensing platform for ultrasensitive OP assay using AChE-controlled silver deposition to enhance the output of electronic signals.

Decoding Live Cell Interactions with Multi-Nanoparticle Systems: Differential Implications for Uptake, Trafficking, and Gene Regulation.

Surface modification with oligonucleotides renders gold nanoparticles to endocytose through very different pathways as compared to unmodified ones. Such oligonucleotide-modified gold nanoparticles (OGNs) have been exploited as effective nanocarriers for gene regulation therapies. Notably, in an effort to reduce overall dosage and provide safer transition to the clinic, cooperative systems composed of two or more discrete nanomaterials have been recently proposed as an alternative to intrinsically multifunctional nanoparticles. Yet, our understanding of such systems designed to synergistically cooperate in their diagnostic or therapeutic functions remains acutely limited. Specifically, cellular interactions and uptake of OGNs are poorly understood when the cell simultaneously interacts with other types of nanoparticles. Here, we investigated the impact of simultaneous uptake of similar-sized iron oxide nanoparticles (IOPs) on the endocytosis and gene regulation function of OGNs, whose analogues have been proposed for sensitization, targeting, and treatment of tumors. We discovered that both the OGN uptake amount and, remarkably, the gene regulation function remained stable when exposed to a very wide range of extracellular concentrations of IOPs. Additionally, the co-localization analysis showed that a proportion of OGNs was co-localized with IOPs inside cells, which hints at the presence of similar trafficking pathways for OGNs and IOPs following endocytosis. Taken together, our observations indicate that while the OGN endocytosis is highly independent of the IOP endocytosis, it shares transport pathways inside cells-but does so without affecting the gene regulation behavior. These results provide key insights into concomitant interactions of cells with diverse nanoparticles and offer a basis for the future design and optimization of cooperative nanomaterials for diverse theranostic applications.

Zebrafish fatty acids receptor Gpr84 enhances macrophage phagocytosis.

GPR84 was identified as a receptor for medium-chain fatty acids with carbon chain lengths of 9-14. It has previously been reported that lipopolysaccharide (LPS) induces significantly up-regulation of zebrafish gpr84, and zebrafish gpr84 overexpression markedly increased the LPS-stimulated production of the cytokine IL-12. Here we expanded on these studies to further investigate the roles of zebrafish Gpr84 in immune reaction. Flow cytometric assay was used to assess the effects of zebrafish Gpr84 on the phagocytosis of bacteria by macrophages. It was found that overexpression of zebrafish gpr84 significantly increased both the phagocytic ability (PA) and phagocytic index (PI) values of the macrophages engulfing the bacteria, suggesting that zebrafish Gpr84 was able to promote the phagocytosis of bacteria by the macrophages. The data proves the direct effect of Gpr84 in immune reaction.

Functional Characterization of Thyrostimulin in Amphioxus Suggests an Ancestral Origin of the TH Signaling Pathway.

Thyrostimulin, consisting of GpA2 and GpB5 subunits, has been identified in amphioxus, but to date, little is known about the roles of GPA2/GPB5‒type hormone in this evolutionarily important animal. We showed here that amphioxus GpA2, GpB5, and TSH receptor (TSHR) represent the archetypes of vertebrate TSHα, TSHß, and TSHR, respectively, and both gpa2 and gpb5 were coexpressed in the Hatschek pit, a homolog of the vertebrate pituitary, in amphioxus. We also showed that recombinant amphioxus GpA2 and GpB5, like zebrafish TSHα and TSHß, bound to both amphioxus and zebrafish TSHR and that tethered amphioxus thyrostimulin activated both protein kinase A and protein kinase C pathways in the cells expressing amphioxus TSHR. Moreover, we demonstrated that recombinant amphioxus thyrostimulin induced the production of thyroid hormone (TH) T4. Because genuine TSH is absent in amphioxus and thyrostimulin is the only and sole glycoprotein hormone, our data likely provide evidence that amphioxus thyrostimulin is a functional glycoprotein hormone that plays a role as TSH does in vertebrates. The data also suggest that the TH signaling pathway evolved in the basal chordate more than 500 million years ago.