KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Photoelectrochemical Solution Gated Graphene Field-Effect Transistor Functionalized by Enzymatic Cascade Reaction for Organophosphate Detection.

Solution Gated Graphene Field-Effect Transistors (SGGT) are eagerly anticipated as an amplification platform for fabricating advanced ultra-sensitive sensors, allowing significant modulation of the drain current with minimal gate voltage. However, few studies have focused on light-matter interplay gating control for SGGT. Herein, this challenge is addressed by creating an innovative photoelectrochemical solution-gated graphene field-effect transistor (PEC-SGGT) functionalized with enzyme cascade reactions (ECR) for Organophosphorus (OPs) detection. The ECR system, consisting of acetylcholinesterase (AChE) and CuBTC nanomimetic enzymes, selectively recognizes OPs and forms o-phenylenediamine (oPD) oligomers sediment on the PEC electrode, with layer thickness related to the OPs concentration, demonstrating time-integrated amplification. Under light stimulation, the additional photovoltage generated on the PEC gate electrode is influenced by the oPD oligomers sediment layer, creating a differentiated voltage distribution along the gate path. PEC-SGGT, inherently equipped with built-in amplification circuits, sensitively captures gate voltage changes and delivers output with an impressive thousandfold current gain. The seamless integration of these three amplification modes in this advanced sensor allows a good linear range and highly sensitive detection of OPs, with a detection limit as low as 0.05 pm. This work provides a proof-of-concept for the feasibility of light-assisted functionalized gate-controlled PEC-SGGT for small molecule detection.

Achieving Non-Interfacial Blocking Zinc Ion Transport Based on MOF Derived Manganese Oxides and Amorphous Carbon Hybrid Materials.

How to coordinate electron and ion transport behavior across scales and interfaces within ion battery electrodes? The exponential increase in surface area observed in nanoscale electrode materials results in an incomprehensibly vast spatial interval. Herein, to address the problems of volume expansion, dissolution of cathode material, and the charge accumulation problem existing in manganiferous materials for zinc ion batteries, metal organic framework is utilized to form the architecture of non-interfacial blocking ~10 nm Mn2O3 nanoparticles and amorphous carbon hybrid electrode materials, demonstrating a high specific capacity of 361 mAh g-1 (0.1 A g-1), and excellent cycle stability of 105 mAh g-1 after 2000 cycles under 1 A g-1. The uniform and non-separated disposition of Mn and C atoms constitutes an interconnected network with high electronic and ionic conductivity, minimizing issues like structural collapse and volume expansion of the electrode material during cycling. The cooperative insert mechanism of H+ and Zn2+ are analyzed via ex-situ XRD and in-situ Raman tests. The model battery is assembled to present practical possibilities. The results indicate that MOF-derived carbonization provides an effective strategy for exploring Mn-based electrode materials with high ion and electron transport capacity.

A study on the role of serum uric acid in differentiating acute inflammatory demyelinating polyneuropathy from acute-onset chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND PURPOSE: Clinical symptoms and laboratory indices for acute inflammatory demyelinating polyneuropathy (AIDP), a variant of Guillain-Barré syndrome, and acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) were analyzed to identify factors that could contribute to early differential diagnosis. METHODS: A retrospective chart review was performed on 44 AIDP and 44 A-CIDP patients looking for any demographic characteristics, clinical manifestations or laboratory parameters that might differentiate AIDP from acutely presenting CIDP. RESULTS: In Guillain-Barré syndrome patients (N = 63), 69.84% (N = 44) were classified as having AIDP, 19.05% (N = 12) were found to have acute motor axonal neuropathy, 6.35% (N = 4) were found to have acute motor and sensory axonal neuropathy, and 4.76% (N = 3) were found to have Miller Fisher syndrome. Serum uric acid (UA) was higher in A-CIDP patients (329.55 ± 72.23 µmol/L) than in AIDP patients (221.08 ± 71.32 µmol/L) (p = 0.000). Receiver operating characteristic analyses indicated that the optimal UA cutoff was 283.50 µmol/L. Above this level, patients were more likely to present A-CIDP than AIDP (specificity 81.80%, sensitivity 81.80%). During the follow-up process, serum samples were effectively collected from 19 AIDP patients during the rehabilitation phase and 28 A-CIDP patients during the remission stage, and it was found that UA levels were significantly increased in A-CIDP (remission) (298.9 ± 90.39 µmol/L) compared with AIDP (rehabilitation) (220.1 ± 108.2 µmol/L, p = 0.009). CONCLUSION: These results suggest that serum UA level can help to differentiate AIDP from A-CIDP with high specificity and sensitivity, which is helpful for early diagnosis and guidance of treatment.

Design and preparation of an artificial vascular scaffold with internal surface modification.

BACKGROUND: Advances in regeneration methods have brought us improved vascular scaffolds with small diameters (φ < 6 mm) for enhancing biological suitability that solve their propensity for causing intimal hyperplasia post-transplantation. METHODS: The correlation between the rehydration ratio of the hydrogel and its material concentration is obtained by adjusting the material ratio of the hydrogel solution. The vascular model with helical structure has been established and analyzed to verify the effect of helical microvascular structure on thrombosis formation by the fluid simulation methods. Then, the helical structure vascular has been fabricated by self-developed 3D bioprinter, the vascular scaffolds are freeze-dried and rehydrated in polyethylene glycol (PEG) solution. RESULTS: The experimental results showed that the hybrid hydrogel had a qualified rehydration ratio when the content of gelatin, sodium alginate, and glycerol was 5, 6, and 3 wt%. The established flow channel model can effectively reduce thrombus deposition and improve long-term patency ratio. After PEG solution modification, the contact angle of the inner wall of the vascular scaffold was less than 30°, showing better hydrophilic characteristics. CONCLUSION: In study, a small-diameter inner wall vascular scaffold with better long-term patency was successfully designed and prepared by wrinkling and PEG modification of the inner wall of the vascular scaffold. This study not only creates small-diameter vascular scaffolds with helical structure that improves the surface hydrophilicity to reduce the risk of thrombosis but also rekindles confidence in the regeneration of small caliber vascular structures.

Dealloying Synthesis of Silicon Nanotubes for High-Performance Lithium Ion Batteries.

The front cover artwork is provided by Dr. Ping Nie and Prof. Limin Chang at Jilin Normal University. The image shows one-dimensional silicon-nitrogen-doped carbon nanotube composite fabricated through a dealloying process. The nanotube engineered silicon coupled with conductive carbon coating synergistically boosts the electrochemical performance. Read the full text of the Research Article at 10.1002/cphc.202100832.

Dealloying Synthesis of Silicon Nanotubes for High-Performance Lithium Ion Batteries.

Practical applications of silicon-based anodes in lithium ion batteries have attracted unprecedented attentions due to the merits of extraordinary energy density, high safety and low cost. Nevertheless, the inevitable huge volume change upon lithiation and delithiation brings about silicon electrode integrity damage and fast capacity fading, hampering the large-scale application. Herein, a novel one-dimensional tubular silicon-nitrogen doped carbon composite (Si@NC) with a core-shell structure has been fabricated using silicon magnesium alloy and polydopamine as a template and precursor. The as-obtained composite exhibits remarkable specific capacity and ultrafast redox kinetics, an outstanding cycling stability with fine capacity of 583.6 mAh g-1 at 0.5 A g-1 over 200 cycles is delivered. Moreover, a full cell matched with LiFePO4 cathode has demonstrated a reversible capacity of 148.8 mAh g-1 with high Coulombic efficiency as well as an excellent energy density of 396 Wh kg-1 . The nanotube structure engineering and silicon confined in nitrogen doped carbon effectively alleviate the volume expansion and endow the composite with superior stability. The robust strategy developed here gives a new insight into designing silicon anodes for enhanced lithium storage properties.

Administration of mesenchymal stem cells in diabetic kidney disease: mechanisms, signaling pathways, and preclinical evidence.

Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes. Currently, the prevalence and mortality of DKD are increasing annually. However, with no effective drugs to prevent its occurrence and development, the primary therapeutic option is to control blood sugar and blood pressure. Therefore, new and effective drugs/methods are imperative to prevent the development of DKD in patients with diabetes. Mesenchymal stem cells (MSCs) with multi-differentiation potential and paracrine function have received extensive attention as a new treatment option for DKD. However, their role and mechanism in the treatment of DKD remain unclear, and clinical applications are still being explored. Given this, we here provide an unbiased review of recent advances in MSCs for the treatment of DKD in the last decade from the perspectives of the pathogenesis of DKD, biological characteristics of MSCs, and different molecular and signaling pathways. Furthermore, we summarize information on combination therapy strategies using MSCs. Finally, we discuss the challenges and prospects for clinical application.

Effect of Hydrogel Contact Angle on Wall Thickness of Artificial Blood Vessel.

Vascular replacement is one of the most effective tools to solve cardiovascular diseases, but due to the limitations of autologous transplantation, size mismatch, etc., the blood vessels for replacement are often in short supply. The emergence of artificial blood vessels with 3D bioprinting has been expected to solve this problem. Blood vessel prosthesis plays an important role in the field of cardiovascular medical materials. However, a small-diameter blood vessel prosthesis (diameter < 6 mm) is still unable to achieve wide clinical application. In this paper, a response surface analysis was firstly utilized to obtain the relationship between the contact angle and the gelatin/sodium alginate mixed hydrogel solution at different temperatures and mass percentages. Then, the self-developed 3D bioprinter was used to obtain the optimal printing spacing under different conditions through row spacing, printing, and verifying the relationship between the contact angle and the printing thickness. Finally, the relationship between the blood vessel wall thickness and the contact angle was obtained by biofabrication with 3D bioprinting, which can also confirm the controllability of the vascular membrane thickness molding. It lays a foundation for the following study of the small caliber blood vessel printing molding experiment.

Antidiarrheal effect of the ethanol extract from Scutellaria barbata and its effect on the contraction of jejunum smooth muscles.

Scutellaria barbata (S. barbata), a traditional herbal medicine used in southern China, possesses anti-inflammatory, antitumor, spasmolytic and expectorant effects. However, there are not many recent studies on its gastrointestinal effects. This study aimed to evaluate the antidiarrheal effect of the ethanol extract of S. barbata (SBE) and its effect on the isolated jejunum smooth muscle. METHODS: The antidiarrheal effect of SBE (doses: 125, 250 and 500 mg/kg) on castor oil-induced diarrhea was investigated in vivo. The effect of SBE (0.01-10 mg/mL) on spontaneous or acetylcholine chloride (ACh, 10µM)/KCl (60mM)-induced contraction of isolated rabbit jejunum smooth muscle was examined in vitro. The possible spasmolytic mechanism of SBE (1 and 3mg/mL) was analyzed by accumulating CaCl2 in a Ca2+-free high-K+ (60mM) solution. RESULTS: SBE (125, 250 and 500mg/kg) could delay the initial semi-solid onset time of mice and also reduce the diarrhea index in vivo. Furthermore, SBE (0.01-10mg/mL) could alleviate the spontaneous or ACh/KCl-induced contraction in vitro. SBE (1 and 3mg/mL) also inhibited the contraction induced by CaCl2, and the concentration-response curves of CaCl2 moved downward and to the right, similar to those of verapamil (0.01 and 0.1µM). CONCLUSIONS: SBE exerts antidiarrheal and spasmolytic effects, which provides a pharmacological basis for its use in functional gastrointestinal disorders.

Clinical and pathological analysis of renal biopsies of elderly patients in Northeast China: a single-center study.

PURPOSE: To identify the clinical characteristics, histopathological features, and prognosis of kidney disease in a large cohort of elderly patients from Northeast China. METHODS: We retrospectively analyzed the renal disease spectrum in 7,122 patients who underwent renal biopsies at the Second Hospital of Jilin University from 2006 to 2020. Patients were grouped according to age: below 60 years (non-elderly group, n = 5923) and at least 60 years (elderly group, n = 1199). The clinical and pathological characteristics of renal biopsy patients in the groups were analyzed using the t-test and chi-square test. RESULTS: Compared with the non-elderly group, the elderly group had significantly fewer patients with primary glomerulonephritis, but more patients with tubulointerstitial disorders (p < .05). The incidence of IgA nephropathy, mesangial proliferative glomerulonephritis, and lupus nephritis was significantly lower in elderly patients than in non-elderly patients. The incidence of membranous nephropathy, membranoproliferative glomerulonephritis, diabetic nephropathy, hypertensive nephropathy, systemic vasculitis-associated renal damage, and amyloid nephropathy was significantly higher in elderly patients than in non-elderly patients (p < .05). The incidence of perinephric hematoma (≥4 cm2) in elderly patients with renal biopsy was lower than that in non-elderly patients. We noted that 79.9% of primary glomerulonephritis patients who received immunosuppressive therapy showed a remission rate of 83.5%. CONCLUSION: The spectrum of kidney disease in the elderly is different from that in the younger population.

Correlation between esthetic expectations for orthognathic treatment and psychological characteristics among Chinese adult patients.

INTRODUCTION: This study aimed to evaluate the association of esthetic expectations with self-reported personal characteristics, anxiety, depression, self-esteem, oral health-related quality of life, and the Orthognathic Quality of Life Questionnaire (OQLQ) in Chinese adult patients before orthognathic treatment. METHODS: This study involved 213 patients with clinically significant skeletal deformity requiring orthognathic surgery for comprehensive treatment. Each patient completed a series of Chinese version scales, including the self-rating anxiety scale, self-rating depression scale, self-esteem scale, the Oral Health Impact Profile-14 questionnaire, and the OQLQ. The patients' self-reported personal characteristics were also recorded, including facial appearance ratings before and after orthognathic treatment, highest education level, mean monthly income, and enthusiasm toward orthodontic or orthognathic treatment. The Least Absolute Shrinkage and Selection Operator multivariate linear regression model was conducted for the selection of the above factors. The final multivariate linear regression model was built with variables identified under the optimal tuning parameter. RESULTS: A total of 213 patients (87 men and 126 women) were included in this study. The patients' esthetic expectation scores were significantly associated with their total scores, which encompassed the education level, mean monthly income, enthusiasm toward orthodontic or orthognathic treatment, self-esteem scale, the Chinese version of the 14-item Oral Health Impact Profile questionnaire, OQLQ, etc. In the multivariate linear regression model, the OQLQ, enthusiasm toward orthognathic treatment, depression, and expected facial appearance score after the treatment were the most important factors to predict esthetic expectation. CONCLUSIONS: High esthetic expectations for orthognathic treatment were mostly associated with higher expected facial appearance scores after the treatment, greater enthusiasm toward orthognathic treatment, worse depression (confusion), and 2 domains (social aspects of deformity and oral function) of OQLQ. Therefore, OQLQ, enthusiasm toward orthognathic treatment, and expected facial appearance score after treatment may be used to predict patients' esthetic expectations before commencing orthognathic treatment in daily clinical practice.

Purification, biochemical characterization and DNA protection against oxidative damage of a novel recombinant superoxide dismutase from psychrophilic bacterium Halomonas sp. ANT108.

A novel superoxide dismutase (referred hereafter to as HsSOD) from the psychrophilic bacterium Halomonas sp. ANT108 was purified and characterized. Escherichia coli (E. coli) was selected as the expression host. After recombinant HsSOD (rHsSOD) was purified, the specific activity was determined to be 213.47 U/mg with a purification ratio of approximately 3.61-fold. SDS-PAGE results demonstrated that rHsSOD has the molecular weight of 31.3 kDa, and type identification revealed that it belongs to Cu/Zn SOD. The optimum activity of rHsSOD was at 35 °C and 28% of its maximum activity remained at 0 °C. Further enzymatic assays indicated that rHsSOD exhibited thermal instability with a half-life of 20 min at 60 °C. Moreover, Cu2+ and Zn2+ significantly promoted rHsSOD activity. The values of Km and Vmax were 0.33 mM and 476.19 U/mg, respectively. Interestingly, rHsSOD could avoid DNA strand breakage formed by metal-catalyzed oxidation, demonstrating its antioxidant capacity. To summarize, the results suggested that rHsSOD has relatively high catalytic efficiency and oxidation resistance at low temperatures.

Pathological spectrum of glomerular disease in patients with renal insufficiency: a single-center study in Northeastern China.

Background: To investigate the pathological spectrum of glomerular disease in patients with renal insufficiency (RI) from 2008 to 2017. Methods and results: We calculated the estimated glomerular filtration rate (eGFR) with the Chronic Kidney Disease Epidemiology Collaboration creatinine (CKD-EPI) equation and defined RI as an eGFR <60 ml/min/1.73 m2. A total of 969 RI patients were included in our study. IgA nephropathy (IgAN) was the most common subtype of primary glomerulonephritis (37.2%). The frequencies of IgAN and non-IgA mesangioproliferative glomerulonephritis decreased from 27.3% and 9.5% during 2008-2012 to 20.7% and 2.6% during 2013-2017, respectively. However, the frequency of membranous nephropathy increased from 6.8% to 16.2%. Lupus nephritis was the most common subtype of secondary glomerulonephritis (32.1%). The frequencies of both ANCA-associated systemic vasculitis and diabetic nephropathy increased from 3.8% to 7.6% and from 4.3% to 7.6%, respectively. The number of elderly patients (≥60 years) in our study increased sharply, from 15.6% in 2008 to 35.0% in 2017. Membranous nephropathy, minimal change disease, membranoproliferative glomerulonephritis, lupus nephritis and renal amyloidosis are more frequently observed in the elderly patients than in nonelderly patients (<60 years) (p < .05). Excluding those with acute kidney injury, IgAN was the leading cause of RI (24.9%), followed by membranous nephropathy (13.3%) and lupus nephritis (12.0%). Conclusions: IgAN and lupus nephritis were the most prevalent primary glomerulonephritis and secondary glomerulonephritis in patients with RI, respectively. The frequencies of membranous nephropathy, ANCA-associated systemic vasculitis and diabetic nephropathy increased significantly. The number of elderly patients with RI increased sharply.

RTK with the Assistance of an IMU-Based Pedestrian Navigation Algorithm for Smartphones.

Real-time kinematic (RTK) technique is widely used in modern society because of its high accuracy and real-time positioning. The appearance of Android P and the application of BCM47755 chipset make it possible to use single-frequency RTK and dual-frequency RTK on smartphones. The Xiaomi Mi 8 is the first dual-frequency Global Navigation Satellite System (GNSS) smartphone equipped with BCM47755 chipset. However, the performance of RTK in urban areas is much poorer compared with its performance under the open sky because the satellite signals can be blocked by the buildings and trees. RTK can't provide the positioning results in some specific areas such as the urban canyons and the crossings under an overpass. This paper combines RTK with an IMU-based pedestrian navigation algorithm. We utilize attitude and heading reference system (AHRS) algorithm and zero velocity update (ZUPT) algorithm based on micro electro mechanical systems (MEMS) inertial measurement unit (IMU) in smartphones to assist RTK for the sake of improving positioning performance in urban areas. Some tests are carried out to verify the performance of RTK on the Xiaomi Mi 8 and we respectively assess the performances of RTK with and without the assistance of an IMU-based pedestrian navigation algorithm in urban areas. Results on actual tests show RTK with the assistance of an IMU-based pedestrian navigation algorithm is more robust and adaptable to complex environments than that without it.

A Novel Cold-Adapted and Salt-Tolerant RNase R from Antarctic Sea-Ice Bacterium Psychrobacter sp. ANT206.

A novel RNase R, psrnr, was cloned from the Antarctic bacterium Psychrobacter sp. ANT206 and expressed in Escherichia coli (E. coli). A bioinformatics analysis of the psrnr gene revealed that it contained an open reading frame of 2313 bp and encoded a protein (PsRNR) of 770 amino acids. Homology modeling indicated that PsRNR had reduced hydrogen bonds and salt bridges, which might be the main reason for the catalytic efficiency at low temperatures. A site directed mutation exhibited that His 667 in the active site was absolutely crucial for the enzyme catalysis. The recombinant PsRNR (rPsRNR) showed maximum activity at 30 °C and had thermal instability, suggesting that rPsRNR was a cold-adapted enzyme. Interestingly, rPsRNR displayed remarkable salt tolerance, remaining stable at 0.5-3.0 M NaCl. Furthermore, rPsRNR had a higher kcat value, contributing to its efficient catalytic activity at a low temperature. Overall, cold-adapted RNase R in this study was an excellent candidate for antimicrobial treatment.

Graphene Caging Silicon Particles for High-Performance Lithium-Ion Batteries.

Silicon holds great promise as an anode material for lithium-ion batteries with higher energy density; its implication, however, is limited by rapid capacity fading. A catalytic growth of graphene cages on composite particles of magnesium oxide and silicon, which are made by magnesiothermic reduction reaction of silica particles, is reported herein. Catalyzed by the magnesium oxide, graphene cages can be conformally grown onto the composite particles, leading to the formation of hollow graphene-encapsulated Si particles. Such materials exhibit excellent lithium storage properties in terms of high specific capacity, remarkable rate capability (890 mAh g-1 at 5 A g-1 ), and good cycling retention over 200 cycles with consistently high coulombic efficiency at a current density of 1 A g-1 . A full battery test using LiCoO2 as the cathode demonstrates a high energy density of 329 Wh kg-1 .

The histone deacetylase inhibitor panobinostat exerts anticancer effects on esophageal squamous cell carcinoma cells by inducing cell cycle arrest.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Histone deacetylase inhibitors (HDACIs) have been demonstrated as an emerging class of anticancer drugs for a range of haematological and solid tumours. However, the effect of HDACIs has not yet been investigated on ESCC cells. In this study, HDACIs were initially considered to have anticancer activity for ESCC, due to the high expression of HDAC genes in ESCC cell lines by analysing expression data of 27 ESCC cell lines from the Broad-Novartis Cancer Cell Line Encyclopedia. Next, we used five ESCC cell lines and one normal immortalized esophageal epithelial cell line to screen three HDACIs, panobinostat (LBH589), vorinostat (SAHA), and trichostatin A (TSA), for the ability to inhibit growth. Here, we report that LBH589 more effectively suppressed cell proliferation of ESCC cell lines, in a dose-dependent manner, than TSA and SAHA, as well as had lower toxicity against the SHEE normal immortalized esophageal epithelial cell line. Further experiments indicated that LBH589 treatment significantly inhibited TP53 (mutated TP53) expression, both at the mRNA and protein level, and simultaneously increased p21 and decreased cyclin D1 expression. Taken together, we propose that LBH589 inhibits ESCC cell proliferation mainly through inducing cell cycle arrest by increasing p21 and decreasing cyclin D1 in a p53-independent manner. SIGNIFICANCE OF THE STUDY: In this study, the antitumor activity of HDACIs LBH589, SAHA, and TSA on ESCC was characterized, with LBH589 displaying the most potent anti-proliferative activity while not harming normal immortalized esophageal epithelial cells. Furthermore, we propose that LBH589 exerts its anti-proliferative effect by inducing cell cycle arrest. The ability to specifically target cancer cells indicates therapeutic potential for use of LBH589 in the treatment of ESCC.

Fascin phosphorylation sites combine to regulate esophageal squamous cancer cell behavior.

Filopodia are dynamic membrane extensions generated by F-actin bundling and are involved in cancer cell migration, invasion and metastasis. Fascin is the crucial actin-bundling protein in filopodia, with phosphorylation at fascin serine 39 being well characterized to regulate fascin-mediated actin bundling in filopodia. However, increasing evidence indicates that fascin is phosphorylated at a number of sites. Whether phosphorylation at other sites also regulates fascin function is unknown. In this study, we show that four potential phosphorylation sites in fascin, specifically tyrosine 23, serine 38, serine 39 and serine 274, regulate cell behavior and filopodia formation in esophageal squamous cancer cells. Expression of non-phosphorylatable mutations at each of the four sites promoted anchorage-independent growth, cell motility and filopodia formation, whereas phosphomimetic mutations at each of these sites inhibited these cell behaviors, implying that fascin function in esophageal squamous cancer is regulated by fascin phosphorylation at multiple sites. Furthermore, phosphorylation at S38 and S39 cooperatively regulated cell behavior and filopodia formation, with dual dephosphorylation at both S38 and S39 residues maximally enhancing cell proliferation, migration and filopodia formation, and phosphorylation at any of the two phosphorylatable sites resulting in reduced enhancement. Taken together, our results reveal that phosphorylation at fascin amino acids Y23, S38, S39 and S274, in combination, downregulates the extent of anchorage-independent growth, cell migration and filopodia formation in esophageal squamous cancer cells.

ADAM10 is essential for cranial neural crest-derived maxillofacial bone development.

Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development.