Photothermal-Controllable Microneedles with Antitumor, Antioxidant, Angiogenic, and Chondrogenic Activities to Sequential Eliminate Tracheal Neoplasm and Reconstruct Tracheal Cartilage.

The optimal treatment for tracheal tumors necessitates sequential tumor elimination and tracheal cartilage reconstruction. This study introduces an innovative inorganic nanosheet, MnO2 /PDA@Cu, comprising manganese dioxide (MnO2 ) loaded with copper ions (Cu) through in situ polymerization using polydopamine (PDA) as an intermediary. Additionally, a specialized methacrylic anhydride modified decellularized cartilage matrix (MDC) hydrogel with chondrogenic effects is developed by modifying a decellularized cartilage matrix with methacrylic anhydride. The MnO2 /PDA@Cu nanosheet is encapsulated within MDC-derived microneedles, creating a photothermal-controllable MnO2 /PDA@Cu-MDC microneedle. Effectiveness evaluation involved deep insertion of the MnO2 /PDA@Cu-MDC microneedle into tracheal orthotopic tumor in a murine model. Under 808 nm near-infrared irradiation, facilitated by PDA, the microneedle exhibited rapid overheating, efficiently eliminating tumors. PDA's photothermal effects triggered controlled MnO2 and Cu release. The MnO2 nanosheet acted as a potent inorganic nanoenzyme, scavenging reactive oxygen species for an antioxidant effect, while Cu facilitated angiogenesis. This intervention enhanced blood supply at the tumor excision site, promoting stem cell enrichment and nutrient provision. The MDC hydrogel played a pivotal role in creating a chondrogenic niche, fostering stem cells to secrete cartilaginous matrix. In conclusion, the MnO2 /PDA@Cu-MDC microneedle is a versatile platform with photothermal control, sequentially combining antitumor, antioxidant, pro-angiogenic, and chondrogenic activities to orchestrate precise tracheal tumor eradication and cartilage regeneration.

[Artificial intelligence-assisted identification of mucus plugs in asthma].

Airway mucus plug is an important clinical feature of bronchial asthma and is related to the prognosis of the disease. Clinically, chest CT is a preferred tool for evaluating airway mucus plugs. At present, the interpretation of CT images relies on manual reading, but the airway mucus plugs of patients with bronchial asthma are mostly distributed in the small and medium airways, which are difficult to identify with the naked eye. In recent years, with the continuous progress of deep learning and big data technology, artificial intelligence (AI)-assisted image reading technology has been introduced into clinical application, which has significantly improved the efficiency and accuracy of mucus plug identification. Currently, AI-assisted airway mucus plug identification has been used in respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and bronchial asthma. Therefore, the application of AI counting to mucus plugs in patients with bronchial asthma is of great significance.

Quantification of bone marrow interstitial pH and calcium concentration by intravital ratiometric imaging.

The fate of hematopoietic stem cells (HSCs) can be directed by microenvironmental factors including extracellular calcium ion concentration ([Ca2+]e), but the local [Ca2+]e around individual HSCs in vivo remains unknown. Here we develop intravital ratiometric analyses to quantify the absolute pH and [Ca2+]e in the mouse calvarial bone marrow, taking into account the pH sensitivity of the calcium probe and the wavelength-dependent optical loss through bone. Unexpectedly, the mean [Ca2+]e in the bone marrow (1.0 ± 0.54 mM) is not significantly different from the blood serum, but the HSCs are found in locations with elevated local [Ca2+]e (1.5 ± 0.57 mM). With aging, a significant increase in [Ca2+]e is found in M-type cavities that exclusively support clonal expansion of activated HSCs. This work thus establishes a tool to investigate [Ca2+]e and pH in the HSC niche with high spatial resolution and can be broadly applied to other tissue types.

Characteristics of Radiation-Related Intracranial Aneurysms: A Multicenter Retrospective Study.

BACKGROUND AND PURPOSE: Intracranial aneurysms, a rare complication of radiation therapy, have been reported mainly in case reports or case series. We performed a multicenter, retrospective cohort study to investigate the characteristics of radiation-induced intracranial aneurysms. MATERIALS AND METHODS: Data on 2641 patients with intracranial aneurysms were retrospectively collected from 3 hospitals between January 2005 and June 2014. An additional 1519 patients were recruited from a single center between July 2014 and March 2020. Aneurysms in patients with a history of radiation therapy for at least 6 months were defined as radiation-related aneurysms. Patients' demographic profiles, clinical characteristics, and aneurysm parameters detected on CTA were compared between radiation-related and control groups. RESULTS: Of the 4160 patients, the average age was 57.9 (SD, 13.5) years, 2406 (57.8%) were women, 477 (11.5%) had multiple aneurysms, 3009 (72.3%) had SAH, and 34 (0.8%) had radiation-related aneurysms. The male-to-female ratio in the radiation-related group was significantly higher than that in the control group (2.4:1 versus 0.72:1, P = .001). The mean age of the radiation-related group was significantly younger than in the control group (51.4 [SD, 15.0] years versus 58.2 [SD, 13.5] years, P = .003). More patients in the radiation-related group presented with SAH than in the control group (without age and sex matching, 88.2% versus 72.2%, P = .037; with age and sex matching, 88.2% versus 58.8%, P = .006). Of the 4813 intracranial aneurysms, only 43 (0.9%) aneurysms were categorized as in the radiation-related group, whereas 4770 (99.1%) aneurysms constituted the control group. Compared with the control group, there was a significantly higher proportion of sidewall aneurysms (46.5% versus 32.3%, P = .048) and a predilection for aneurysms involving the ICA and posterior circulation arteries (72.1% versus 52.2%, P = .046) in the radiation-related group. CONCLUSIONS: Compared with the control group, radiation-related aneurysms are more prone to occur in men and young patients, with a higher percentage of sidewall aneurysms located in the ICA and posterior circulation arteries. Furthermore, SAH is highly prevalent in patients with radiation-induced aneurysms, indicating that dedicated screening for aneurysms after radiation therapy is necessary, but further studies are needed to determine when and how to screen.

Enhancement of cadmium accumulation in sweet sorghum as affected by nitrate.

The Cadmium (Cd)-polluted soils are is an increasing concern worldwide. Phytoextraction of Cd pollutants by high biomass plants, such as sweet sorghum, is considered an environmentally-friendly, cost-effective and sustainable strategy for remediating this problem. Nitrogen (N) is a macronutrient essential for plant growth, development and stress resistance. Nevertheless, how nitrate, as an important form of N, affects Cd uptake, translocation and accumulation in sweet sorghum is still unclear. In the present study, a series of nitrate levels (N1, 0.5 mm; N2, 2 mm; N3, 4 mm; N4, 8 mm and N5, 16 mm) with or without added 5 µm CdCl2 treatment in sweet sorghum was investigated hydroponically. The results indicate that Cd accumulation in the aboveground parts of sweet sorghum was enhanced by optimum nitrate supply, resulting from both increased dry weight and Cd concentration. Although root-to-shoot Cd translocation was not enhanced by increased nitrate, some Cd was transferred from cell walls to vacuoles in leaves. Intriguingly, expression levels of Cd uptake and transport genes, SbNramp1, SbNramp5 and SbHMA3, were not closely related to increased Cd as affected by nitrate supply. The expression of SbNRT1.1B in relation to nitrate transport showed an inverted 'U' shape with increasing nitrate levels under Cd stress, which was in agreement with trends in Cd concentration changes in aboveground tissues. Based on the aforementioned results, nitrate might regulate Cd uptake and accumulation through expression of SbNRT1.1B rather than SbNramp1, SbNramp5 or SbHMA3, the well-documented genes related to Cd uptake and transport in sweet sorghum.

[Significance of prostate central gland/total gland volume ratio combined with PSA in the diagnosis of prostate cancer patients].

Objective: To explore the significance of prostate central gland/total gland volume (PVc/PV) ratio combined with PSA in the diagnosis of PSA 4-20 ng/ml prostate cancer patients. Methods: Data of patients undergoing prostate puncture in Minghang Branch, Zhongshan Hospital from July 2015 to December 2018 were retrospectively analyzed. The anteroposterior, transverse and axial diameters of the prostate and the central prostate gland were measured by magnetic resonance imaging (MRI). The differences of tPSA, f/tPSA, PSAD and PVc/PV between the prostate cancer group and non-prostate cancer group were compared. Receiver operating characteristic (ROC) curves of prostate cancer diagnosis were plotted according to tPSA, f/tPSA, PSAD, PVc/PV alone and PVc/PV combined with tPSA, respectively, and the area under the curve (AUC) was calculated and compared using tPSA as the reference. Results: There was no significant difference in tPSA between the two groups (P>0.05). However, significant differences were observed in f/tPSA, PSAD and PVc/PV between the two groups (P<0.05). The AUC value of PVc/PV combined with tPSA, PVc/PV and PSAD was 0.901 2,0.866 7 and 0.848 1,respectively, which were statistically different from that of tPSA (P<0.05). The AUC value of f/tPSA was 0.716, which was not statistically different from that of tPSA (P>0.05). Conclusion: The PVc/PV ratio combined with tPSA can be used as an important reference index for the diagnosis of prostate cancer in PSA 4-20 ng/ml patients.

LncRNA HOTAIR promotes colon cancer development by down-regulating miRNA-34a.

OBJECTIVE: To investigate the characteristics of long non-coding RNA (lncRNA) HOTAIR in colon cancer, and to further explore its function in the development of colon cancer and its potential regulatory mechanisms. PATIENTS AND METHODS: Quantitative Real-time polymerase chain reaction (qRT-PCR) was performed to detect HOTAIR expression in 72 colon cancer tissues along with adjacent normal tissues. Meanwhile, the relationship between HOTAIR level and colon cancer pathological parameters and patient prognosis were analyzed, respectively. QRT-PCR further verified the HOTAIR expression in colon cancer cells. Besides, knockdown and overexpression of HOTAIR models were constructed using lentivirus in HT29 and HCT-116 colon cancer cell lines. Cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EDU) and cell colony formation assays were used to analyze the effects of HOTAIR on biological function of colon cancer cell. In addition, dual luciferase reporter gene assay was performed to explore the underlying mechanisms. RESULTS: QRT-PCR results showed that HOTAIR expression in colon cancer was significantly higher than that in normal tissues. The incidence of distant metastasis was higher in patients with high expression of HOTAIR while their survival rate was lower than that of patients with low HOTAIR expression. Meanwhile, cell proliferation, invasion as well as migration ability of the cells in HOTAIR knockdown group was significantly decreased than those in the negative control group. QRT-PCR results showed that mRNA levels of miR-34a and HOTAIR in colon cancer tissues were negatively correlated. Besides, luciferase reporter gene assay revealed that overexpression of miR-34a significantly attenuated the luciferase activity of the wild-type HOTAIR vector group without attenuating the mutant HOTAIR vector group (p>0.05) In addition, the recovery experiment also found a mutual regulation between HOTAIR and miR-34a, together they could affect the malignant progression of colon cancer. CONCLUSIONS: HOTAIR expression was significantly increased in colon cancer, which was in association with distant metastasis and poor prognosis of colon cancer. In addition, HOTAIR may promote malignant progression of colon cancer by regulating miR-34a.

[The application of retroperitoneal laparoscopic nephron-sparing surgery in stage T(1b) renal cell carcinoma].

Objective: To investigate the safety and feasibility of retroperitoneal laparoscopic nephron-sparing surgery (NSS) in stage T(1b) renal cell carcinoma (RCC) patients . Methods: Between March 2014 and June 2017, 52 stage T(1b) RCC cases (36 males, 16 females) treated with retroperitoneal laparoscopic NSS in Zhongshan Hospital and Central Hospital of Minhang District were enrolled and retrospectively analyzed, with a tumor size range of 4.0 to 6.8 cm, and a mean size of(4.7±0.45)cm.The anatomic characteristics of tumors, operative time, intra-operative blood loss, warm ischemia time, intra- and post-operative complications, length of hospital stay, and oncological outcomes were reviewed. Results: Only 2 cases converted to open surgery due to uncontrollable bleeding in operation. The rest 50 cases successfully underwent retroperitoneal laparoscopic NSS, with mean operative time of (122±20.86) min (range: 100-220 min), mean blood loss of (140±128.85)ml (range: 50-800 ml), mean warm ischemia time of (30±3.52)min (range: 25-42 min), pre-operative mean serum creatinine of (100±23.54)µmol/L (range: 65-148 µmol/L), mean serum creatinine three monthsafter operation of (104±30.84)µmol/L (range: 72-224 µmol/L), mean drainage of (180±82.33)ml (range: 80-550 ml), mean length of hospital stay after operation of (8±1.56)d (range: 5-15 d). There was no significant difference in renal function between pre- and post-operation (P=0.056). One patient suffered pulmonary embolism was cured conservatively. Fifty patients were followed up, among which 47 cases with malignant pathology were followed up for 3-29 months, and two of them suffered from pulmonary metastasis. Conclusions: After pre-operative comprehensive assessment of tumors, stage T(1b) renal cell carcinoma could be treated with retroperitoneal laparoscopic NSS safely.

Expression and function of peripheral blood miRNA16a in patients with ankylosing spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is a progressive spinal disease presented as rheumatoid factor negative. As an autoimmune disorder, AS is featured with an inflammatory change of tendon and ligament, accompanied by elevates serum levels of inflammatory factors. MicroRNA (miR) participates in the regulation of various diseases including tumor, inflammation, cardiovascular disease and immune response. MiR16a exerts critical roles in inflammatory disease. Its function in AS, however, has not been fully illustrated. PATIENTS AND METHODS: AS patients (at stable and active phase) and healthy controlled individuals were recruited to test peripheral expression of miR16a by Real-time PCR (RT-PCR). Enzyme-linked immunosorbent assay (ELISA) was used to test serum helper T cell 1 (Th1) cytokine levels including interferon (IFN)-γ, tumor necrosis factor-α (TNF-α) and Th2 cytokines including interleukin-4 (IL-4) and IL-10. The correlations between miR16a and cytokine levels, C reactive protein (CRP), erythrocyte sedimentation rate (ESR) and AS activity, were analyzed. RESULTS: MiR16a expression in peripheral blood of AS patients was significantly higher compared to control people (p<0.05 compared to control group). AS patients at active phase had significantly higher miR16a levels, compared to stable phase (p<0.05). Serum IL-4 and IL-10 levels in AS patients were significantly increased, while IFN-γ and TNF-α expressions were depressed (p<0.05 compared to healthy controls). MiR16a expression was positively correlated with IL-4/IL-10 or disease active index, and was negatively correlated with IFN-γ and TNF-α levels (p<0.05), but not with CRP or ESR. CONCLUSIONS: Peripheral miR16a was up-regulated in AS patients, and reflected disease activity, probably via regulating Th1/Th2 balance.

ZEB1 promotes prostate cancer proliferation and invasion through ERK1/2 signaling pathway.

OBJECTIVE: Prostate cancer is a kind of malignancy with high occurrence in the male urogenital system. However, the mechanism of the occurrence, the progression, and the metastasis of prostate cancer are still unclear. Searching for the effective molecule target is of great significance to improve the curative effect on prostate cancer. Zinc finger E box binding protein-1 (ZEB1) protein is a member of the zinc finger transcription factor family that participates in the embryonic development and formation. ZEB1 was found to be involved in the occurrence and in the development of multiple cancers, while its role in prostate cancer still needs elucidation. MATERIALS AND METHODS: Normal prostate cell line PC-3M and prostate cancer cell line DU145 were cultured in vitro and transfected by ZEB1 siRNA. ZEB1 mRNA and protein expressions were detected by real-time PCR and Western blot assay. Cell proliferation was determined by using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell migration was evaluated by transwell assay. Cell apoptosis was evaluated by caspase-3 activity. The impact of ZEB1 on extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling pathway was assessed by Western blot assay. RESULTS: ZEB1 expression significantly increased in DU145 cells compared with PC-3M cells (p<0.05). ZEB1 mRNA and protein obviously declined, cell proliferation inhibited, cell invasion suppressed, and Caspase-3 activity enhanced in DU145 cells after ZEB1 siRNA transfection (p<0.05). ZEB1 siRNA markedly decreased ERK1/2 phosphorylation in DU145 cells compared with control (p<0.05). CONCLUSIONS: Inhibition of ZEB1 promoted prostate cancer apoptosis, restrained proliferation, and suppressed invasion through down-regulating ERK1/2 signaling pathway.

[Analysis of early failure of the PHILOS in proximal humerus fractures].

OBJECTIVE: To analyze the reasons of early failure of the PHILOS in proximal humerus fractures. METHODS: From Nov. 2010 to Nov. 2014, there were 117 patients with humerus fractures treated with PHILOS locking plate in Department of Orthopaedics, Xuanwu Hospital. All of the patients were treated with the plate by open reduction internal fixation, and we analyzed these cases retrospectively. After the operation, we removed the drainage tube within 48 h, and the patients were allowed to do the passive motion 3 days after the surgery if the X-Ray showed the plate and screws were reliable. Eight cases failed within 4 weeks after the operation. We analyzed the reasons of the failure. RESULTS: The rate of the failed cases was 6.83%(8/117). The average age was 72.4(66-82) years. In the 8 failed cases, 3 were on the right side, and the other 5 on the left side. As for the reason of the fractures, 2 cases were because of car accidents, and the other 6 because of daily life injury. According to the Neer classification, 3 cases were 2-part fractures, and the other 5 3-part fractures. Three cases were total failure, and the other 5 partial failure. All the 8 failed cases failed within 4 weeks after the operation, of which 1 was on the sixth day after surgery, the other 7 2 to 4 weeks after the surgery.The 3 totally failed cases were treated by removing the screws and plates, the other 5 by conservative methods. All of the cases were malunion at the end. CONCLUSION: The early failure of the PHILOS locking plate in proximal humerus fractures is related to the bad reduction during the operation, the loss of medial cortex support, the limitation of screw length, the osteoporosis and the improper rehabilitation after operation.It is very important to do good preoperative plan for a surgeon. During the operation, we should try our best in the fracture reduction, use the appropriate plate and screws, and then pay attention to the rehabilitation after the operation. After all of this, the rate of failure may be decreased.

[Analysis of early failure of the PHILOS in proximal humerus fractures].

OBJECTIVE: To analyze the reasons of early failure of the PHILOS in proximal humerus fractures. METHODS: From Nov. 2010 to Nov. 2014, there were 117 patients with humerus fractures treated with PHILOS locking plate in Department of Orthopaedics, Xuanwu Hospital. All of the patients were treated with the plate by open reduction internal fixation, and we analyzed these cases retrospectively. After the operation, we removed the drainage tube within 48 h, and the patients were allowed to do the passive motion 3 days after the surgery if the X-Ray showed the plate and screws were reliable. Eight cases failed within 4 weeks after the operation. We analyzed the reasons of the failure. RESULTS: The rate of the failed cases was 6.83%(8/117). The average age was 72.4(66-82) years. In the 8 failed cases, 3 were on the right side, and the other 5 on the left side. As for the reason of the fractures, 2 cases were because of car accidents, and the other 6 because of daily life injury. According to the Neer classification, 3 cases were 2-part fractures, and the other 5 3-part fractures. Three cases were total failure, and the other 5 partial failure. All the 8 failed cases failed within 4 weeks after the operation, of which 1 was on the sixth day after surgery, the other 7 2 to 4 weeks after the surgery.The 3 totally failed cases were treated by removing the screws and plates, the other 5 by conservative methods. All of the cases were malunion at the end. CONCLUSION: The early failure of the PHILOS locking plate in proximal humerus fractures is related to the bad reduction during the operation, the loss of medial cortex support, the limitation of screw length, the osteoporosis and the improper rehabilitation after operation.It is very important to do good preoperative plan for a surgeon. During the operation, we should try our best in the fracture reduction, use the appropriate plate and screws, and then pay attention to the rehabilitation after the operation. After all of this, the rate of failure may be decreased.

A novel frameshift mutation in the cylindromatosis (CYLD) gene in a Chinese family with multiple familial trichoepithelioma.

Multiple familial trichoepithelioma (MFT) (OMIM: 601606) is an autosomal dominantly inherited disorder characterized by numerous, skin-colored papules and nodules with pilar differentiation. Recently, several mutations in the cylindromatosis (CYLD) gene have been reported in MFT. In this study, a mutation analysis of the CYLD was conducted in a Chinese pedigree of typical MFT. Affected individuals were identified through probands from Shanxi Province, China. Lesional skin biopsy of the proband revealed the typical histopathological characteristics of trichoepithelioma. Individuals belonging to five consecutive generations were similarly affected, which indicated an autosomal dominant inheritance pattern. Genomic DNA was extracted from peripheral blood lymphocytes using standard phenol/chloroform extraction method. All the coding exons (4-20) and exon-intron boundaries of the CYLD gene were amplified by polymerase chain reaction (PCR). Direct sequencing of all PCR products amplified from the complete coding regions of the CYLD gene was performed to identify mutations. Sequencing of the CYLD gene was performed in a further 100 unrelated, unaffected control individuals to exclude the possibility of polymorphism. A novel heterozygous frameshift mutation c.1169_1170delCA (p.Thr390Argfs) was identified in exon 10 of the CYLD gene in the affected family members. This mutation was also detected in unaffected family members, but not in the unrelated, healthy individuals who were also analyzed. Our study expands the database on the CYLD gene mutations in MFT and should be useful in providing genetic counseling and prenatal diagnosis for families affected by MFT.

Dietary intake of meat, fruits, vegetables, and selective micronutrients and risk of bladder cancer in the New England region of the United States.

BACKGROUND: Despite many studies on diet and bladder cancer, there are areas that remain unexplored including meat mutagens, specific vegetable groups, and vitamins from diet. METHODS: We conducted a population-based case-control study of bladder cancer in Maine, New Hampshire, and Vermont. A total of 1171 cases were ascertained through hospital pathology records and cancer registries from 2001 to 2004. Overall, 1418 controls were identified from the Department of Motor Vehicles (<65 years) and Center for Medicaid and Medicare Services (65-79 years) and were frequency-matched to cases by state, sex, and age (within 5 years). Diet was assessed with a self-administered Diet History Questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Processed meat intake was positively associated with bladder cancer (highest vs lowest quartile OR: 1.28; 95% CI: 1.00-1.65; P(trend)=0.035), with a stronger association for processed red meat (OR: 1.41; 95% CI: 1.08-1.84; P(trend)=0.024). There were no associations between intake of fruits or vegetables and bladder cancer. We did, however, observe an inverse association with vitamin B12 intake (OR: 0.77; 95% CI: 0.61-0.99; P=0.019). CONCLUSION: Vitamin B12 from diet may be protective against bladder cancer, whereas consuming processed meat may increase risk.

RING domains functioning as E3 ligases reveal distinct structural features: a molecular dynamics simulation study.

RING domain, a cysteine-rich motif that chelates two zinc ions, has been shown to regulate many biological processes such as mediating a crucial step in the ubiquitinylation pathway. In order to investigate the distinct structural features for the RING domains functioning as E3 ligases, several molecular dynamics simulations involving the c-Cbl, CNOT4 (with E3 ligase function), and p44 (no E3 ligase function) RING domains were conducted in this study. Our results reveal that the structural stability of the recognition site is a basic requirement for the RING domains functioning as E3 ligases. The structural stability of the recognition site is maintained by the hydrophobic core and hydrogen bonding network. Another important structural feature of the RING domains functioning as E3 ligases is the stable distances between the recognition site and the zinc ion binding sites S1 and S2. Moreover, the RING domains functioning as E3 ligases seem to exhibit lower beta stability due to the higher proportion of proline residues in their sequences. However, no significant difference of the other secondary (alpha and turn) and the tertiary structural stabilities can be observed among these three RING domains.

Formation of a stable heterodimer between Smad2 and Smad4.

Smad proteins mediate transforming growth factor beta signaling from the cell membrane to the nucleus. Upon phosphorylation by the activated receptor kinases, the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4. This heterocomplex is then translocated into the nucleus, where it associates with other transcription factors and regulates expression of ligand-responsive genes. The stoichiometry between receptor-regulated Smad and co-mediator Smad is important for understanding the molecular mechanisms of the signaling process. Using purified recombinant proteins, we demonstrate that Smad2 and Smad4 form a stable heterodimer and that the Smad4 activation domain is important for the formation of this complex. Many tumor-derived missense mutations disrupt the formation of this heterocomplex in in vitro interaction assays. Mapping these mutations onto the structures of Smad4 and Smad2 identifies a symmetric interface between these two Smad proteins. Importantly, two previous models on the formation of a heterocomplex are incompatible with our observations and other reported evidence.

[Expression of c-jun mRNA in brain stem following moderate lateral fluid percussion brain injury in rats].

AIM: To study the expression of c-jun in brain stem following moderate lateral fluid percussion brain injury in rats, and to observe the temporal patterns of its expressions following percussion. METHODS: Male Sprague-Dawley rats were divided into normal control, sham operation control and injury groups. The rats of injury group subjected to moderate lateral fluid percussion injury (0.2MPa), and then were subdivided into 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 12 h groups according to the time elapsed after injury. The expression of c-jun was studied by immunohistochemistry and in situ hybridization. RESULTS: After percussion for 15 min, Jun positive neurons increased in brain stem progressively. At 5 min after percussion, the induction of c-jun mRNA was increased, remained elevated up to 2h after brain injury and then decreased gradually. CONCLUSION: The induction and expression of the c-jun in brain stem after fluid percussion brain injury were increased rapidly and lasted for a long time.

Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.

Ligand-induced phosphorylation of the receptor-regulated Smads (R-Smads) is essential in the receptor Ser/Thr kinase-mediated TGF-beta signaling. The crystal structure of a phosphorylated Smad2, at 1.8 A resolution, reveals the formation of a homotrimer mediated by the C-terminal phosphoserine (pSer) residues. The pSer binding surface on the MH2 domain, frequently targeted for inactivation in cancers, is highly conserved among the Co- and R-Smads. This finding, together with mutagenesis data, pinpoints a functional interface between Smad2 and Smad4. In addition, the pSer binding surface on the MH2 domain coincides with the surface on R-Smads that is required for docking interactions with the serine-phosphorylated receptor kinases. These observations define a bifunctional role for the MH2 domain as a pSer-X-pSer binding module in receptor Ser/Thr kinase signaling pathways.