Caspase-1 Inhibition Ameliorates Photoreceptor Damage Following Retinal Detachment by Inhibiting Microglial Pyroptosis.

Retinal detachment (RD) is a sight-threatening condition that occurs in several retinal diseases. Microglia that reside in retina are activated after RD and play a role in the death of photoreceptor cells. The involvement of microglial pyroptosis in the early pathological process of RD is still unclear. VX-765, an inhibitor of caspase-1, may exert neuroprotective effects by targeting microglial pyroptosis in nervous system disease; however, whether it plays a role in RD is uncertain. This study detected and localized pyroptosis to specific cells by immunofluorescence co-staining and flow cytometry in rat RD models. The majority of gasdermin D N-terminal (GSDMD-N)-positive cells exhibited IBA1-positive or P2RY12-positive microglia in the early stage of RD, indicating the pyroptosis of microglia. Administration of VX-765 shifted the microglia phenotype from M1 to M2, inhibited microglial migration toward the outer nuclear layer (ONL) post-RD, and most importantly, inhibited microglial pyroptosis. The thickness of ONL increased with VX-765 administration, and the photoreceptors were more structured and orderly under hematoxylin and eosin staining and transmission electron microscopy, revealing the protective effects of VX-765 on photoreceptors. Overall, this study demonstrated that inflammation induced by pyroptosis of microglia is the early pathological process of RD. VX-765 may serve as a candidate therapeutic approach for the treatment of RD by targeting microglia.

Randomized trial comparing the effects of a 3D head-up system and microscope eyepiece-assisted simulated vitrectomy with intraocular illumination on the ocular surface of an operator.

BACKGROUND: To compare the effects of a 3D head-up system and microscope eyepiece-assisted simulated vitrectomy intraocular illumination on the ocular surface of an operator. METHODS: This was a prospective randomized controlled study. According to the application system, thirty ophthalmic operators (60 eyes) were randomly divided into 3D and eyepiece groups. Under different intensities of intraocular illumination, operators in both groups viewed the fundus model through a 3D display screen or microscopic eyepiece for 2 h. Objective examinations and a subjective symptom questionnaire were used immediately after the test to evaluate the ocular surface of the operators. Objective examinations included nonintrusion tear meniscus height (NIKTMH), nonintrusion break-up time (NIKBUT), and bulbar redness and strip meniscometry tube (SMTube) measurements. Statistical analyses were performed by using SPSS 26.0 software. RESULTS: After the test, the NIKTMH, NIKBUT and SMTube measurements decreased; however, the degree of change varied among the groups of different systems. The differences between the 3D group and the eyepiece group in NIKTMH measurements, SMTube measurements, subjective symptom scores (eye dryness, difficulty focusing, and cervical pain), and light intensity reaching the ocular surface of the operators were statistically significant (P < 0.05). All of the objective and subjective tests showed that the 3D group had fewer effects on the NIKTMH and SMTube measurements, and the subjective comfort of the 3D group was greater. CONCLUSION: For both 3D screens and eyepieces, simulated vitrectomy with intraocular illumination for two hours can lead to discomfort and abnormalities in the operator's ocular surface; however, these abnormalities are less severe in the 3D group. TRIAL REGISTRATION: This trial was registered on December 22, 2022, at the Chinese Clinical Trials Registry with NO. ChiCTR2200066989.

Oxymatrine suppresses colorectal cancer progression by inhibiting NLRP3 inflammasome activation through mitophagy induction in vitro and in vivo.

Chinese herb Radix sophorae tonkinensis extract oxymatrine shows anticancer effects. This study evaluated the role of oxymatrine in colorectal cancer (CRC) and the underlying molecular events in vitro and in vivo. CRC cells were treated with different doses of oxymatrine to assess cell viability, reactive oxygen species production, gene expression, and gene alterations. Meanwhile, mouse xenograft and liver metastasis models were used to assess the effects of oxymatrine using histology examination, transmission electron microscopy, and Western blot, respectively. Our results showed that oxymatrine treatment triggered CRC cell mitophagy to inhibit CRC cell growth, migration, invasion, and metastasis in vitro and in vivo. At the gene level, oxymatrine inhibited LRPPRC to promote Parkin translocation into the mitochondria and reduce the mitophagy-activated NLRP3 inflammasome. Thus, oxymatrine had an anticancer activity through LRPPRC inhibition, mitophagy induction, and NLRP3 inflammasome suppression in the CRC cell xenograft and liver metastasis models. In conclusion, the study demonstrates the oxymatrine anti- CRC activity through its unique role in regulating CRC cell mitophagy and NLRP3 inflammasome levels in vitro and in vivo.

Chinese Guideline on the Management of Polypoidal Choroidal Vasculopathy (2022).

Background In mainland China, patients with neovascular age-related macular degeneration (nAMD) have approximately an 40% prevalence of polypoidal choroidal vasculopathy (PCV). This disease leads to recurrent retinal pigment epithelium detachment (PED), extensive subretinal or vitreous hemorrhages, and severe vision loss. China has introduced various treatment modalities in the past years and gained comprehensive experience in treating PCV.Methods A total of 14 retinal specialists nationwide with expertise in PCV were empaneled to prioritize six questions and address their corresponding outcomes, regarding opinions on inactive PCV, choices of anti-vascular endothelial growth factor (anti-VEGF) monotherapy, photodynamic therapy (PDT) monotherapy or combined therapy, patients with persistent subretinal fluid (SRF) or intraretinal fluid (IRF) after loading dose anti-VEGF, and patients with massive subretinal hemorrhage. An evidence synthesis team conducted systematic reviews, which informed the recommendations that address these questions. This guideline used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to assess the certainty of evidence and grade the strengths of recommendations. Results The panel proposed the following six conditional recommendations regarding treatment choices. (1) For patients with inactive PCV, we suggest observation over treatment. (2) For treatment-na?ve PCV patients, we suggest either anti-VEGF monotherapy or combined anti-VEGF and PDT rather than PDT monotherapy. (3) For patients with PCV who plan to initiate combined anti-VEGF and PDT treatment, we suggest later/rescue PDT over initiate PDT. (4) For PCV patients who plan to initiate anti-VEGF monotherapy, we suggest the treat and extend (T&E) regimen rather than the pro re nata (PRN) regimen following three monthly loading doses. (5) For patients with persistent SRF or IRF on optical coherence tomography (OCT) after three monthly anti-VEGF treatments, we suggest proceeding with anti-VEGF treatment rather than observation. (6) For PCV patients with massive subretinal hemorrhage (equal to or more than four optic disc areas) involving the central macula, we suggest surgery (vitrectomy in combination with tissue-plasminogen activator (tPA) intraocular injection and gas tamponade) rather than anti-VEGF monotherapy. Conclusions Six evidence-based recommendations support optimal care for PCV patients' management.

FOLDABLE CAPSULAR VITREOUS BODY IMPLANTATION FOR COMPLICATED RETINAL DETACHMENT CAUSED BY SEVERE OCULAR TRAUMA.

PURPOSE: To explore the effectiveness, safety and psychological impact of foldable capsular vitreous body (FCVB) implantation for complicated retinal detachment caused by severe ocular trauma. METHODS: This was a prospective, single-arm, surgical interventional case series study. A standard 3-port 23-gauge pars plana vitrectomy was performed, and the FCVB was implanted into the vitreous cavity. Observed indicators, including the best-corrected visual acuity, intraocular pressure (IOP), retinal reattachment, complications, and patient satisfaction, were analyzed to evaluate the study. RESULTS: A total of 28 cases (eyes) were enrolled, with a mean follow-up of 16.93 ± 9.67 months and an average age of 51.11 ± 10.14 years, including 22 men (78.57%). The FCVB was successfully implanted, and the retina was reattached in all cases. The postoperative best-corrected visual acuity improved in 7 cases, and remained unchanged in 21 cases ( P > 0.05). The average IOP was 7.01 ± 2.43 mmHg before surgery and 8.54 ± 2.93 mmHg after surgery ( P < 0.05). Complications such as FCVB displacement, endophthalmitis, secondary glaucoma, silicone oil emulsification, and escape did not occur during the follow-up period. Patients with FCVB implantation are highly satisfied. Most patients feel hope, positive, and optimistic about life. CONCLUSION: Foldable capsular vitreous body implantation for complicated retinal detachment caused by severe ocular trauma is effective and safe, and it allows patients to face life positively and optimistically.

Downregulation of angiogenic factors in aqueous humor associated with less intraoperative bleeding in PDR patients with NVG receiving conbercept: a randomized controlled trial.

BACKGROUND: To analyze the level changes of 28 cytokines in aqueous humor of patients with proliferative diabetic retinopathy (PDR) coexisting neovascular glaucoma (NVG) after intravitreal injection of conbercept (IVC), and to investigate whether these cytokines are associated with intraoperative bleeding (IOB). METHODS: Totally 34 eyes with NVG secondary to PDR were enrolled. Patients were randomized into two groups, and all of them underwent 25-gauge pars plana vitrectomy (PPV) combined with trabeculectomy. Group I, 18 eyes received IVC 3 days before PPV, and 100 µL aqueous humor was collected at the time of IVC pretreatment and 3 days later at the beginning of PPV respectively. Group II, 16 eyes received IVC after PPV, and 100 µL aqueous humor was collected only at the beginning of PPV. Aqueous humor from 19 eyes with age-matched cataract patients served as controls. Luminex bead-based multiplex array was used to measure the levels of 28 cytokines in aqueous humor. The baseline cytokine levels were compared among the three groups. All NVG patients were divided into IOB and non-bleeding (INB) groups. The cytokine levels of aqueous humor at the beginning of PPV were compared between group I and II, also between IOB and INB groups. IOB in NVG patients was graded according to vitreous bleeding amount. The correlation between cytokine levels and the grades of IOB were analyzed. RESULTS: Compared with controls, the baseline levels of 18 cytokines associated with inflammation and angiogenesis showed significantly increased in group I and group II (all, P < 0.0167). The IOB rate as well as the levels of IL-4, IL-22, Ang-2, PLGF and VEGF-A in group I were significantly lower than in group II (all, P < 0.05). The levels of IL-4, IL-22, Ang-2, PLGF and VEGF-A were significantly lower in INB group than in IOB group (all, P < 0.05). The levels of IL-4, Ang-2, PLGF and VEGF-A were positively correlated with the grades of IOB in NVG patients (all, rs > 0.4, P < 0.05). CONCLUSIONS: IVC 3 days before PPV combined with trabeculectomy reduces IOB in NVG patients, in which the downregulation of IL-4, Ang-2, PLGF and VEGF-A after IVC may be an underlying mechanism. TRIAL REGISTRATION: ChiCTR2100048118 , retrospectively registered on 2 July 2021.

Tissue-Protective Effect of Erdosteine on Multiple-Organ Injuries Induced by Fine Particulate Matter.

BACKGROUND Fine particulate matter (PM2.5) is the air pollutant that most threatens global public health. The purpose of this study was to observe the inflammatory and oxidative stress injury of multiple organs induced by PM2.5 in rats and to explore the tissue-protective effect of erdosteine. MATERIAL AND METHODS We randomly divided 40 male Wistar rats into a blank control group, a saline group, a PM2.5 exposure group, and an erdosteine intervention group. We assessed changes in organs tissue homogenate and biomarkers of inflammation and oxidative stress in serum and bronchoalveolar lavage fluid (BALF). RESULTS (1) The expressions of IL-6, IL-1ß, TNF-alpha, 8-OHdG, 4-HNE, and PCC in serum and BALF of the PM2.5 exposure group increased, but decreased after treatment with erdosteine, suggesting that erdosteine treatment attenuates inflammatory and oxidative stress injury. (2) The expression of γ-GCS in serum and lungs in the PM2.5 exposure group increased, but did not change significantly after treatment with erdosteine. This suggests that PM2.5 upregulates the level of γ-GCS, while erdosteine does not affect this protective response. (3) The expression of T-AOC in serum, lungs, spleens, and kidneys of the PM2.5 exposure group decreased, but increased after treatment with erdosteine. Our results suggest that PM2.5 can cause imbalance of oxidation/anti-oxidation in multiple organs, and erdosteine can alleviate this imbalance. CONCLUSIONS PM2.5 exposure can lead to inflammatory and oxidative stress damage in serum and organ tissues of rats. Erdosteine may be an effective anti-inflammatory and antioxidant that can reduce this injury.

IL-6-induced acetylation of E2F1 aggravates oxidative damage of retinal pigment epithelial cell line.

Oxidative damage in retinal pigment epithelial cells (RPE) is considered to be a crucial pathogenesis of age-related macular degeneration (AMD). Although dysregulation of the DNA repair system has been found in RPE cells of AMD patients, the detailed molecular mechanisms of this dysregulation and their relationship with the intraocular microenvironment of AMD patients remain unclear. Here, we established an RPE model of H2O2-induced oxidative stress and found that Sirtuin 1 (Sirt1)-mediated deacetylation of E2F transcription factor 1 (E2F1) was required for oxidation resistance in RPE cells. Moreover, E2F1 induced the expression of the chromatin-binding protein, high mobility group AT-Hook 1 (HMGA1), which promoted the transcription of glucose 6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, to increase NADPH level for antioxidant defense. Interrupting the E2F1/HMGA1/G6PD regulatory axis increased reactive oxygen species (ROS) levels, DNA damage, and apoptosis in RPE cells under oxidative stress. Notably, interleukin 6 (IL-6), an inflammatory cytokine that is known to be upregulated in the intraocular fluid of AMD patients, induced phosphorylation (S47) of Sirt1 by activating PI3K/AKT/mTOR signaling, thereby inhibiting Sirt1 activity and increasing the acetylation of E2F1. Specific inhibitors of PI3K/AKT/mTOR signaling decreased DNA damage and ROS while increasing NADPH in RPE cells. Collectively, our findings demonstrate that IL-6-induced acetylation of E2F1 impairs the antioxidant capacity of RPE cells by disturbing the pentose phosphate pathway, which elucidates a relationship between the intraocular microenvironment and RPE oxidative damage in AMD and provides a possible therapeutic target for AMD.

Alkyl polyglycoside and earthworm (Eisenia fetida) enhance biodegradation of green waste and its use for growing vegetables.

Managing municipal green waste is a challenge to municipalities, partly because of the slow rate of decomposition of green waste during composting due to its high lignin and cellulose contents. Hence, this study evaluated the effect of alkyl polyglycoside (APG), a biosurfactant, and the earthworm Eisenia fetida on the composting process. Addition of APG and E. fetida significantly increased total bacteria, cellulolytic fungi, phosphate solubilizing bacteria and nitrogen fixing bacteria populations, and the activities of cellulase, urease and alkaline phosphatase in composts as compared with the control. The APG and earthworm treatments also increased surface roughness and porosity of the green waste; Compared with control, APG and earthworm addition increased the degradation rate of TOC, lignin and cellulose by 5.9-17.9, 10.3-32.0 and 10.8-18.8%, respectively, and resulted in better compost quality, as was reflected in the neutral pH, higher cation exchange capacity (CEC) and nutrient concentrations (N, P, K, Ca, Mg, Fe, Cu, Zn, Mn). Final germination percentage and growth rate of tomato, eggplant and pepper seedlings were higher (P < 0.05) or similar in all composts produced with the addition of APG and earthworm, while plant growth was lower (P < 0.05) in the compost produced with the control than in peat substrate. The combination of APG+E. fetida enhanced the decomposition of green waste and improved final compost quality the most. Further research is needed to determine the best level of APG addition and optimum earthworm density for composting green waste.

Application of seasonal freeze-thaw to pretreat raw material for accelerating green waste composting.

The recalcitrance of green waste, caused by its high lignocellulose content, is a technical challenge for accelerating green waste composting. However, because lignocellulose degradation in litter (similar to green waste) can be promoted during the freeze-thaw season, and the composting is difficult to implement in this period (due to the low temperature); seasonal freeze-thaw was intended to be used as a pretreatment strategy for the existing technical challenge in the winter of cold regions. In this process, green waste was pretreated with seasonal freeze-thaw to enhance its lignocellulose degradation for subsequent composting. To verify this assumption, two strategies for the pretreatment were used: the green waste was either drenched or immersed in water during the freeze-thaw season, and the effects on subsequent composting were evaluated. The results demonstrated that both strategies can significantly promote the mineralization of TOC (total organic carbon, by 2.73%-8.01% compared with the control, the following comparisons were all based on the control), TN (total nitrogen, by 0.21%-0.52%), and lignocellulose (lignin degradation was promoted by 3.52%-3.73%, cellulose degradation was promoted by 13.23%-14.26%) during composting and that the synthesis of humus was also enhanced (by 19.19%-21.43%). Furthermore, since the loss of NH4+N and NO3-N was significantly less in the drenched treatment than in the immersed treatment (by 9.15% for the loss of NH4+N and 7.66% for the loss of NO3-N), drenching the green waste during the freeze-thaw season might be a better strategy than immersing for nitrogen conservation. An additional advantage of drenching compared to immersing is water conservation.

Spent mushroom substrate and cattle manure amendments enhance the transformation of garden waste into vermicomposts using the earthworm Eisenia fetida.

Garden wastes (GW) having high lignin contents could hinder the growth of earthworms and microorganisms in vermicomposting. This study investigated the Eisenia fetida-based vermicomposting of GW mixed with cattle manure (CM) and/or spent mushroom substrate (SMS) at different ratios of GW alone (control), 3:1 GW:SMS, 1:1 GW:SMS, 3:1 GW:CM, 1:1 GW:CM and 2:1:1 GW:SMS:CM to promote earthworm growth and improve the final vermicompost quality. In general, treatments with the addition of SMS and/or CM increased the survival rate, biomass, cocoon and juvenile numbers of E. fetida compared to the control. The addition of SMS and/or CM also significantly increased the activities of dehydrogenase, cellulase, urease, and alkaline phosphatase compared to the control. Furthermore, the addition of SMS and/or CM facilitated the decomposition of organic matter, cellulose and lignin, increased nutrient (N, P and K) concentrations, and accelerated nitrification compared to the control. The addition of SMS and CM led to greater chemical changes of the substrate compared to control. Heavy metal concentrations were increased in the final vermicomposts comparatively to the initial materials, but none of them exceeded the permissible limits. The highest germination index of Chinese cabbage and tomato seeds were both observed in the treatment of 2:1:1 GW:SMS:CM which reached 146.9 and 148.1. Overall, the 2:1:1 GW:SMS:CM treatment had the highest growth and reproduction rates of E. fetida, higher percentage degradation of organic matter, cellulose and lignin, as well as the best quality of the final vermicompost.

Gα12 is required for renal cystogenesis induced by Pkd1 inactivation.

Mutation of PKD1, encoding the protein polycystin-1 (PC1), is the main cause of autosomal dominant polycystic kidney disease (ADPKD). The signaling pathways downstream of PC1 in ADPKD are still not fully understood. Here, we provide genetic evidence for the necessity of Gα12 (encoded by Gna12, hereafter Gα12) for renal cystogenesis induced by Pkd1 knockout. There was no phenotype in mice with deletion of Gα12 (Gα12-/-). Polyinosine-polycytosine (pI:pC)-induced deletion of Pkd1 (Mx1Cre+Pkd1f/fGα12+/+) in 1-week-old mice resulted in multiple kidney cysts by 9 weeks, but the mice with double knockout of Pkd1 and Gα12 (Mx1Cre+Pkd1f/fGα12-/-) had no structural and functional abnormalities in the kidneys. These mice could survive more than one year without kidney abnormalities except multiple hepatic cysts in some mice, which indicates that the effect of Gα12 on cystogenesis is kidney specific. Furthermore, Pkd1 knockout promoted Gα12 activation, which subsequently decreased cell-matrix and cell-cell adhesion by affecting the function of focal adhesion and E-cadherin, respectively. Our results demonstrate that Gα12 is required for the development of kidney cysts induced by Pkd1 mutation in mouse ADPKD.

Bamboo biochar amendment improves the growth and reproduction of Eisenia fetida and the quality of green waste vermicompost.

Vermicomposting is a promising method for reusing urban green waste. However, high lignin content in the green waste could hinder the development of earthworm and microorganisms and the vermicomposting process, resulting in a low-quality vermicompost product. The objective of this study was to evaluate the effect of bamboo biochar addition (at 0%, 3%, and 6% on a dry w/w basis) on the activity of Eisenia fetida and the obtained vermicompost. Biochar addition increased (P < 0.05) earthworm biomass, juvenile and cocoon numbers of Eisenia fetida, as well as the activities of dehydrogenase, cellulase, urease and alkaline phosphatase. Compared to the control, lignin degradation rate was enhanced up to 13.89% by biochar addition. Biochar addition also improved the vermicompost quality in terms of cation exchange capacity (CEC), dissolved organic carbon (DOC) degradation, humification, nitrogen transformation, toxicity to germinating seeds (Brassica rapa L., Chinensis group) and heavy metals concentrations. The 6% bamboo biochar addition rate achieved maturity after 60 days of vermicomposting and resulted in the highest quality vermicompost based on parameters such as CEC, DOC, NH4+-N/NO3--N ratio, germination index and heavy metal concentration. We conclude that 6% biochar addition promoted earthworm growth and the vermicomposting of green waste.

Nasopharyngeal carcinoma with intracranial extension in the era of intensity-modulated radiotherapy: case-control study using propensity score matching method.

The objective of the study was to evaluate long-term survival outcomes and toxicity of T4 classification nasopharyngeal carcinoma (NPC) with intracranial extension (IE group) or without intracranial extension (non-IE group) after intensity-modulated radiotherapy (IMRT) using the propensity score matching method. After generating propensity scores given the covariates of age, sex, N classification, and concurrent chemotherapy, 132 patients in each group were matched. The 5-year local failure-free survival rate and the 5-year overall survival rate in the IE group were lower than the patients in the non-IE group (74.6 vs. 88.9 %, p = .008; 51.1 vs. 71.9 %, p = .005). Grade 2 hypothyroidism was more common in the IE group (13.2 vs. 3.4 %, p = .029). For patients with T4 classification NPC after IMRT, patients with intracranial extension need more attention to the thyroid gland function and are more likely to experience local failure and death than patients without intracranial extension.

Intensity-modulated radiotherapy for cervical esophageal squamous cell carcinoma: clinical outcomes and patterns of failure.

The objective of the study was to report clinical outcomes and patterns of failure for these patients with cervical esophageal squamous cell carcinoma (CESCC) treated with intensity-modulated radiotherapy (IMRT). A total of 64 patients with CESCC treated with definitive IMRT from May 2005 to March 2012 in our center were analyzed. Forty-two patients received radiotherapy alone and 22 patients received concurrent chemoradiotherapy. The location and extent of locoregional failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. For all patients, the overall 2-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival rate was 74.5, 88.0, 66.6 and 42.5 %, respectively. Twenty-eight patients had developed treatment failure. Of the 28 patients, 14, 5, and 18 had developed local failure, regional failure, and distant metastasis, respectively. All of the 14 local failures were considered in-field failures. Of the five regional failures, three were considered in-field failures and two were marginal failures. The most frequently observed acute toxicity was mainly Grade 1 or 2. The incidence of acute Grade 3 mucositis (including pharyngitis), skin reaction, and leukopenia was 4.7, 12.5 and 10.9 %, respectively. IMRT provides satisfactory locoregional control for CESCC. Distant metastasis remains the predominate pattern of failure and the predominate pattern of locoregional failures is in-field failure.

Polycystin-1 and Gα12 regulate the cleavage of E-cadherin in kidney epithelial cells.

Interaction of polycystin-1 (PC1) and Gα12 is important for development of kidney cysts in autosomal dominant polycystic kidney disease (ADPKD). The integrity of cell polarity and cell-cell adhesions (mainly E-cadherin-mediated adherens junction) is altered in the renal epithelial cells of ADPKD. However, the key signaling pathway for this alteration is not fully understood. Madin-Darby canine kidney (MDCK) cells maintain the normal integrity of epithelial cell polarity and adherens junctions. Here, we found that deletion of Pkd1 increased activation of Gα12, which then promoted the cystogenesis of MDCK cells. The morphology of these cells was altered after the activation of Gα12. By using liquid chromatography-mass spectrometry, we found several proteins that could be related this change in the extracellular milieu. E-cadherin was one of the most abundant peptides after active Gα12 was induced. Gα12 activation or Pkd1 deletion increased the shedding of E-cadherin, which was mediated via increased ADAM10 activity. The increased shedding of E-cadherin was blocked by knockdown of ADAM10 or specific ADAM10 inhibitor GI254023X. Pkd1 deletion or Gα12 activation also changed the distribution of E-cadherin in kidney epithelial cells and caused ß-catenin to shift from cell membrane to nucleus. Finally, ADAM10 inhibitor, GI254023X, blocked the cystogenesis induced by PC1 knockdown or Gα12 activation in renal epithelial cells. Our results demonstrate that the E-cadherin/ß-catenin signaling pathway is regulated by PC1 and Gα12 via ADAM10. Specific inhibition of this pathway, especially ADAM10 activity, could be a novel therapeutic regimen for ADPKD.

Dopaminergic neurons modulate GABA neuron migration in the embryonic midbrain.

Neuronal migration, a key event during brain development, remains largely unexplored in the mesencephalon, where dopaminergic (DA) and GABA neurons constitute two major neuronal populations. Here we study the migrational trajectories of DA and GABA neurons and show that they occupy ventral mesencephalic territory in a temporally and spatially specific manner. Our results from the Pitx3-deficient aphakia mouse suggest that pre-existing DA neurons modulate GABA neuronal migration to their final destination, providing novel insights and fresh perspectives concerning neuronal migration and connectivity in the mesencephalon in normal as well as diseased brains.

Definitive intensity-modulated radiotherapy compared with definitive conventional radiotherapy in cervical oesophageal squamous cell carcinoma.

PURPOSE: The authors compared definitive intensity-modulated radiotherapy (IMRT) with definitive conventional radiotherapy (2D-RT) in cervical oesophageal squamous cell carcinoma (CESCC). MATERIALS AND METHODS: A total of 101 patients with CESCC treated with definitive radiotherapy from January 2001 to April 2012 were analysed. 37 patients were irradiated using 2D-RT, whereas 64 cases were treated using IMRT. RESULTS: The median follow-up time was 15.5 months for all the patients. For all patients, the overall 2-year local failure-free survival (LFFS), regional failure-free survival (RFFS), and overall survival (OS) rate was 67.4, 85.2 and 46.2%, respectively. The 2-year LFFS rate and the 2-year RFFS rate in the IMRT group were higher than the 2D-RT group, although no statistically significant difference was observed in LFFS and RFFS. No statistically significant difference was observed in overall survival (OS) between the groups. Compared with 2D-RT, the rate of grade 3 dysphagia after radiotherapy was lower (6.3 vs. 8.1%) and none had hypothyroidism requiring lifelong thyroxine replacement in the IMRT group. Matched-cases analysis did not show a statistical difference in terms of LFFS, RFFS and OS between the groups. CONCLUSIONS: Although no statistically significant difference was observed in OS, LFFS and RFFS between the IMRT group and the 2D-RT group, the incidence of late toxicity declined using IMRT, thereby resulting in an improved therapeutic ratio for patients with CESCC.

Endothelial VEGF sculpts cortical cytoarchitecture.

Current models of brain development support the view that VEGF, a signaling protein secreted by neuronal cells, regulates angiogenesis and neuronal development. Here we demonstrate an autonomous and pivotal role for endothelial cell-derived VEGF that has far-reaching consequences for mouse brain development. Selective deletion of Vegf from endothelial cells resulted in impaired angiogenesis and marked perturbation of cortical cytoarchitecture. Abnormal cell clusters or heterotopias were detected in the marginal zone, and disorganization of cortical cells induced several malformations, including aberrant cortical lamination. Critical events during brain development-neuronal proliferation, differentiation, and migration were significantly affected. In addition, axonal tracts in the telencephalon were severely defective in the absence of endothelial VEGF. The unique roles of endothelial VEGF cannot be compensated by neuronal VEGF and underscores the high functional significance of endothelial VEGF for cerebral cortex development and from disease perspectives.

Light Quality Effect on Internal N Retranslocation in Podocarpus macrophyllus Precultured with Exponential Nutrient Loading.

Streetlamp light is inevitable in the night landscape of a city and may affect the phenology of newly planted ornamental plants, but it has rarely been fully examined. Newly transplanted ornamental plants probably suffer periodic shocks, which mainly result from the inefficient reuse of internal nutrients for new growth. Exponential nutrient loading (ENL) is well known for its ability to overcome transplant shocks by promoting retranslocation for the reuse of strengthened nutrients from internal reserves in precultured seedlings. Transplantation to urbanized lands is distinct from that of montane areas; this is mainly due to a high frequency of exposure to the artificial illumination of night lighting. It is suspected that this lighting modifies vegetative phenology and generates potential risks by increasing reliance on internal nutrient retranslocation. In this study, Podocarpus macrophyllus seedlings were cultured with ENL at low and high rates of nitrogen (N) deliveries (40 and 120 mg N seedling-1, respectively), and the high-rate treatment was identified as being able to trap seedlings within toxic states. A labeled 15N isotope was pulsed to transplanted seedlings exposed to simulated light qualities in red, green, and blue light spectra. The seedlings harvested at one month showed rare responses to the interactive spectra and preculture treatments, but most of them responded to the low-rate N preculture treatment with stronger abilities in terms of the reuse of internal N and the synthesizing of photosynthetic pigments. In conclusion, it was verified that night light enforces the effect on newly transplanted plants; the red light invoked internal N for reuse, and the blue light promoted the uptake of the current N. The internal N reserve established through preculture ENL rarely made a contribution to the night light effect, except for the enhancement of height growth in the red light. The red light spectrum was recommended for the exposure of newly transplanted seedlings due to its effect on the enhancement of the retranslocation of internal N and the induction of a steady state of uptake from the current N input.