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BackgroundWith the development of surgical technics, endoscopic thyroid surgery has been gradually accepted and utilized in thyroid disease treatment, including thyroid carcinoma. This study aimed to evaluate the learning curve for endoscopic hemithyroidectomy (EHT) with ipsilateral central neck dissection (CND) and investigate how many cases must be performed before a surgeon becomes competent and proficient in this approach.MethodsNinety-nine consecutive patients who underwent EHT with ipsilateral CND for papillary thyroid microcarcinoma by a single surgeon between June 2015 and October 2017 were analyzed. Multidimensional cumulative summation (CUSUM) analysis was performed to evaluate the learning curve.ResultsThe CUSUM graph showed the learning curve ascended in the first 31 cases and declined in the following cases. The number of lymph nodes removed in phase 2 (the following 68 cases) was significantly more than that in phase 1 (the first 31 cases) (5.06 ± 1.44 vs. 4.19 ± 1.51, P = 0.001). The operation time in phase 2 was shorter than that in phase 1 (123.38 ± 12.71 min vs. 132.90 ± 13.95 min, P = 0.008) and the rate of accidental removal of parathyroid gland decreased from 35.5% in phase 1 to 16.2% in phase 2 (P = 0.040). There was a declining trend but no significant difference in the rate of postoperative complications (9.7% in phase 2 vs. 4.4% in phase 1, P = 0.309).ConclusionEHT with ipsilateral CND performed by surgeons was mastered after 31 cases, and the safety and feasibility of this endoscopic approach can also be demonstrated.

Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3–KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment. Lipopolysaccharide derived from gut bacteria can accelerate the formation of cerebral cavernous malformations by activating TLR4 on endothelial cells, and polymorphisms that increase expression of the genes encoding TLR4 or its co-receptor CD14 are associated with higher CCM lesion burden in humans. Microbiome driven cerebral malformations Cerebral cavernous malformations (CCMs) are malformations of the vascular system, seen mainly in the brain where they can cause haemorrhagic stroke and seizures. CCMs arise from loss-of-function mutations in components of a complex that negatively regulates MEKK3–KLF2/4 signalling and Rho/ROCK signalling in brain endothelial cells. Mark Kahn and colleagues now identify upstream regulators that activate this pathway in brain endothelial cells. They find that lipopolysaccharide derived from gut bacteria can accelerate CCM formation by activating TLR4 on endothelial cells. The authors further show that polymorphisms in the TLR4 gene or CD14 , the gene encoding its co-receptor, are associated with higher CCM lesion burden in humans. These findings suggest that the gut microbiome and TLR4 are important drivers of CCMs and represent potential therapeutic targets.

Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.

China consumes 35% of the world’s fertilizer every year; however, most of the nitrogen fertilizers, which are essential for rice cultivation, are not used effectively. In this study, factors affecting the nitrogen leaching loss rate were studied in typical soil and rice varieties in South China. The effects of various irrigation measures on rice growth and nitrogen leaching loss were investigated by conducting experiments with eight groups. These groups included traditional irrigation (TI) and shallow wet irrigation (SWI). The TI is a common irrigation method for farmers in South China, maintaining a water layer of 5-8 cm depth. For SWI, after establishing a shallow water layer usually maintaining at 1-2 cm, paddy is irrigated when the field water level falls to a certain depth, then this process is then repeat as necessary. The nitrogen distribution characteristics were determined using 15 N isotope tracing. In addition, the effects of nitrification, denitrification, and microbial composition on soil nitrogen transformation at different depths were studied by microbial functional gene quantification and high-throughput sequencing. The results revealed that in the SWI groups, the total nitrogen leaching loss rate reduced by 0.3-0.8% and the nitrogen use efficiency (NUE) increased by 2.18-4.43% compared with those in the TI groups. After the 15 N-labeled nitrogen fertilizer was applied, the main pathways of nitrogen were found to be related to plant absorption and nitrogen residues. Furthermore, paddy soil ammonia-oxidizing archaea were more effective than ammonia-oxidizing bacteria for soil ammonia oxidation by SWI groups. The SWI measures increased the relative abundance of Firmicutes in paddy soil, enhancing the ability of rice to fix nitrogen to produce ammonium nitrogen, thus reducing the dependence of rice on chemical fertilizers. Moreover, SWI enhanced the relative abundance of nirS and nosZ genes within surface soil bacteria, thereby promoting denitrification in the surface soil of paddy fields. SWI also promoted ammonia oxidation and denitrification by increasing the abundance and activity of Proteobacteria , Nitrospirae , and Bacteroidetes . Collectively, SWI effectively reduced the nitrogen leaching loss rate and increase NUE.

The massive loss of nitrogen (N) and phosphorus (P) from farmland ditches contributes to non-point source pollution, posing a significant global environmental challenge. Effectively removing these nutrients remains difficult in intensive agricultural systems. To address this, a novel composite ecological ditch system (CEDS) was developed by modifying traditional drainage ditches to integrate a grit chamber, zeolite, and ecological floating beds. Dynamic monitoring of N and P levels in water, plants, and zeolite was conducted to evaluate the system’s nutrient interception performance and mechanisms. The results showed the following: (1) Water quality improved markedly after passing through the CEDS, with nutrient concentrations decreasing progressively along the flow path. The system intercepted 41.0% of N and 31.9% of P, with inorganic N and particulate P as the primary forms of nutrient loss. (2) Zeolite removes N primarily through ion exchange, and P likely through chemical reactions, with maximum capacities of 3.47 g/kg for N and 1.83 g/kg for P. (3) Ecological floating beds with hydroponic cultivation enhanced nutrient uptake by the roots of Canna indica and Iris pseudacorus, with N uptake surpassing P. (4) Nutrient interception efficiency was positively correlated with temperature, ditch inlet concentrations, and rice runoff concentrations, but negatively with precipitation. This study demonstrates the CEDS’s potential for improving farmland water quality and suggests further enhancements in design and management to increase its economic and aesthetic value.

Cerebral cavernous malformation is a common human vascular disease that arises due to loss-of-function mutations in genes encoding three intracellular adaptor proteins, cerebral cavernous malformations 1 protein (CCM1), CCM2, and CCM3. CCM1, CCM2, and CCM3 interact biochemically in a pathway required in endothelial cells during cardiovascular development in mice and zebrafish. The downstream effectors by which this signaling pathway regulates endothelial function have not yet been identified. Here we have shown in zebrafish that expression of mutant ccm3 proteins (ccm3Delta) known to cause cerebral cavernous malformation in humans confers cardiovascular phenotypes identical to those associated with loss of ccm1 and ccm2. CCM3Delta proteins interacted with CCM1 and CCM2, but not with other proteins known to bind wild-type CCM3, serine/threonine protein kinase MST4 (MST4), sterile 20-like serine/threonine kinase 24 (STK24), and STK25, all of which have poorly defined biological functions. Cardiovascular phenotypes characteristic of CCM deficiency arose due to stk deficiency and combined low-level deficiency of stks and ccm3 in zebrafish embryos. In cultured human endothelial cells, CCM3 and STK25 regulated barrier function in a manner similar to CCM2, and STKs negatively regulated Rho by directly activating moesin. These studies identify STKs as essential downstream effectors of CCM signaling in development and disease that may regulate both endothelial and epithelial cell junctions.

Mutations in CCM1 (aka KRIT1), CCM2, or CCM3 (aka PDCD10) gene cause cerebral cavernous malformation in humans. Mouse models of CCM disease have been established by deleting Ccm genes in postnatal animals. These mouse models provide invaluable tools to investigate molecular mechanism and therapeutic approaches for CCM disease. However, the full value of these animal models is limited by the lack of an accurate and quantitative method to assess lesion burden and progression. In the present study we have established a refined and detailed contrast enhanced X-ray micro-CT method to measure CCM lesion burden in mouse brains. As this study utilized a voxel dimension of 9.5μm (leading to a minimum feature size of approximately 25μm), it is therefore sufficient to measure CCM lesion volume and number globally and accurately, and provide high-resolution 3-D mapping of CCM lesions in mouse brains. Using this method, we found loss of Ccm1 or Ccm2 in neonatal endothelium confers CCM lesions in the mouse hindbrain with similar total volume and number. This quantitative approach also demonstrated a rescue of CCM lesions with simultaneous deletion of one allele of Mekk3. This method would enhance the value of the established mouse models to study the molecular basis and potential therapies for CCM and other cerebrovascular diseases.

Loss-of-function mutations in cerebral cavernous malformation (CCM) genes and gain-of-function mutation in the MAP3K3 gene encoding MEKK3 cause CCM. Deficiency of CCM proteins leads to the activation of MEKK3-KLF2/4 signaling, but it is not clear how this occurs. Here, we demonstrate that deletion of the CCM3 interacting kinases STK24/25 in endothelial cells causes defects in vascular patterning during development as well as CCM lesion formation during postnatal life. While permanent deletion of STK24/25 in endothelial cells caused developmental defects of the vascular system, inducible postnatal deletion of STK24/25 impaired angiogenesis in the retina and brain. More importantly, deletion of STK24/25 in neonatal mice led to the development of severe CCM lesions. At the molecular level, a hybrid protein consisting of the STK kinase domain and the MEKK3 interacting domain of CCM2 rescued the vascular phenotype caused by the loss of ccm gene function in zebrafish. Our study suggests that CCM2/3 proteins act as adapters to allow recruitment of STK24/25 to limit the constitutive MEKK3 activity, thus contributing to vessel stability. Loss of STK24/25 causes MEKK3 activation, leading to CCM lesion formation.

In keratinocytes aquaporin-3 (AQP3), an efficient glycerol transporter, is associated with phospholipase D2 (PLD2) in caveolin-rich membrane microdomains. PLD catalyzes both phospholipid hydrolysis to produce phosphatidate and a transphosphatidylation reaction using primary alcohols to generate phosphatidylalcohols. As PLD2 can utilize the physiological alcohol glycerol to form phosphatidylglycerol (PG), we hypothesized that AQP3 provides glycerol to PLD2 for PG synthesis, which then modulates keratinocyte function. Acidic medium inhibits AQP3 transport activity; both glycerol uptake and PG synthesis were inhibited by low versus physiological pH. Co-transfection experiments were performed in which AQP3 or empty vector was introduced into keratinocytes simultaneously with reporter constructs in which differentiation or proliferation promoters directed expression of a luciferase reporter gene. AQP3 coexpression decreased the promoter activity of keratin 5, increased that of keratin 10 and enhanced the effect of a differentiating agent on the promoter activity of involucrin, consistent with promotion of early differentiation. Glycerol inhibited DNA synthesis, whereas equivalent concentrations of xylitol or sorbitol, as osmotic controls, had no effect. Direct provision of PG, but not phosphatidylpropanol, inhibited DNA synthesis in proliferative cells. Thus, our results support the idea that AQP3 supplies PLD2 with glycerol for synthesizing PG, a lipid signal that promotes early keratinocyte differentiation.