性别因素对GRK5缺陷小鼠AD样病理改变的影响

目的性别在阿尔茨海默病（AD）的发病中是一不容忽视的危险因素。研究揭示G蛋白偶联受体（GPCRs）激酶5（GRK5）缺陷引起的相关GPCRs脱敏障碍在早期AD病理发生机制中具有重要作用,而且GRK5敲除／缺陷（GRK5KO）小鼠表现出早期AD样病理特征和短时期记忆功能损害。但这种病理变化在不同性别间有无差异,目前不得而知。本研究旨在探讨GRK5KO小鼠出现的AD样病理变化是否存在性别差异。方法用Campbell-Switzer银染来观察老龄GRK5KO小鼠海马内肿胀轴突的病理变化;Western blotting检测海马内突触蛋白水平和数个胆碱能标记物的变化;同时对上述改变在不同性别间进行深入比较。结果雌性GRK5KO小鼠海马内肿胀轴突数目比雄性小鼠高出2．5倍;而且雌性GRK5KO小鼠海马内数个突触蛋白水平比雄性小鼠显著减低。双因素方差分析显示性别和GRK5缺陷双因素之间呈显著协同效应,共同促进了雌性GRK5KO小鼠轴突缺陷和部分突触蛋白水平的降低。另外,胆碱能标记物检测显示,雌性GRK5KO小鼠毒蕈碱受体2、4以及乙酰胆碱酯酶水平较雄性小鼠显著增高。结论在促进早期AD病理发生的过程中,GRK5缺陷和性别双因素表现出协同效应,共同加剧了雌性GRK5KO小鼠脑内的AD样病理改变。     

营养元素亏缺对人参根分泌物主成分的影响

采用营养液培养的方法,研究了氮、磷、钾元素亏缺对生长发育初期人参根系分泌物组成的影响.结果表明：氮、钾元素亏缺处理的人参根系分泌物组分与对照相当,分别检测到28、29和27个强色谱峰,磷元素缺失处理人参根系分泌物组分相对较少,检测到22种强色谱峰.用化学标准品分别对上述4种处理的根系分泌物中的14、14、11和10个化合物进行了鉴定.与对照相比,氮、磷元素亏缺处理人参根系分泌物有机酸和酚酸类化合物种类增多,磷元素缺失处理人参根系分泌物种类减少.说明人参生长发育初期对氮、钾元素需求比较旺盛,而对磷元素需求较少,氮、钾元素亏缺会促进根对有机酸和酚酸物质的分泌.     

Using plant analysis to predict yield losses caused by sulphur deficiency

Yield losses in agricultural crops as a result of sulphur deficiency are increasing in the UK, because of the decrease in sulphur dioxide emissions and changes in fertiliser practices. Therefore, there is a need for a reliable and practical diagnostic indicator to predict early in the growing season whether it is necessary to apply S fertiliser, but also to avoid the application of fertiliser when not necessary. A successful diagnostic indicator should be reliable and stable throughout plant development, but also easily measured with great accuracy and as little effort as possible. In this paper the difficulties and problems with currently used diagnostic tests for S deficiency, such as total S, sulphate or the N:S ratio, will be discussed. A more reliable and practical indicator of S deficiency is the malate: sulphate peak area ratio which is at present being developed for use by commercial laboratories and their customers.     

Estimation of physiologically active zinc in maize by biochemical assay

Summary The enzymes ribonuclease, aldolase and carbonic anhydrase were evaluated as biochemical assays for physiologically active zinc in maize. Seedlings were cultured for 14 or 30 days on a black-earth soil with factorial combinations of phosphorus and zinc fertilizers so as to produce in the leaves varying levels of active zinc at a constant level of total zinc. Enzyme activity was correlated with plant growth, leaf nutrient composition and the occurrence of visual symptoms of zinc deficiency. Ribonuclease and aldolase activities in leaf tissues were insensitive to the changes in active zinc concentration, though aldolase activity was sensitive to phosphorus deficiency. In contrast, leaf carbonic anhydrase activity correlated well with the onset and correction of zinc deficiency symptoms and, as early as 14 days after emergence, was more sensitive to the deficiency than was plant growth. The sensitivity of carbonic anhydrase to changes in active zinc and its specificity for such changes were further examined in 10 to 30 day-old plants grown in solution culture. Zinc was added to plants which had been cultured without zinc for 16 days. A 2.5-fold increase in carbonic anhydrase activity preceded responses by either zinc concentration or plant growth. We propose the use of leaf carbonic anhydrase as an index of active zinc in maize, particularly to supplement inorganic analysis in the diagnosis of zinc deficiency when much of the zinc in the plants is inactive. The assay is simple, is sensitive to and specific for zinc status, and enables early detection of a deficiency before irreversible biochemical events predispose a large yield reduction.     

Biliary lithiasis in early pregnancy and abnormal development of facial and distal limb bones (Binder syndrome): a possible role for vitamin K deficiency

BACKGROUND: Binder syndrome is a maxillonasal dysostosis characterized by midface and nasal hypoplasia, sometimes associated with short terminal phalanges of fingers and toes and transient radiological features of chondrodysplasia punctata. Warfarin- or phenytoin-induced vitamin K deficiency during early pregnancy is a well-established etiology for this syndrome, which occurs nevertheless sporadically in most cases. CASE(S): We describe here the first case, to our knowledge, of Binder syndrome in a child whose mother presented with biliary lithiasis in early pregnancy. The mother proved to have a decrease in clotting factors II, VII, and X, and in prothrombin time, at 11 weeks of gestation, which was highly suggestive of vitamin K deficiency. CONCLUSIONS: The biliary lithiasis-induced vitamin K deficiency in early pregnancy is likely to have resulted in Binder syndrome. This observation should prompt physicians to carefully check for vitamin K deficiency in pregnant women presenting with biliary lithiasis, in order to prevent Binder syndrome in the fetus by providing intravenous vitamin K supplementation as soon as possible. Finally, reassuring genetic counseling regarding the genetic risk for future pregnancies is to be provided to the parents.     

Vitamin D and maternal and child health: Overview and implications for dietary requirements

The essentiality of vitamin D for normal growth and development has been recognized for over 80 years, and vitamin D fortification programs have been in place in the United States for more than 70 years. Despite the above, vitamin D deficiency continues to be a common finding in certain population groups. Vitamin D deficiency has been suggested as a potential risk factor for the development of preeclampsia, and vitamin D deficiency during infancy and early childhood is associated with an increased risk for numerous skeletal disorders, as well as immunological and vascular abnormalities. Vitamin D deficiency can occur through multiple mechanisms including the consumption of diets low in this vitamin and inadequate exposure to environmental ultraviolet B rays. The potential value of vitamin D supplementation in high‐risk pregnancies and during infancy and early childhood is discussed. Currently, there is vigorous debate concerning what constitutes appropriate vitamin D intakes during early development as exemplified by differing recommendations from the Institute of Medicine Dietary Reference Intake report and recent recommendations by the Endocrine Society. As is discussed, a major issue that needs to be resolved is what key biological endpoint should be used when making vitamin D recommendations for the pregnant woman and her offspring. Birth Defects Research (Part C) 99:24–44, 2013. © 2013 Wiley Periodicals, Inc.     

Some outstanding problems in the detection of trace element deficiency diseases

Knowledge of the functional roles of many essential trace elements has grown rapidly. Despite this, it is rarely possible to relate this information to observed pathological consequences of deficiency. Few studies of the effect of deficiency upon enzyme activity have attempted to determine whether such changes influence substrate-product relations and thus may have pathological significance. Evidence that the differing susceptibility of tissues to deficiency may reflect metabolic activity or the lifespan of cells and their organelles is considered. The need is growing for more effective biochemical diagnostic techniques for the early detection of covert pathological changes in trace element deficient subjects. Progress towards satisfying this need will reflect the future availability of information from which to predict the nature of rate-limiting metabolic defects in sensitive populations of cells.     

Influence of preconditioning-like hypoxia on the liver of developing methyl-deficient rats

Deficiency in nutritional determinants of homocysteine (HCY) metabolism, such as vitamin B(12) and folate, during pregnancy is known to influence HCY levels in the progeny, which in turn may exert adverse effects during development, including liver defects. Since short hypoxia has been shown to induce tolerance to subsequent stress in various cells including hepatocytes, and as vitamins B deficiency and hypoxic episodes may simultaneously occur in neonates, we aimed to investigate the influence of brief postnatal hypoxia (100% N(2) for 5 min) on the liver of rat pups born from dams fed a deficient regimen, i.e., depleted in vitamins B(12), B(2), folate, and choline. Four experimental groups were studied: control, hypoxia, deficiency, and hypoxia + deficiency. Although hypoxia transiently stimulated HCY catabolic pathways, it was associated with a progressive increase of hyperhomocysteinemia in deficient pups, with a fall of cystathionine beta-synthase activity at 21 days. At this stage, inducible NO synthase activity was dramatically increased and glutathione reductase decreased, specifically in the group combining hypoxia and deficiency. Also, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio. In parallel, early exposure to the methyl-deficient regimen induced oxidative stress and led to hepatic steatosis, which was found to be more severe in pups additionally exposed to hypoxia. In conclusion, brief neonatal hypoxia may accentuate the long-term adverse effects of impaired HCY metabolism in the liver resulting from an inadequate nutritional regimen during pregnancy, and our data emphasize the importance of early factors on adult disease.     

Influence of Ca2+ and pH on the Stability of Different Boron Fractions in Intact Roots of Vicia faba L.

Abstract: An experimental setup was developed which allowed the detection of different boron fractions in intact plant roots. The B fractions were water-soluble B (WSB), BaCI₂-soluble B (BaSB) and the respective insoluble fractions (WIB and BaIB). In root tips of V. faba seedlings, WSB represents approx. 4%, BaSB 9% of B_tot. BaSB consists of (at least) two compounds, the larger of which (65 % ) interacts with phosphate and is considered a soluble B complex. Within 2 h of B deficiency, WSB and a large part of BaSB disappear, suggesting that they may be involved in early deficiency reactions in root tips. Concerning insoluble fractions, there was no decline in WIB within the first 6 h of B deficiency. Within the same time frame, BaIB dropped to 35% of the initial B content, indicating a stabilizing effect of Ca on B complexes under in vivo conditions. The concentration of WSB in root tips was lower at pH 3.6 as compared to pH 6.0, indicating that changes in apoplastic pH rapidly alter the equilibrium between free and bound B. WIB was more tightly bound in older root parts, as indicated by a maximum loss of 34% of B_tot after 24 h of continuous B removal, as compared to 99.5% in root tips. Our results indicate that different fractions of B (additional to B-RGII) are affected in the early stages of B deficiency and that Ca is not only a stabilizing agent for B complexes but is also necessary to bind soluble B complexes in the apoplast of intact roots.     

VITAMIN A AND UROLITHIASIS—A Review

The early observations of Osborne, Mendel, and Ferry, and later of Higgins, showed that the incidence of urolithiasis was high in rats fed on diets deficient in fat soluble vitamins. Subsequently, the results of dark adaptation studies were interpreted as showing a relationship between vitamin A deficiency and calculous disease. However, a review of the literature including more recent data discloses that there is no evidence either clinical or experimental to support the claim that vitamin A deficiency is an etiologic factor in calculous disease in man in the United States.     

Vitamin A and urolithiasis; a review

The early observations of Osborne, Mendel, and Ferry, and later of Higgins, showed that the incidence of urolithiasis was high in rats fed on diets deficient in fat soluble vitamins. Subsequently, the results of dark adaptation studies were interpreted as showing a relationship between vitamin A deficiency and calculous disease. However, a review of the literature including more recent data discloses that there is no evidence either clinical or experimental to support the claim that vitamin A deficiency is an etiologic factor in calculous disease in man in the United States.     

ApoE is required for maintenance of the dentate gyrus neural progenitor pool

Many genes regulating adult neurogenesis have been identified and are known to play similar roles during early neuronal development. We recently identified apolipoprotein E (ApoE) as a gene the expression of which is essentially absent in early brain progenitors but becomes markedly upregulated in adult dentate gyrus stem/progenitor cells. Here, we demonstrate that ApoE deficiency impairs adult dentate gyrus development by affecting the neural progenitor pool over time. We utilized ApoE-deficient mice crossed to a nestin-GFP reporter to demonstrate that dentate gyrus progenitor cells proliferate more rapidly at early ages, which is subsequently accompanied by an overall decrease in neural progenitor cell number at later time points. This appears to be secondary to over-proliferation early in life and ultimate depletion of the Type 1 nestin- and GFAP-expressing neural stem cells. We also rescue the proliferation phenotype with an ApoE-expressing retrovirus, demonstrating that ApoE works directly in this regard. These data provide novel insight into late hippocampal development and suggest a possible role for ApoE in neurodegenerative diseases.     

A systematic review of the natural history and biomarkers of primary lecithin:cholesterol acyltransferase deficiency

Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe and characterized by early and progressive chronic kidney disease (CKD). No treatment is currently available for FLD, but novel therapeutics are under development. Furthermore, although biomarkers of LCAT deficiency have been identified, their suitability to monitor disease progression and therapeutic efficacy is unclear, as little data exist on the rate of progression of renal disease. Here, we systematically review observational studies of FLD, FED, and heterozygous subjects, which summarize available evidence on the natural history and biomarkers of LCAT deficiency, in order to guide the development of novel therapeutics. We identified 146 FLD and 53 FED patients from 219 publications, showing that both syndromes are characterized by early corneal opacity and markedly reduced HDL-C levels. Proteinuria/hematuria were the first signs of renal impairment in FLD, followed by rapid decline of renal function. Furthermore, LCAT activity toward endogenous substrates and the percentage of circulating esterified cholesterol (EC%) were the best discriminators between these two syndromes. In FLD, higher levels of total, non-HDL, and unesterified cholesterol were associated with severe CKD. We reveal a nonlinear association between LCAT activity and EC% levels, in which subnormal levels of LCAT activity were associated with normal EC%. This review provides the first step toward the identification of disease biomarkers to be used in clinical trials and suggests that restoring LCAT activity to subnormal levels may be sufficient to prevent renal disease progression.     

Increase of Lipid Hydroperoxides in Tissues of Vitamin E-Deficient Rats

The level of lipid hydroperoxides was determined by a newly developed method in rat tissues of vitamin E deficiency, which was a good in viuo model of enhanced radical reactions. In the heart, lung and kidney, the level of lipid hydroperoxides increased significantly as early as 4 weeks after feeding on a tocopherol-deficient diet compared with that of the control group. After 8 weeks of the deficiency, similar results were obtained. These results indicate that the lipid hydroperoxide is available as an extremely sensitive indicator of lipid peroxidation in these organs, because it takes several months to detect manifestations of the vitamin deficiency based on conventional indices.     

Methylenetetrahydrofolate reductase (MR) deficiency: thermolability of residual MR activity, methionine synthase activity, and methylcobalamin levels in cultured fibroblasts.

Methylenetetrahydrofolate reductase (MR) deficiency is the most common inborn error of folate metabolism with more than two dozen patients described. The phenotypic spectrum ranges from severe neurological deterioration and early death to asymptomatic adults. Some patients with a severe deficiency of MR have been shown to have thermolabile reductase at 55 degrees C. Since methyltetrahydrofolate, the product of MR, is a methyl donor for methylcobalamin (MeCbl), the cofactor for methionine synthase (MS), we have looked at MeCbl accumulation and MS activity in fibroblasts from 15 patients with MR deficiency. Thermolabile MR was most often but not always seen in later onset disease. MeCbl levels were often lowest in the patients with early onset disease. All but two patients had levels of methionine synthase within the control range.     

Sequential changes in plasma methylmalonic acid and vitamin B12 in sheep eating cobalt-deficient grass

Methylmalonic acid (MMA) concentrations are elevated in plasma as a result of vitamin B12 deficiency. This study reports the sequential changes in plasma MMA in lambs maintained on a cobalt-deficient pasture compared with supplemented controls. The results indicate that MMA is elevated in the early stages of deficiency, preceding the onset of loss of production and clinical signs of disease. It remains elevated as long as the lambs are unsupplemented with cobalt (Co). The most striking clinical sign was a loss of body condition as opposed to weight. The defect in the methylmalonyl CoA mutase is obviously an early defect in cobalt deficiency.     

Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus

Gestational-neonatal iron deficiency, a common micronutrient deficiency affecting the offspring of more than 30% of pregnancies worldwide, leads to long-term cognitive and behavioral abnormalities. Preclinical models of gestational-neonatal iron deficiency result in reduced energy metabolism and expression of genes critical for neuronal plasticity and cognitive function, which are associated with a smaller hippocampal volume and abnormal neuronal dendrite growth. Because insulin-like growth factor (IGF) modulates early postnatal cellular growth, differentiation, and survival, we used a dietary-induced rat model to assess the effects of gestational iron deficiency on activity of the IGF system. We hypothesized that gestational iron deficiency attenuates postnatal hippocampal IGF signaling and results in downstream effects that contribute to hippocampal anatomic and functional deficits. At postnatal day (P) 15 untreated gestational-neonatal iron deficiency markedly suppressed hippocampal IGF activation and protein kinase B signaling, and reduced neurogenesis, while elevating extracellular signal-regulated kinase 1/2 signaling and hypoxia-inducible factor-1α expression. Iron treatment beginning at P7 restored IGF signaling, increased neurogenesis, and normalized all parameters by the end of rapid hippocampal differentiation (P30). Expression of the neuron-specific synaptogenesis marker, disc-large homolog 4 (PSD95), increased more rapidly than the glia-specific myelination marker, myelin basic protein, following iron treatment, suggesting a more robust response to iron therapy in IGF-I-dependent neurons than IGF-II-dependent glia. Collectively, our findings suggest that IGF dysfunction is in part responsible for hippocampal abnormalities in untreated iron deficiency. Early postnatal iron treatment of gestational iron deficiency reactivates the IGF system and promotes neurogenesis and differentiation in the hippocampus during a critical developmental period.     

Diagnosing sulfur deficiency in field-grown oilseed rape (Brassica napus L.) and wheat ( Triticum aestivum L.)

The effects of increasing sulfur applications on field-grown oilseed rape (Brassica napus L.) and wheat (Triticum aestivum L.) were investigated in 1998 and 1999, and the critical values and efficiency of several diagnostic indicators for S deficiency were determined. Critical values for leaf concentrations of total S, sulfate and glutathione changed over time and were not suitable for diagnosing S deficiency early in the growth season. The N:S ratio was more reliable but involved two analytical measurements. A practical and reliable indicator for S deficiency was the malate:sulfate peak area ratio as measured by ion chromatography, which required only a single analysis and was independent of the time of sampling or calibration of the samples. A malate:sulfate ratio ≤ 1 indicated S sufficiency at the time of sampling, whereas a ratio > 1 suggested S deficiency at the time of sampling. The malate:sulfate ratio was reliable at growth stage 3.6–3.7 (flower stalks extending to first flowers yellow) for oilseed rape and at growth stage 22–25 (main stem and 2–5 tillers) for wheat, which was sufficiently early in the growth season to apply remedial sulfur fertilizer, if necessary. This revised version was published online in June 2006 with corrections to the Cover Date.     

Effect of protein-calorie deficiency on the ultrastructure of synapses in the molecular layer of the cerebellar cortex in developing and adult animals

The influence of protein-caloric deficiency on the ultrastructure of synapses in the molecular layer of the cerebellum has been quantitatively assessed in young and adult mice. It has been found that protein-caloric deficiency in the early postnatal period delays the time of axo-dendritic synapse development in the neuropil. Adult mice were more resistant to the influence of protein-caloric deficiency because of an increase in compensatory-adaptive reactions found in the cerebellum.     

Plant lncRNAs are enriched in and move systemically through the phloem in response to phosphate deficiency

In response to phosphate (Pi) deficiency, it has been shown that micro-RNAs (miRNAs) and mRNAs are transported through the phloem for delivery to sink tissues. Growing evidence also indicates that long non-coding RNAs (lncRNAs) are critical regulators of Pi homeostasis in plants. However, whether lncRNAs are present in and move through the phloem, in response to Pi deficiency, remains to be established. Here, using cucumber as a model plant, we show that lncRNAs are enriched in the phloem translocation stream and respond, systemically, to an imposed Pi-stress. A well-known lncRNA, IPS1, the target mimic (TM) of miRNA399, accumulates to a high level in the phloem, but is not responsive to early Pi deficiency. An additional 24 miRNA TMs were also detected in the phloem translocation stream; among them miRNA171 TMs and miR166 TMs were induced in response to an imposed Pi stress. Grafting studies identified 22 lncRNAs which move systemically into developing leaves and root tips. A CU-rich PTB motif was further identified in these mobile lncRNAs. Our findings revealed that lncRNAs respond to Pi deficiency, non-cell-autonomously, and may act as systemic signaling agents to coordinate early Pi deficiency signaling, at the whole-plant level.