−13915*G DNA polymorphism associated with lactase persistence in Africa interacts with Oct-1

Lactase gene expression declines with aging (lactase non-persistence) in the majority of humans worldwide. Lactase persistence is a heritable autosomal dominant condition and has been strongly correlated with several single nucleotide polymorphisms (SNPs) located ~14-kb upstream (−13907, −13910 and −13915) of the lactase gene in different ethnic populations. In contrast to the −13907*G and −13910*T SNPs, the −13915*G SNP was previously believed not to interact with Oct-1. In the present study, however, Oct-1 is shown to interact with the −13915*G SNP region DNA sequence by EMSAs and gel supershift. In addition, Oct-1 is capable of enhancing promoter activity of a lactase promoter–reporter construct harboring the 13915*G SNP sequence in cell culture. Oct-1 binding to the −13907 to −13915 SNP region therefore remains a candidate interaction involved in lactase persistence.     

Is the ApoE polymorphism associated with dilated cardiomyopathy?

Apolipoprotein E (ApoE) is 34 kDa protein involved in the modulation of cholesterol transport and homeostasis. Polymorphism of the ApoE gene has been implicated in many chronic cardiovascular and neuronal diseases. ApoE epsilon4 allele has been reported to be associated with increased risk of cardiovascular diseases such as myocardial infarction, hypertension, coronary heart disease, etc. Fifty patients with the end-stage dilated cardiomyopathy (DCM) and advanced congestive heart failure were examined in our study. For evaluation of ApoE polymorphism, novel approach of fast screening of ApoE gene polymorphism by combination of PCR and blotting (CVD StripAssay) was used. Individual genotypes were correlated with basic cardiologic clinical parameters. The reported frequency of this allele in Caucasian population is 14.7 %. Our results showed that in patients with DCM frequency of the ApoE epsilon4 allele is 40 %. Frequency of the genotype epsilon2/4 was 58 % and epsilon3/4 was 22 %. Comparison with control Caucasian groups monitored by others clearly revealed that frequency of epsilon4 alelle is increased in patients with advanced stages of DCM. This observation suggests association of ApoE polymorphism with severe form of DCM. Physiological consequences of this observation remain to be clarified.     

Is A163G polymorphism in the osteoprotegerin gene associated with heel velocity of sound in postmenopausal women?

Osteoprotegerin (OPG) plays an important inhibitory role in osteoclastogenesis. Polymorphisms in the OPG gene recently have been associated with various bone phenotypes including fractures. The aim of the present study was to investigate the association between three informative OPG polymorphisms and quantitative ultrasound variables of the heel. In a cohort of 165 perimenopausal women polymorphisms in the OPG promoter (A163G, T245G) and in exon 1 (G1181C) were assessed by PCR-RFLP analysis. The distribution of the investigated genotypes was similar to other Caucasian women (A163G-AA 68 %, AG 30 %, GG 2 %, T245G-TT 84.4 %, TG 15 %, GG 0.6 %, G1181C- GG 22 %, CG 55 %, CC 23 %). After adjustment for body mass index and years since menopause, in a subgroup of 87 postmenopausal subjects, calcaneal velocity of sound (VOS, m/s) was significantly associated with A163G polymorphism (p=0.0102, ANCOVA). Women with the presence of G allele (AG+GG genotypes) had significantly lower VOS than women with AA genotype. Neither T245G nor G1181C were associated with calcaneal ultrasound indices. In conclusion, A163G polymorphism was significantly associated with VOS at the heel in a limited cohort of postmenopausal women. The present study replicated in part the previous findings about OPG gene variations and peripheral bone mass in Caucasian women.     

Fetal genes in mother's blood: A novel mechanism for telegony?

Telegony is a discredited genetic phenomenon that a previous male may influence the characteristics of offspring subsequently borne by the same female to another male. Although its reality was acknowledged by such authorities as Charles Darwin and Herbert Spencer, it has been met with skepticism because of a lack of understanding of the theoretical basis for telegony. With the discovery of fetal genes in mother's blood, the penetration of somatic cells by sperm, and the ability of RNA to program genome rearrangement, mechanisms might exist for telegony.     

The human lactase persistence-associated SNP ?13910*T enables in vivo functional persistence of lactase promoter–reporter transgene expression

Lactase is the intestinal enzyme responsible for digestion of the milk sugar lactose. Lactase gene expression declines dramatically upon weaning in mammals and during early childhood in humans (lactase nonpersistence). In various ethnic groups, however, lactase persists in high levels throughout adulthood (lactase persistence). Genetic association studies have identified that lactase persistence in northern Europeans is strongly associated with a single nucleotide polymorphism (SNP) located 14 kb upstream of the lactase gene: -13910*C/T. To determine whether the -13910*T SNP can function in vivo to mediate lactase persistence, we generated transgenic mice harboring human DNA fragments with the -13910*T SNP or the ancestral -13910*C SNP cloned upstream of a 2-kb rat lactase gene promoter in a luciferase reporter construct. We previously reported that the 2-kb rat lactase promoter directs a post-weaning decline of luciferase transgene expression similar to that of the endogenous lactase gene. In the present study, the post-weaning decline directed by the rat lactase promoter is impeded by addition of the -13910*T SNP human DNA fragment, but not by addition of the -13910*C ancestral SNP fragment. Persistence of transgene expression associated with the -13910*T SNP represents the first in vivo data in support of a functional role for the -13910*T SNP in mediating the human lactase persistence phenotype.     

The −14010*C variant associated with lactase persistence is located between an Oct-1 and HNF1α binding site and increases lactase promoter activity

In most people worldwide intestinal lactase expression declines in childhood. In many others, particularly in Europeans, lactase expression persists into adult life. The lactase persistence phenotype is in Europe associated with the −13910*T single nucleotide variant located 13,910 bp upstream the lactase gene in an enhancer region that affects lactase promoter activity. This variant falls in an Oct-1 binding site and shows greater Oct-1 binding than the ancestral variant and increases enhancer activity. Several other variants have been identified very close to the −13910 position, which are associated with lactase persistence in the Middle East and Africa. One of them, the −14010*C, is associated with lactase persistence in Africa. Here we show by deletion analysis that the −14010 position is located in a 144 bp region that reduces the enhancer activity. In transfections the −14010*C allele shows a stronger enhancer effect than the ancestral −14010*G allele. Binding sites for Oct-1 and HNF1α surrounding the −14010 position were identified by gel shift assays, which indicated that −14010*C has greater binding affinity to Oct-1 than −14010*G.     

CD93 in macrophages: A novel target for atherosclerotic plaque imaging?

Noninvasive imaging atherosclerotic (AS) plaque is of great importance for early diagnosis. Recently, CD93 in MΦ was linked to atherosclerosis development. Herein, we have investigated whether CD93 in MΦ is a potential novel target for atherosclerotic plaque imaging. CD93^hi and CD93^lo MΦ were prepared with or without LPS stimulation, before biological activity was evaluated. A rat AS model was produced with left carotid artery clamped. Whole‐body/ex vivo phosphor autoradiography of the artery and biodistribution were investigated after incorporation of ³H‐2‐DG into CD93^hi and CD93^lo MΦ or after ¹²⁵I‐α‐CD93 (¹²⁵I‐anti‐CD93mAb) injection. The plaque tissue was subjected to CD93/CD68 immunofluorescence/immunohistochemistry staining. CD93^hi and CD93^lo MΦ cells were successfully prepared without significant effect on bioactivity after incorporative labelled with ³H‐2‐DG. The AS model was successfully established. Biodistribution studies showed that adoptive transfer of ³H‐2‐DG‐CD93^hi MΦ or ¹²⁵I‐ α‐CD93 injection resulted in accumulation of radioactivity within the atherosclerotic plaque in the clamped left carotid artery. T/NT (target/non‐target, left/right carotid artery) ratio was higher in the ³H‐2‐DG‐CD93^hi MΦ adoptive transfer group than in the ³H‐2‐DG‐CD93^lo MΦ group (p < .05). Plaque radioactivity in the ¹²⁵I‐α‐CD93 injection group was significantly higher than in the ¹²⁵I‐IgG control group (p < .01). The higher radioactivity accumulated in the clamped left carotid artery was confirmed by phosphor autoradiography. More importantly, CD93/CD68 double‐positive MΦ accumulated at the atherosclerotic plaque in ³H‐2‐DG‐CD93^hi MΦ adoptive transfer group, which correlated with plaque radioactivity (r = .99, p < .01). In summary, both adoptive‐transferred ³H‐2‐DG‐labelled CD93^hi MΦ and ¹²⁵I‐α‐CD93 injection specifically targeted CD93 in atherosclerotic plaque. CD93 is a potential target in atherosclerotic plaque imaging.     

Riboflavin-binding sites associated with flagella of Euglena: A candidate for blue-light photoreceptor?

The hypothesis was tested that reversible riboflavin (RF)-binding sites are part of the photoreceptor in Euglena gracilis. Published evidence shows that the phototactic stimulus — with a flavin-type action spectrum — is perceived at the paraflagellar body (PFB). Flagella with PFBs were isolated from Euglena gracilis by a combined cold and Ca²⁺ shock. Saturable binding of [¹⁴C]RF was demonstrated with such preparations, in the oxidized state as well as under reducing conditions in the presence of dithionite. Affinities for RF were high: K _D (oxidized)=0.08 M, and K _D (reduced)=0.7 M. Flavin mononucleotide and flavin adenine dinucleotide showed lower binding affinities. The in vitro RF binding per unit of protein was enriched approximately tenfold in the flagellar preparations when compared with homogenates of whole cells. The number of (reduced) binding sites per entire flagellum was determined to be in the order of 10⁶. This number is in line with published estimates of chromophores bound in or at the PFB.Abbreviations FAD flavin adenine dinucleotide - FMN flavin mononucleotide - PFB paraflagellar body - RF riboflavin This work was supported by the Deutsche Forscungsgemeinschaft.     

A single nucleotide polymorphism in NF-κB inducing kinase is associated with mortality in septic shock

We tested the hypothesis that single nucleotide polymorphisms (SNPs) within genes of the NF-κB pathway are associated with altered clinical outcome of septic shock patients. We genotyped 59 SNPs in the NF-κB pathway in a discovery cohort of septic shock patients (St. Paul's Hospital [SPH], N = 589), which identified the C allele of rs7222094 T/C within MAP3K14 (NF-κB inducing kinase; NIK) associated with increased 28-d mortality (uncorrected p = 0.00024, Bonferroni corrected p = 0.014). This result was replicated in a second cohort of septic shock patients (Vasopressin and Septic Shock Trial [VASST; N = 616]) in which the CC genotype of rs7222094 was associated with increased 28-d mortality (Cox regression: SPH cohort hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.12-1.64; p = 0.002 Caucasian only; and VASST cohort HR, 1.24; 95% CI, 1.00-1.52; p = 0.048 Caucasian only). Patients having the CC genotype of rs7222094 in SPH experienced more renal and hematological dysfunction (p = 0.003 and p = 0.011), while patients of the VASST cohort with the rs7222094 CC genotype showed the same trend toward more renal dysfunction. In lymphoblastoid cell lines, we found the rs7222094 genotype most strongly associated with mRNA expression of CXCL10, a chemokine regulated by NF-κB. Accordingly, we measured CXCL10 protein levels and found that the CC genotype of rs7222094 was associated with significantly lower levels than those of the TT genotype in lymphoblastoid cell lines (p < 0.05) and in septic shock patients (p = 0.017). This suggests that the CC genotype of NIK rs7222094 is associated with increased mortality and organ dysfunction in septic shock patients, perhaps due to altered regulation of NF-κB pathway genes, including CXCL10.     

Targeting detoxification pathways: an efficient approach to obtain plants with multiple stress tolerance?

A serious factor limiting the engineering of stress tolerance has been our ignorance about the function of stress-induced genes. A stress-activated novel aldose-aldehyde reductase was cloned from alfalfa. The ectopic expression of this gene in tobacco resulted in tolerance to oxidative stress and dehydration. Physiological analysis suggested that aldose reductase probably functions by reducing the level of reactive aldehydes. This provides a promising perspective for the development of crop plants with improved stress tolerance.     

How do plants achieve tolerance to phosphorus deficiency? Small causes with big effects

Genotypic differences in phosphorus (P) uptake from P-deficient soils may be due to higher root growth or higher external root efficiency (micrograms of P taken up per square centimeter of root surface area). Both factors are highly interrelated because any additional P provided by externally efficient roots will also stimulate root growth. It will be necessary to separate both factors to identify a primary mechanism to formulate hypotheses on pathways and genes causing genotypic differences in P uptake. For this purpose, a plant growth model was developed for rice (Oryza sativa) grown under highly P-deficient conditions. Model simulations showed that small changes in root growth-related parameters had big effects on P uptake. Increasing root fineness or the internal efficiency for root dry matter production (dry matter accumulated per unit P distributed to roots) by 22% was sufficient to increase P uptake by a factor of three. That same effect could be achieved by a 33% increase in external root efficiency. However, the direct effect of increasing external root efficiency accounted for little over 10% of the 3-fold increase in P uptake. The remaining 90% was due to enhanced root growth as a result of higher P uptake per unit root size. These results demonstrate that large genotypic differences in P uptake from a P-deficient soil can be caused by rather small changes in tolerance mechanisms. Such changes will be particularly difficult to detect for external efficiency because they are likely overshadowed by secondary root growth effects.     

PCSK9: A novel inflammation modulator in atherosclerosis?

Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the secretory serine protease family. It binds to low-density lipoprotein receptor (LDLR) for endocytosis and lysosome degradation in the liver, resulting in an increasing in circulating LDL-cholesterol (LDL-c) level. Since a PCSK9 induced increase in plasma LDL-c contributes to atherosclerosis, PCSK9 inhibition has become a new strategy in preventing and treating atherosclerosis. However, in addition to the effect of PCSK9 on elevating blood LDL-c levels, accumulating evidence shows that PCSK9 plays an important role in inflammation, likely representing another major mechanism for PCSK9 to promote atherosclerosis. In this review, we discuss the association of PCSK9 and inflammation, and highlight the specific effects of PCSK9 on different vascular cellular components involved in the atherosclerotic inflammation. We also discuss the clinical evidence for the association between PCSK9 and inflammation in atherosclerotic cardiovascular disease. A better understanding of the direct association of PCSK9 with atherosclerotic inflammation might help establish a new role for PCSK9 in vascular biology and identify a novel molecular mechanism for PCSK9 therapy.     

Does size matter for hypoxia tolerance in fish?

Fish cover a large size range, from milligrams to tonnes, and many of them are regularly exposed to large variations in ambient oxygen levels. For more than half a century, there have been various, often divergent, claims regarding the effect of body size on hypoxia tolerance in fish. Here, we attempt to link old and new empirical data with the current understanding of the physiological mechanisms behind hypoxia tolerance. Three main conclusions are drawn: (1) body size per se has little or no impact on the ability to take up oxygen during hypoxic conditions, primarily because the respiratory surface area matches metabolic rate over a wide size range. If size-related differences are seen in the ability for oxygen uptake in a species, these are likely to reflect adaptation to different life-styles or habitat choice. (2) During severe hypoxia and anoxia, where fish have to rely on anaerobic ATP production (glycolysis) for survival, large individuals have a clear advantage over smaller ones, because small fish will run out of glycogen or reach lethal levels of anaerobic end-products (lactate and H(+)) much faster due to their higher mass-specific metabolic rate. (3) Those fish species that have evolved extreme adaptations to hypoxia, including haemoglobins with exceptionally high oxygen affinities and an alternative anaerobic end-product (ethanol), reveal that natural selection can be a much more powerful determinant of hypoxia tolerance than scaling of physiological functions.     

An α-spectrin mutation responsible for hereditary elliptocytosis associated in cis with the αV/41 polymorphism

The 207 LeuPro mutation in spectrin has recently been identified as a cause of ^I/50-46a hereditary elliptocytosis (HE) or pyropoikilocytosis among Black people. We have found this mutation in a Moroccan family in both the heterozygous and homozygous states. The mutated -spectrin allele carried, in cis, the ^V/41 polymorphism, a common polymorphism altering the peptide maps and associated with a low-expression level. This is the first report of the cis combination of an HE mutation and the ^V/41 polymorphism. Presumably, such a combination accounts for the very low expression of the abnormal allele in the heterozygous state.     

Mitochondrial translation in trypanosomatids: a novel target for chemotherapy?

Trypanosomatids cause widespread disease in humans and animals. Treatment of many of these diseases is hampered by the lack of efficient and safe drugs. New strategies for drug development are therefore urgently needed. It has long been known that the single mitochondrion of trypanosomatids exhibits many unique features. Recently, the mitochondrial translation machinery of trypanosomatids has been the focus of several studies, which revealed interesting variations to the mammalian system. It is the aim of this article to review these unique features and to discuss them in the larger biological context. It is our opinion that some of these features represent promising novel targets for chemotherapeutic intervention that should be studied in more detail.     

A 25-kDa dehydrin associated with genotype- and age-dependent leaf freezing-tolerance in Rhododendron: a genetic marker for cold hardiness?

Dehydrins are plant proteins that may play a critical role in stabilizing cell functions during freezing and other dehydrative stresses. This study examines whether dehydrin expression in leaves is associated with varying levels of freezing-tolerance among F₂ segregants, species, and cultivars of evergreen Rhododendron. Experiments were also conducted to determine whether physiological and chronological aging affects freezing-tolerance and dehydrin accumulation in Rhododendron leaf tissues. Our results indicate that in cold-acclimated F₂ populations, levels of a 25-kDa dehydrin were closely associated with differences in leaf freezing-tolerance (LFT) among segregants. Studies of wild and cultivated plants indicated that LFT increased with both chronological age and developmental phase-change (juvenile to mature plants) and that this trend was accompanied by increased accumulation of the 25-kDa dehydrin. It is suggested that presence or absence of the 25-kDa dehydrin could serve as a genetic marker to distinguish between super cold-hardy and less cold-hardy rhododendron genotypes. Similarly, the relative level of this protein within a genotype can serve as a physiological indicator of freezing-tolerance status under a range of phenological (acclimation) or developmental (age) conditions. Received: 5 March 1999 / Accepted: 12 May 1999     

Lablab purpureus—A Crop Lost for Africa?

In recent years, so-called ‘lost crops’ have been appraised in a number of reviews, among them Lablab purpureus in the context of African vegetable species. This crop cannot truly be considered ‘lost’ because worldwide more than 150 common names are applied to it. Based on a comprehensive literature review, this paper aims to put forward four theses, (i) Lablab is one of the most diverse domesticated legume species and has multiple uses. Although its largest agro-morphological diversity occurs in South Asia, its origin appears to be Africa. (ii) Crop improvement in South Asia is based on limited genetic diversity. (iii) The restricted research and development performed in Africa focuses either on improving forage or soil properties mostly through one popular cultivar, Rongai, while the available diversity of lablab in Africa might be under threat of genetic erosion. (iv) Lablab is better adapted to drought than common beans (Phaseolus vulgaris) or cowpea (Vigna unguiculata), both of which have been preferred to lablab in African agricultural production systems. Lablab might offer comparable opportunities for African agriculture in the view of global change. Its wide potential for adaptation throughout eastern and southern Africa is shown with a GIS (geographic information systems) approach.