Amino acid analysis of bone from a possible case of prehistoric iron deficiency anemia from the American southwest

It is possible that dietary conditions can result in the production of abnormal bone protein. For example, a heavily maize-dependent diet could be deficient in one or more essential amino acids necessary to normal human biochemistry and consequently necessary for normal bone protein synthesis. Amino acid analysis of bone tissues, thus, could provide a useful diagnostic tool in paleopathology. To test this potential we have compared the amino acid analyses of bone samples from a prehistoric Southwest Indian child exhibiting porotic hyperostosis with samples taken from (1) two children's skeletons lacking bone lesions but from the same area and time, (2) a modern child who died from accidental causes, and (3) adult human compact bone. Analytical results of the nonpathological prehistoric specimens were virtually identical to that of the modern infant, indicating remarkable preservation of bone protein. The pathological bone sample differed from the three control specimens by having as much as 25% less of those amino acids containing hydroxyl group and acidic side chains. We interpret the amino acid profile for the diseased child as indicating the presence of a greater proportion of helical protein (or less noncollagenous protein) as well as a lowered degree of hydroxylation of proline and lysine. One explanation for our data is that protein biosynthesis is altered in the child exhibiting porotic hyperostosis, and either some proteins important in the early phases of mineralization are not produced in sufficient quantity, or some necessary enzyme cofactors (e.g., dietary ferrous ions) are missing. We conclude that our data are compatible with, but do not prove, the hypothesis that the porotic hyperostosis exhibited by the Southwest Indian child is the result of iron deficiency anemia.     

EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart

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Porotic hyperostosis: new evidence to support the anemia theory

The etiology of skull lesions known as porotic hyperostosis has long been a matter for speculation. The most widely accepted theory at present suggests that an anemia, either acquired or genetic, is responsible for lesion development. However, acceptance of this theory is not universal and the nature of the relationship between orbital and vault lesions remains a controversial issue. This paper provides a much broader field of supportive evidence on which to base the anemia theory. This involves a synthesis of information from the clinical and anthropological literature as well as new data from two skeletal collections: Poundbury Camp, a Romano-British series, and the Hodgson collection, a 19th century East Asian series. A comparison is made between clinical and anthropological data at the macroscopic, microscopic, radiographic, and demographic levels of analysis. This approach reveals the similarities in expression between clinically diagnosed anemias and porotic hyperostosis.     

中国十个地理品系卤虫同工酶的研究

本文采用聚丙烯酰胺凝胶垂直板电泳法,对中国十个不同地理品系卤虫的十种同工酶进行了研究。分析了编码七种多态酶的19个座位、42个等位基因,用Nei(1972、1975)的方法计算各地理品系卤虫的遗传相似系数、遗传距离和平均杂合度并进行聚类分析。实验和分析结果证明十个不同地理品系的卤虫可分为A.parthenogenetica和有性品系A.sp.两大姊妹种;十种同工酶中三种酶为单态酶,七种为多态酶;雌雄个体无电泳差异。     

Immature erythroid cells with novel morphology and cytoskeletal organization in adultXenopus

Summary Nucleated erythrocytes of non-mammalian vertebrates are a useful model system for studying the correlation between changes in cell shape and cytoskeletal organization during cellular morphogenesis. They are believed to transform from spheres to flattened discs to ellipsoids. Our previous work on developing erythroblasts suggested that pointed cells containing incomplete, pointed marginal bands (MBs) of microtubules might be intermediate stages in the larval axolotl. To test whether the occurrence of such pointed cells was characteristic of amphibian erythrogenesis, we have utilized phenylhydrazine (PHZ)-induced anemia in adultXenopus. In this system, circulating erythrocytes are destroyed and replaced by erythroblasts that differentiate in the blood, making them experimentally accessible. Thus, we followed the time-course of morphological and cytoskeletal changes in the new erythroid population during recovery. During days 7–9 post-PHZ, pointed cells did indeed begin to appear, as did spherical and discoidal cells. The percentage of pointed cells peaked at days 11–13 in different animals, subsequently declining as the percentage of elliptical cells increased. Since degenerating old erythrocytes were still present when pointed cells appeared, we tested directly whether pointed ones were old or new cells. Blood was removed via the dorsal tarsus vein, and the erythrocytes washed, fluorescently tagged, and re-injected. In different animals, 2–8% of circulating erythrocytes were labeled. Subsequent to induction of anemia in these frogs, time-course sampling showed that no pointed cells were labeled, identifying them as new cells. Use of propidium iodide revealed large nuclei and cytoplasmic staining indicative of immaturity, and video-enhanced phase contrast and anti-tubulin immunofluorescence showed that the pointed cells contained pointed MBs. The results show that pointed cells, containing incomplete, pointed MBs are a consistent feature of amphibian erythrogenesis. These cells may represent intermediate stages in the formation of elliptical erythrocytes.Abbreviations MB marginal band - MS membrane skeleton - PHZ phenylhydrazine     

Effect of nickel on red blood cell parameters and on serum vitamin B12, folate and homocysteine concentrations during pregnancy with and without anemia

BackgroundResearch to date suggests that nickel affects not only the metabolism of vitamin B12 but also folates and thus may affect hematopoiesis processes.ObjectiveThe aim of the study was to examine the relationship of nickel (Ni) status to red blood cell (RBC) parameters and serum vitamin B12, folate and homocysteine concentrations in the course of normal pregnancy and in pregnant women with anemia.MethodsThe study included fifty-three pregnant women recruited to the study from the Lower Silesia region of Poland, 17 % of whom developed anemia. Nickel concentration was determined in urine, whole blood and food samples by atomic absorption spectrometry. At the same time as the food and urine samples were taken, blood was also collected for the determination of RBC parameters and serum vitamin B12, homocysteine and folate concentrations.ResultsThe median reported Ni intake, and the urinary and whole blood nickel contents for the studied pregnant women for the first trimester were respectively – 162.46 μg/day, 3.98 μg/L and 3.32 μg/L; for the second trimester – 110.48 μg/day, 6.86 μg/L and 1.04 μg/L; and for the third trimester – 132.20 μg/day, 3.41 μg/L and 0.70 μg/L. With regard to Ni concentration in whole blood (p = 0.0204) and in urine (p = 0.0003), the differences in the values for individual trimesters were statistically significant. The whole blood Ni level was significantly higher (9.28 vs 3.62 μg/L, p = 0.0114), while the concentration of homosysteine was significantly lower (4.09 vs 5.04 μmol/L, p = 0.0165) in pregnant women with anemia compared to those without anemia. The whole blood Ni concentration was negatively correlated with almost all RBC parameters in non-anemic pregnant women.ConclusionsNi status changes with the development of normal pregnancy, and in the case of anemia, an increase in Ni concentration in whole blood is observed. The demonstrated correlations between the Ni status in pregnant women and RBC parameters as well as serum vitamin B12 and folate concentrations suggest that nickel is associated with the methionine–folate cycle, iron homeostasis and bacterial synthesis of vitamin B12 in humans.     

SLX4: multitasking to maintain genome stability

The SLX4/FANCP tumor suppressor has emerged as a key player in the maintenance of genome stability, making pivotal contributions to the repair of interstrand cross-links, homologous recombination, and in response to replication stress genome-wide as well as at specific loci such as common fragile sites and telomeres. SLX4 does so in part by acting as a scaffold that controls and coordinates the XPF–ERCC1, MUS81–EME1, and SLX1 structure-specific endonucleases in different DNA repair and recombination mechanisms. It also interacts with other important DNA repair and cell cycle control factors including MSH2, PLK1, TRF2, and TOPBP1 as well as with ubiquitin and SUMO. This review aims at providing an up-to-date and comprehensive view on the key functions that SLX4 fulfills to maintain genome stability as well as to highlight and discuss areas of uncertainty and emerging concepts.     

Combination of Ascorbate and α-Tocopherol as a Preventive Therapy against Structural and Functional Defects of Erythrocytes in Visceral Leishmaniasis

The redox unbalance in erythrocytes has been found to contribute significantly in the development of anemia in visceral leishmaniasis (VL). The present study revealed enhanced production of reactive oxygen species (ROS) and gradual depletion of α-tocopherol and ascorbate in the erythrocytes of infected animals. The response of erythrocytes to chronic treatment with antioxidants was studied in hamsters during leishmanial infection. Treatment with a combination of α-tocopherol and ascorbate proved to be the most effective preventive for the proteolytic degradation of erythrocyte membrane. Erythrocytes from infected animals were thermally more sensitive compared to the control ones. Combination of both antioxidants was most successful in resisting heat induced structural defects in the cells. Cross-linking of membrane proteins subsequent to oxidative damage in the red cells was accompanied by the formation of high molecular weight protein band at the top of the resolving gel in the presence of the cross-linking agent dimethyladepimidate (DMA). Marked inhibition of cross-linking was observed with combination of both antioxidants. Treatment with α-tocopherol and ascorbate together could withstand osmotic lysis of erythrocytes in the infected animals very efficiently. Decreased hemoglobin (Hb) level was successfully replenished and was coupled with significant increase in the life span of red cells after treating the animals with both antioxidants. Results indicate better efficacy of the combination therapy with α-tocopherol and ascorbate in protecting the erythrocytes from structural and functional damages during leishmanial infection.     

FANCD2, FANCJ and BRCA2 cooperate to promote replication fork recovery independently of the Fanconi Anemia core complex

Fanconi Anemia (FA) is an inherited multi-gene cancer predisposition syndrome that is characterized on the cellular level by a hypersensitivity to DNA interstrand crosslinks (ICLs). To repair these lesions, the FA pathway proteins are thought to act in a linear hierarchy: Following ICL detection, an upstream FA core complex monoubiquitinates the central FA pathway members FANCD2 and FANCI, followed by their recruitment to chromatin. Chromatin-bound monoubiquitinated FANCD2 and FANCI subsequently coordinate DNA repair factors including the downstream FA pathway members FANCJ and FANCD1/BRCA2 to repair the DNA ICL. Importantly, we recently showed that FANCD2 has additional independent roles: it binds chromatin and acts in concert with the BLM helicase complex to promote the restart of aphidicolin (APH)-stalled replication forks, while suppressing the firing of new replication origins. Here, we show that FANCD2 fulfills these roles independently of the FA core complex-mediated monoubiquitination step. Following APH treatment, nonubiquitinated FANCD2 accumulates on chromatin, recruits the BLM complex, and promotes robust replication fork recovery regardless of the absence or presence of a functional FA core complex. In contrast, the downstream FA pathway members FANCJ and BRCA2 share FANCD2's role in replication fork restart and the suppression of new origin firing. Our results support a non-linear FA pathway model at stalled replication forks, where the nonubiquitinated FANCD2 isoform – in concert with FANCJ and BRCA2 – fulfills a specific function in promoting efficient replication fork recovery independently of the FA core complex.