Separating significant matches from spurious matches in DNA sequences

Word matches are widely used to compare genomic sequences. Complete genome alignment methods often rely on the use of matches as anchors for building their alignments, and various alignment-free approaches that characterize similarities between large sequences are based on word matches. Among matches that are retrieved from the comparison of two genomic sequences, a part of them may correspond to spurious matches (SMs), which are matches obtained by chance rather than by homologous relationships. The number of SMs depends on the minimal match length (?) that has to be set in the algorithm used to retrieve them. Indeed, if ? is too small, a lot of matches are recovered but most of them are SMs. Conversely, if ? is too large, fewer matches are retrieved but many smaller significant matches are certainly ignored. To date, the choice of ? mostly depends on empirical threshold values rather than robust statistical methods. To overcome this problem, we propose a statistical approach based on the use of a mixture model of geometric distributions to characterize the distribution of the length of matches obtained from the comparison of two genomic sequences.     

Perception of color and volumetric shape of objects]

The problem of recognition of coloration of volume objects, illuminated simultaneously with bright point ans weak diffuse sources (having arbirary and previously unknown spectra) is considered. A mathematical model, in which a process of recognition of coloration is accompanied by determining orientations of surface elements relatively the point source is described. The information on orientation allows in many cases to calculate the volume shape of objects of the external world form their monocular "retinal" image.     

西花蓟马对花卉寄主颜色和挥发物的选择性

【目的】探究寄主颜色、挥发物在西花蓟马Frankliniella occidentalis(Pergande)寄主选择中的作用。【方法】采用叶碟法和Y型嗅觉仪法,测定了西花蓟马对4种寄主(黄花美人蕉、黄花槐、凤尾兰和夹竹桃)的颜色和挥发物的选择性。【结果】颜色选择中,西花蓟马最偏好夹竹桃的叶,黄花槐和黄花美人蕉的花;对叶、花总的偏好性次序为黄花美人蕉(花)、黄花槐(花)>凤尾兰(花)>黄花美人蕉(叶)、夹竹桃(叶)>黄花槐(叶)、凤尾兰(叶)、夹竹桃(花)。挥发物选择中,与空气对照时,西花蓟马都显著偏好寄主的叶和花;叶相互对照中,最为偏好黄花美人蕉和黄花槐;花相互对照中,最为偏好黄花美人蕉;叶与花对照时,西花蓟马对花的偏好性显著强于叶,其对寄主叶、花挥发物总的偏好性为黄花美人蕉(花)>黄花槐(花)>凤尾兰(花)>夹竹桃(花)>黄花美人蕉(叶)≥黄花槐(叶)、夹竹桃(叶)>凤尾兰(叶),与其对颜色的偏好性并不完全一致。【结论】寄主颜色和挥发物对西花蓟马的寄主选择有着重要影响,西花蓟马不仅对不同寄主的颜色和挥发物有不同偏好性,对寄主不同器官的颜色和挥发物也具有不同的偏好性。     

Perception of sound-source motion by the human brain

We assessed the human brain network for sound-motion processing using the same virtual stimulus in three independent functional imaging experiments. All experiments show a bilateral posterior network of activation, including planum temporale (PT) and parieto-temporal operculum (PTO). This was demonstrated in contrasts between sound movement and two control conditions: externalized stationary stimuli (in the midline or to the side of the head) and midline sounds within the head with similar spectro-temporal structure. We suggest specific computational mechanisms in PT for disambiguation of the intrinsic spectro-temporal features of a sound and the spectro-temporal effect of sound movement. The results support the existence of a posteriorly directed temporo-parietal pathway for obligatory perceptual processing of sound-source motion.     

Stereoisomeric selectivity of human deoxyribonucleoside kinases

Deoxynucleoside kinases catalyze the 5'-phosphorylation of 2'-deoxyribonucleosides with nucleoside triphosphates as phosphate donors. One of the cellular kinases, deoxycytidine kinase (dCK), has been shown to phosphorylate several L-nucleosides that are efficient antiviral agents. In this study we investigated the potentials of stereoisomers of the natural deoxyribonucleoside to serve as substrates for the recombinant cellular deoxynucleoside kinases. The cytosolic thymidine kinase exhibited a strict selectivity and phosphorylated only beta-D-Thd, while the mitochondrial thymidine kinase (TK2) and deoxyguanosine kinase (dGK) as well as dCK all had broad substrate specificities. TK2 phosphorylated Thd and dCyd stereoisomers in the order: beta-D- > or = beta-L- > alpha-D- > or = alpha-L-isomer. dCK activated both enantiomers of beta-dCyd, beta-dGuo, and beta-dAdo with similar efficiencies, and alpha-D-dCyd also served as a substrate. dGK phosphorylated the beta-dGuo enantiomers with no preference for the ribose configuration; alpha-L-dGuo was also phosphorylated, and beta-L-dAdo and beta-L-dCyd were substrates but showed reduced efficiencies. The anomers of the 2',3'-dideoxy-D-nucleosides (ddNs) were tested, and TK2 and dCK retained their low selectivities. Unexpectedly, alpha-dideoxycytidine (ddC) was a 3-fold better substrate for dCK than beta-ddC. Similarly, alpha-dideoxythymidine (ddT) was a better substrate for TK2 than beta-ddT. dGK did not accept any D-ddNs. Thus, TK2, dCK, and dGK, similar to herpes simplex virus type 1 thymidine kinase (HSV-1 TK), showed relaxed stereoselectivities, and these results substantiate the functional similarities within this enzyme family. Docking simulations with the Thd isomers and the active site of HSV-1 TK showed that the viral enzyme may in some respects serve as a model for studying the substrate specificities of the cellular enzymes.     

Structural selectivity of human SGLT inhibitors

Human Na(+)-D-glucose cotransporter (hSGLT) inhibitors constitute the newest class of diabetes drugs, blocking up to 50% of renal glucose reabsorption in vivo. These drugs have potential for widespread use in the diabetes epidemic, but how they work at a molecular level is poorly understood. Here, we use electrophysiological methods to assess how they block Na(+)-D-glucose cotransporter SGLT1 and SGLT2 expressed in human embryonic kidney 293T (HEK-293T) cells and compared them to the classic SGLT inhibitor phlorizin. Dapagliflozin [(1S)-1,5,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol], two structural analogs, and the aglycones of phlorizin and dapagliflozin were investigated in detail. Dapagliflozin and fluoro-dapagliflozin [(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-4-F-4-deoxy-D-glucitol] blocked glucose transport and glucose-coupled currents with ≈100-fold specificity for hSGLT2 (K(i) = 6 nM) over hSGLT1 (K(i) = 400 nM). As galactose is a poor substrate for SGLT2, it was surprising that galacto-dapagliflozin [(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-galactitol] was a selective inhibitor of hSGLT2, but was less potent than dapagliflozin for both transporters (hSGLT2 K(i) = 25 nM, hSGLT1 K(i) = 25,000 nM). Phlorizin and galacto-dapagliflozin rapidly dissociated from SGLT2 [half-time off rate (t(1/2,Off)) ≈ 20-30 s], while dapagliflozin and fluoro-dapagliflozin dissociated from hSGLT2 at a rate 10-fold slower (t(1/2,Off) ≥ 180 s). Phlorizin was unable to exchange with dapagliflozin bound to hSGLT2. In contrast, dapagliflozin, fluoro-dapagliflozin, and galacto-dapagliflozin dissociated quickly from hSGLT1 (t(1/2,Off) = 1-2 s), and phlorizin readily exchanged with dapagliflozin bound to hSGLT1. The aglycones of phlorizin and dapagliflozin were poor inhibitors of both hSGLT2 and hSGLT1 with K(i) values > 100 μM. These results show that inhibitor binding to SGLTs is composed of two synergistic forces: sugar binding to the glucose site, which is not rigid, and so different sugars will change the orientation of the aglycone in the access vestibule; and the binding of the aglycone affects the binding affinity of the entire inhibitor. Therefore, the pharmacophore must include variations in both the structure of the sugar and the aglycone.     

Hemispheric difference in human skin color

Previous studies of human skin color have shown a strong relationship between skin color and distance from the equator, which has been interpreted as a link between skin color, latitude, and the intensity of ultraviolet radiation. The underlying assumptions are that UV radiation is greatest at the equator and that it diminishes with increasing latitude to the same extent in both the Northern and Southern Hemispheres. The standard analysis of human skin color is based on these assumptions, such that skin color is assumed to be darkest at the equator, and the decrease of skin color with latitude is assumed to be the same in both hemispheres. A nonlinear piecewise regression model was developed to test these assumptions and applied to mean skin reflectance data from 102 male samples and 65 female samples from across the Old World. For both males and females, skin reflectance (%) is lowest at the equator (darkest skin). Among males, skin reflectance increases roughly 8.2% for every 10 degrees of latitude in the Northern Hemisphere but only 3.3% for every 10 degrees of latitude in the Southern Hemisphere. Among females, the corresponding numbers are 8.1% in the Northern Hemisphere and 4.7% in the Southern Hemisphere. These results indicate that human skin color is darker in the Southern Hemisphere than in the Northern Hemisphere at equivalent latitude. Recent research shows that UV radiation is higher in the Southern Hemisphere than in the Northern Hemisphere at similar latitude. This difference, relating to astronomical and climatic conditions, may have existed in the past at different times and perhaps influenced the evolution of human skin color. Am J Phys Anthropol 104:449–457, 1997. © 1997 Wiley-Liss, Inc.     

Perception of time by human consciousness

The paper presents a survey of 79 publications dedicated to tasks of chronobiology, to significance of studies of time perception by human consciousness, to ideas of the mechanisms of the time perception, of the role of sleep in regulation of temporal relations, techniques of studies of the time perception (including the Author's own), as well as the results of studying the perception of time intervals duration by humans and effects of environments and mental state on this perception; intuitive and logical estimations of the time properties are also considered.     

The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin

Human lactoferrin (hLF) is an iron-binding glycoprotein involved in the host defence against infection and excessive inflammation. As the availability of (human milk-derived) natural hLF is limited, alternative means of production of this biopharmaceutical are extensively researched. Here we report the crystal structure of recombinant hLF (rhLF) expressed in the milk of transgenic cows at a resolution of 2.4 Å. To our knowledge, the first reported structure of a recombinant protein produced in milk of transgenic livestock. Even though rhLF contains oligomannose- and hybrid-type N-linked glycans next to complex-type glycans, which are the only glycans found on natural hLF, the structures are identical within the experimental error (r.m.s. deviation of only 0.28 Å for the main-chain atoms). Of the differences in polymorphic amino acids between the natural and rhLF variant used, only the side-chain of Asp⁵⁶¹ could be modeled into the rhLF electron density map. Taken together, the results confirm the structural integrity of the rhLF variant used in this study. It also confirms the validity of the transgenic cow mammary gland as a vehicle to produce recombinant human proteins.Ellen A. J. Thomassen, Harrie A. van Veen - These authors have contributed equally to this paper.The PDB-code of recombinant human lactoferrin is 2BJJ     

Metabolism and selectivity of arabinonucleoside in human lymphoid cells

The selective toxicity of purine deoxynucleosides against lymphoid cells appears to be mediated by a preferential accumulation of the corresponding triphosphates in these cells. We report a study of the metabolism and toxicity of arabinonucleosides of guanine and cytosine toward human T- and B-lymphoblastoid-cell lines. Both compounds inhibited the growth of T lymphoblasts at concentrations less than 2 microM. However, only ara-G exhibited a strong selectivity for T lymphocytes as indicated by a 100-fold greater toxicity to T than B cells. ara-G is not significantly degraded to guanine but is metabolized to the triphosphate. In common with the other arabinonucleoside, cytotoxicity by ara-G was associated with specific inhibition of DNA synthesis in cells. The capacity of T cells (CCRF-CEM) to accumulate ara-GTP was dependent primarily on deoxycytidine kinase. The level of intracellular ara-GTP accumulated after incubation with the corresponding nucleoside was 20- to 40-fold higher in T cells than either of two B-lymphoblast-cell lines, WI-L2 or PF-2S. The levels of phosphorylating activity for ara-C in extracts of T- and B-cell lines were approximately equal; in contrast, ara-G phosphorylating activity was four- to fivefold higher in B lymphoblasts. After removal of arabinonucleosides from the culture medium, ara-GTP levels in B lymphoblasts declined at a rate that was two to four times faster than that of ara-CTP. In marked contrast, no catabolism of the arabinonucleoside triphosphates was detected in T lymphoblasts. These results suggest that the selectivity of arabinonucleosides to human lymphoid cells of various phenotypes can be correlated with their nucleotide metabolism. The selectivity of ara-G for T and B cells can be correlated with their differential ability to catabolize ara-GTP.     

Physiologic rate of carrier-mediated Ca2+ entry matches active extrusion in human erythrocytes.

The intracellular Ca2+ concentration of nearly all cells is kept at submicromolar levels. The magnitudes of transmembrane Ca2+ movement that maintain this steady state in the human red blood cell have long been debated. Although there is agreement that the physiologic extrusion of Ca2+ by the well-characterized Ca2+. ATPase amounts to 45 mumol/liter cells per h (1982. Nature (Lond.). 298:478-481), the reported passive entry rates in physiological saline (2-20 mumol/liter cells per h) are all substantially lower. This discrepancy could be due to incomplete inhibition of the pump in the previous measurements of Ca2+ entry. We therefore examined both rate and mechanism of entry after completely inactivating the pump. This required pretreatment with iodoacetamide (to lower the intracellular ATP concentration) and vanadate (to inhibit any residual Ca2+ pump activity). The rate of Ca2+ entry (53 mumol/liter cells per h) was now found to be comparable to the accepted extrusion rate. Entry closely obeyed Michaelis-Menten kinetics (Vmax = 321 +/- 17 nmol Ca/g dry wt per h, Km = 1.26 +/- 0.13 mM), was competitively inhibited by external Sr2+ (Ki = 10.8 +/- 1.2 mM), and was accelerated by intracellular Ca2+. 45Ca2+ efflux from these pump-inactivated cells was also accelerated by either external Ca2+ or Sr2+. These accelerating effects of divalent cations on the opposite (trans) face of the membrane rule out a simple channel. Substrate-gated channels are also ruled out: cells equilibrated with 45Ca2+ lost the isotope when unlabeled Ca2+ or Sr2+ was added externally. Thus, passive Ca2+ movements occur predominantly by a reversible carrier-mediated mechanism for which Sr2+ is an alternate substrate. The carrier's intrinsic affinity constants for Ca2+ and Sr2+, 1.46 and 0.37 mM-1, respectively, indicate that Ca2+ is the preferred substrate.     

Genetic matches and the logic of the law

In a recent article Levine and Kobilinsky (1997) point out that current methods in forensic DNA 'identification' are inadequate because the commercial kits commonly used in forensic practice do not detect the true genotype, but rather a genotype based on convenient categorization. For this reason, Levine and Kobilinsky argue that statistics attached to such categorizations are invalid. The authors believe that the arguments of Levine and Kobilinsky are logically flawed. This revised version was published online in July 2006 with corrections to the Cover Date.     

Variations in the anterior patellar groove of the human femur

An analysis of the anterior patellar groove of the human femur shows considerable variation in its medial and lateral spects. The groove itself, measured by the angle it encloses, shows considerably less variation than its individual components. The suggested functional relationship between bicondylar angle and lateral elevation of the patellar groove does not obtain for this sample.     

The modes of the anterior hypothalamic area as the regulatory center for the gonadotropin release

The effects of the anterior hypothalamic area (AHA) implants of gonadal steroid estrogen and progesterone as well as the effects of electrical stimulation and electrolytic lesion confined in this area on the gonadotropin secretion were investigated in ovariectomized estradiol (20 microgram sc)-primed adult Wistar rats housed in light and temperature controlled room. Progesterone implants evoked the rise of serum LH by 6 hr whereas estradiol implants suppressed serum FSH by 24 hr after implantation. Electrical stimulation effectively depleted both gonadotropins with a latency not shorter than 6 hr. The lesion significantly prevented FSH elevation investigated at 72 hr post ovariectomy and potentiated FSH secretion in response to estradiol treatment at 3 week post ovariectomy. The result revealed the involvment of the AHA in LH release mechanism which required progesterone activation while its involvement in FSH regulatory mechanism depended upon estrogen. The area was elucidated as the inhibitory as well as the stimulatory loci for the feedback action of estrogen on FSH release.     

Ionic selectivity of volume-sensitive currents in human epithelial cells.

The ion selectivity of swelling-activated Cl- currents has been investigated in three different human epithelial cell lines, two derived from the airway epithelium (9HTEo- and CFNPE9o-) and one from a colon carcinoma (T84). The relative permeability of volume-sensitive currents with respect to Cl- is: I- (1.19) greater than NO3- (1.07) approximately Br-(1.05) greater than Cl-(1.0) greater than F-(0.5) approximately HCO3-(0.48) greater than isethionate(0.28) greater than aspartate (0.14) approximately gluconate(0.13) approximately SO4(2-)(0.12). This type of ion selectivity is similar to that described for depolarization-activated outwardly rectifying Cl- channels found in epithelial cells.