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Analyses of genetic variation in many taxa have established that neutral genetic diversity is shaped by natural selection at linked sites. Whether the mode of selection is primarily the fixation of strongly beneficial alleles (selective sweeps) or purifying selection on deleterious mutations (background selection) remains unknown, however. We address this question in humans by fitting a model of the joint effects of selective sweeps and background selection to autosomal polymorphism data from the 1000 Genomes Project. After controlling for variation in mutation rates along the genome, a model of background selection alone explains ~60% of the variance in diversity levels at the megabase scale. Adding the effects of selective sweeps driven by adaptive substitutions to the model does not improve the fit, and when both modes of selection are considered jointly, selective sweeps are estimated to have had little or no effect on linked neutral diversity. The regions under purifying selection are best predicted by phylogenetic conservation, with ~80% of the deleterious mutations affecting neutral diversity occurring in non-exonic regions. Thus, background selection is the dominant mode of linked selection in humans, with marked effects on diversity levels throughout autosomes.

An N-dimensional generalization of Nicholson's equation is analyzed. We consider a model including multiple delays, nonlinear coefficients and a nonlinear harvesting term. Inspired by previous results in this subject, we obtain sufficient conditions to guarantee strong and uniform persistence. Furthermore, under extra suitable hypotheses we prove the existence of T-periodic solutions and, reversing the prior conditions in a convenient manner, we show that the zero is a global attractor., 17 pages, 0 figures

Reverse polarity capillary zone electrophoresis coupled to negative ion mode mass spectrometry (CZE-MS) is shown to be an effective and sensitive tool for the analysis of glycosaminoglycan mixtures. Covalent modification of the inner wall of the separation capillary with neutral or cationic reagents produces a stable and durable surface that provides reproducible separations. By combining CZE-MS with a cation-coated capillary and a sheath flow interface, a rapid and reliable method has been developed for the analysis of sulfated oligosaccharides from dp4 to dp12. Several different mixtures have been separated and detected by mass spectrometry. The mixtures were selected to test the capability of this approach to resolve subtle differences in structure, such as sulfation position and epimeric variation of the uronic acid. The system was applied to a complex mixture of heparin/heparan sulfate oligosaccharides varying in chain length from dp3 to dp12 and more than 80 molecular compositions were identified by accurate mass measurement.

Using a Lyapunov-Krasovskii functional, new results concerning the global stability, boundedness of solutions, existence and non-existence of \begin{document}$ T $\end{document}-periodic solutions for a kind of delayed equation for a \begin{document}$ \varphi $\end{document}-Laplacian operator are obtained. An application is given for the well known sunflower equation.

Fucosylated chondroitin sulfates are complex polysaccharides extracted from sea cucumber. They have been extensively studied for their anticoagulant properties and have been implicated in other biological activities. While nuclear magnetic resonance spectroscopy has been used to extensively characterize fucosylated chondroitin sulfate oligomers, we herein report the first detailed mass characterization of fucosylated chondroitin sulfate using high-resolution Fourier transform ion cyclotron resonance mass spectrometry. The two species of fucosylated chondroitin sulfates considered for this work include Pearsonothuria graeffei (FCS-Pg) and Isostichopus badionotus (FCS-Ib). Fucosylated chondroitin sulfate oligosaccharides were prepared by N-deacetylation-deaminative cleavage of the two fucosylated chondroitin sulfates and purified by repeated gel filtration. Accurate mass measurements obtained from electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry measurements confirmed the oligomeric nature of these two fucosylated chondroitin sulfate oligosaccharides with each trisaccharide repeating unit averaging four sulfates per trisaccharide. Collision-induced dissociation of efficiently deprotonated molecular ions through Na/H+ exchange proved useful in providing structurally relevant glycosidic and cross-ring product ions, capable of assigning the sulfate modifications on the fucosylated chondroitin sulfate oligomers. Careful examination of the tandem mass spectrometry of both species deferring in the positions of sulfate groups on the fucose residue (FCS-Pg-3,4- OS) and (FCS-Ib-2,4- OS) revealed cross-ring products 0,2Aαf and 2,4X2αf which were diagnostic for (FCS-Pg-3,4- OS) and 0,2X2αf diagnostic for (FCS-Ib-2,4- OS). Mass spectrometry and tandem mass spectrometry data acquired for both species varying in oligomer length (dp3-dp15) are presented.

Capillary zone electrophoresis (CZE) paired with mass spectrometry (MS) is a powerful analytical technique for examining mixtures of ionic analytes such as glycosaminoglycans. This study examines the mechanics of the electrospray process for a sheath flow CZE-MS interface under reverse polarity negative ionization conditions. Liquid flow in a sheath flow nano-electrospray CZE-MS interface is driven by two mechanisms, electroosmotic flow and electrospray nebulization. The contribution of these two processes to the overall flow of solution to the electrospray tip is influenced by the surface coatings of the sheath flow emitter tip and by the solvent composition. We have investigated the application of this interface to the reverse polarity separation of glycosaminoglycans and find that the role of electroosmotic flow is far less than has been reported previously, and the electrospray process itself is the largest contributor to the flow of the sheath liquid.

This paper proposes an ω -periodic version of the Ellermeyer model of delayed chemostat. We obtain a sufficient condition ensuring the existence of a positive ω -periodic solution. Our proof is based on the application of the generalized continuation theorem. In addition, as a consequence of the implicit function theorem, we obtain a uniqueness result for sufficiently small delays.

An enzyme- and click chemistry-mediated methodology for the site-specific nitroxide spin labeling of glycoproteins has been developed and applied. The procedure relies on the presence of single N-glycosylation sites that are present natively in proteins or that can be engineered into glycoproteins by mutational elimination of all but one glycosylation site. Recombinantly expressing glycoproteins in HEK293S (GnT1-) cells results in N-glycans with high-mannose structures that can be processed to leave a single GlcNAc residue. This can in turn be modified by enzymatic addition of a GalNAz residue that is subject to reaction with an alkyne-carrying TEMPO moiety using copper (I)-catalyzed Click Chemistry. To illustrate the procedure, we have made an application to a two-domain construct of Robo1, a protein that carries a single N-glycosylation site in its N-terminal domains. The construct has also been labeled with (15)N at amide nitrogens of lysine residues to provide a set of sites that are used to derive an effective location of the paramagnetic nitroxide moiety of the TEMPO group. This, in turn, allowed measurements of paramagnetic perturbations to the spectra of a new high affinity heparan sulfate ligand. Calculation of distance constraints from these data facilitated determination of an atomic level model for the docked complex.

A chemoenzymatic approach has been developed for the preparation of diverse libraries of heparan sulfate (HS) oligosaccharides. It employs chemically synthesized oligosaccharides having a chemical entity at a GlcN residue, which in unanticipated manners influences the site of modification by NST, C5-Epi/2-OST and 6-OST(1)/6-OST(3), thus resulting in oligosaccharides differing in N/O-sulfation and epimerization pattern. The enzymatic transformations defined fine substrate requirements of NST, C5-Epi, 2-OST, and 6-OST.

The stereochemistry of the hexuronic acid residues of the structure of glycosaminoglycans (GAGs) is a key feature that affects their interactions with proteins and other biological functions. Electron-based tandem mass spectrometry methods, in particular electron detachment dissociation (EDD), have been able to distinguish glucuronic acid (GlcA) from iduronic acid (IdoA) residues in some heparan sulfate tetrasaccharides by producing epimer-specific fragments. Similarly, the relative abundance of glycosidic fragment ions produced by collision-induced dissociation (CID) or EDD has been shown to correlate with the type of hexuronic acid present in chondroitin sulfate GAGs. The present work examines the effect of charge state and degree of sodium cationization on the CID fragmentation products that can be used to distinguish GlcA and IdoA containing chondroitin sulfate A and dermatan sulfate chains. The cross-ring fragments 2,4A n and 0,2X n formed within the hexuronic acid residues are highly preferential for chains containing GlcA, distinguishing it from IdoA. The diagnostic capability of the fragments requires the selection of a molecular ion and fragment ions with specific ionization characteristics, namely charge state and number of ionizable protons. The ions with the appropriate characteristics display diagnostic properties for all the chondroitin sulfate and dermatan sulfate chains (degree of polymerization of 4–10) studied.

Small non-autonomous perturbations around an equilibrium of a nonlinear delayed system are studied. Under appropriate assumptions, it is shown that the number of \begin{document}$ T $\end{document} -periodic solutions lying inside a bounded domain \begin{document}$ \Omega\subset \mathbb{R}^{N} $\end{document} is, generically, at least \begin{document}$ |\chi \pm 1|+1 $\end{document} , where \begin{document}$ \chi $\end{document} denotes the Euler characteristic of \begin{document}$ \Omega $\end{document} . Moreover, some connections between the associated fixed point operator and the Poincare operator are explored.

Existence, uniqueness, and multiplicity properties are established via a variational formulation for a Painleve II model subject to radiation boundary conditions in two-ion electrodiffusion. Numerical experiments using an adapted shooting method are also presented to support the theoretical results. © 2013 Elsevier Ltd. All rights reserved.

High mass measurement accuracy of peptides in enzymatic digests is critical for confident protein identification and characterization in proteomics research. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) can provide low or sub-ppm mass accuracy and ultrahigh resolving power. While for ESI-FT-ICR-MS, the mass accuracy is generally 1 ppm or better, with matrix-assisted laser desorption/ionization (MALDI)-FT-ICR-MS, the mass errors can vary from sub-ppm with internal calibration to over 100 ppm with conventional external calibration. A novel calibration method for 15N-metabolically labeled peptides from a batch digest of a proteome is described which corrects for space charge induced frequency shifts in FT-ICR spectra without using an internal calibrant. This strategy utilizes the information from the mass difference between the 14N/15N peptide peak pairs to correct for space charge induced mass shifts after data collection. A procedure for performing the mass correction has been written into a computer program and has been successfully applied to high-performance liquid chromatography-MALDI-FT-ICR-MS measurement of 15N-metabolic labeled proteomes. We have achieved an average measured mass error of 1.0 ppm and a standard deviation of 3.5 ppm for 900 peptides from 68 MALDI-FT-ICR mass spectra of the proteolytic digest of a proteome from Methanococcus maripaludis.

To enrich the dynamics of mathematical models of angiogenesis, all mechanisms involved are time-dependent. We also assume that the tumor cells enter the mechanisms of angiogenic stimulation and inhibition with some delays. The models under study belong to a special class of nonlinear nonautonomous systems with delays. Explicit sufficient and necessary conditions for the existence of the positive periodic solutions were obtained via topological methods. Some open problems are presented for further studies. Fil: Amster, Pablo Gustavo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Matemática; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Investigaciones Matemáticas "Luis A. Santaló"; Argentina Fil: Berezansky, L.. Ben Gurion University Of The Negev; Israel Fil: Idels, L.. Vancouver Island University; Canadá

Electron transfer through gas-phase ion–ion reactions has led to the widespread application of electron-based techniques once only capable in ion trapping mass spectrometers. Although any mass analyzer can, in theory, be coupled to an ion–ion reaction device (typically a 3-D ion trap), some systems of interest exceed the capabilities of most mass spectrometers. This case is particularly true in the structural characterization of glycosaminoglycan (GAG) oligosaccharides. To adequately characterize highly sulfated GAGs or oligosaccharides above the tetrasaccharide level, a high-resolution mass analyzer is required. To extend previous efforts on an ion trap mass spectrometer, negative electron transfer dissociation coupled with a Fourier transform ion cyclotron resonance mass spectrometer has been applied to increasingly sulfated heparan sulfate and heparin tetrasaccharides as well as a dermatan sulfate octasaccharide. Results similar to those obtained by electron detachment dissociation are observed.

We study a parabolic problem arising in Financial Mathematics. Under suitable conditions, we prove the existence and uniqueness of solutions in a general domain using the method of upper and lower solutions and a diagonal argument.

The existence of classical solutions to a one-dimensional non-linear fourth-order elliptic equation arising in quantum semiconductor modeling is proved for a class of non-homogeneous boundary conditions using degree theory. Furthermore, some non-existence results for other classes of boundary conditions are presented. To cite this article: P. Amster et al., C. R. Acad. Sci. Paris, Ser. I 346 (2008).

Perfectionistic people set unrealistic goals and, when they fail to reach them, experience self-criticism and blame. Preliminary research revealed that perfectionism appears to be a characteristic of people who stutter (PWS) (Amster, 1995). The purpose of the present study was to explore perfectionism in PWS and to determine if a modified cognitive behavioral therapy approach alone and combined with Stuttering Modification could help reduce perfectionistic tendencies and stuttering behaviors. Degree of perfectionism and scores of stuttering severity were measured with eight adult PWS and compared at pre-treatment, mid-treatment, after 6-weeks of treatment, and at 15 weeks follow-up, after treatment was withdrawn. Initial open-trial testing showed promising results as perfectionism and stuttering severity were reduced and communication attitudes improved. CBT significantly reduced perfectionism by mid-point. Stuttering decreased significantly throughout all phases of the study. Possible implications are discussed.

Two homopolyesters, poly(neopentyl glycol- alt-isophthalic acid) and poly(hexanediol- alt-azelaic acid), and two copolyesters, poly[dipropoxylated bisphenol-A- alt-(isophthalic acid- co-adipic acid)] and poly[neopentyl glycol- alt-(adipic acid- co-isophthalic acid)] were analyzed by internal-source matrix-assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FT-MS). The high resolution and high mass accuracy provided by FT-MS greatly facilitate the characterization of the polyester and copolyester samples. Isobaric resolution allows the ion abundances of overlapping isotopic envelopes to be assessed. Repeat units were confirmed and end group functionality assigned. Single-shot mass spectra of the entire polymeric distribution demonstrate that the dynamic range of this internal MALDI source instrument and the analyzer cell exceeds the performance previously reported for higher field instruments. Corrections of space–charge mass shift effects are demonstrated for the analytes using an external calibrant and (subsequent to confirmation of structure) using internal calibration, which removes the ambiguity due to space–charge differences in calibrant and analyte spectra. Capillary gel-permeation chromatography was used to prepare low polydispersity samples from a high polydispersity polyester, improving the measurement of molecular weight distribution two-fold while retaining the benefits of high resolution mass spectrometry for elucidation of oligomer identity.

This paper is devoted to the study of the general forced pendulum equation in the presence of friction, u" + a(t)u' + b(t) sin u = f(t) with a, b ∈ C([0, T]) and ƒ ∈ L2(0, T). We apply a Lyapunov-Schmidt reduction in order to obtain T-periodic solutions as zeroes of a 2π-periodic continuous real function under appropriate conditions on a, b and ƒ., Amster Pablo, Mariani Maria Cristina. Periodic solutions of the forced pendulum equation with friction. In: Bulletin de la Classe des sciences, tome 14, n°7-12, 2003. pp. 311-320.

Retained products of conception (POC)—a relatively common finding after vaginal and cesarean delivery as well as termination of pregnancy—is a major diagnostic challenge. Sonohysterography has been shown to diagnose retained POC with nearly a 100% success rate, but has a number of drawbacks including the need for special equipment and considerable operator experience, its invasiveness, and high cost. Ultrasonography is a common part of the gynecologic examination and widely available but has not been useful for diagnosis of retained POC. However, with improved ultrasonographic technology and experience with its use, transvaginal sonographic (TVS) evaluation has shown increasing promise for retained POC diagnosis. The investigators conducted a retrospective chart review to assess the accuracy of an evaluation protocol based on clinical treatment with uterotonics combined with TVS evaluation for the detection of retained POC. The participants were 339 women referred to an obstetrics ultrasound unit because of abnormal bleeding, fever, abdominal pain, or a combination of these symptoms after labor or pregnancy termination. Upon enrollment, all participants underwent a TVS evaluation and were divided into 2 groups: one with negative TVS results and the other with positive results. Patients with negative results were discharged and instructed to return to the hospital if bleeding, abdominal pain, or fever recurred. Those with positive results were treated conservatively with methyl ergometrine for 5 days and reexamined with TVS. Patients with positive results in the second TVS evaluation were referred for curettage and pathological examination of the uterine content. The sensitivity, specificity, and positive and negative predictive values were determined for the total cohort. A total of 269 patients (79.4%, 269/339) were negative for retained POC and were discharged. The remaining 20.6% (70/339) with positive results received conservative treatment with methyl ergometrine and were reeval- uated with TVS. For 33 (47.1%) of the 70 positive patients, the results were negative at the second TVS, leaving 37 patients who remained positive. These 37 positive patients and an additional 2 (0.07%) who had been negative initially but were revaluated because of recurrent bleeding underwent uterine curettage. The sensitivity for identifying retained POC with TVS was 94% and the specificity was 98%; the positive and negative predictive values were 84% and 99%, respectively. These findings indicate that that the proposed protocol provides an accurate and highly sensitive diagnosis of retained POC that may help avoid unnecessary surgery in nearly 50% of women with suspected retained POC after labor or abortion.

Ochroconis gallopavum was identified as the causal agent of fatal encephalitis in a young, short-hair, domestic cat. The cat initially developed an ulcerated mass on the left side of the tongue and signs of pain in the abdomen. The tongue lesion was surgically removed and exploratory abdominal surgery revealed abnormalities suggestive of pancreatitis and peritonitis. During the month after surgery, the cat's health declined, manifested by sluggishness, loss of appetite and abnormal behaviour. Following a final rapid deterioration, the cat became non-responsive and was euthanized. Histologic examination of the brain, lung and mediastinal lymph node lesions revealed large numbers of pigmented, septate, branched, hyphal elements with swollen intercalary and terminal vesicles, and short chains of moniliform hyphal cells. Cultures of the mediastinal lymph nodes yielded a dematiaceous, thermotolerant fungus that was identified as O. gallopavum. This report describes the first well-documented infection in a cat ...

Objectives To conduct a prospective evaluation of the incidence and neonatal outcome of fetuses with persistent right umbilical vein. This condition had traditionally been considered to be extremely rare and to be associated with a very poor neonatal prognosis, but later evidence has raised some doubts about the veracity of these contentions. Methods Between August 1995 and November 1998, 8950 low-risk patients were prospectively evaluated at two medical centers. The sonographic diagnosis of a persistent right umbilical vein was made in a transverse section of the fetal abdomen when the portal vein was curved toward the stomach, and the fetal gall bladder was located medially to the umbilical vein. Results Persistent right umbilical vein was detected in 17 fetuses during the study. Four of them had additional malformations, of which three had been detected antenatally. Conclusions We established that the incidence of persistent right umbilical vein in a low-risk population is 1 : 526. We believe that the sonographic finding of this anomaly is an indication for conducting targeted fetal sonography and echocardiography. When the persistent right umbilical vein is connected to the portal system and other anomalies are ruled out, the prognosis can generally be expected to be favorable.

The structural analysis of sulfated carbohydrates such as glycosaminoglycans (GAGs) has been a long-standing challenge for the field of mass spectrometry. The dissociation of sulfated carbohydrates by collisionally-activated dissociation (CAD) or infrared multiphoton dissociation (IRMPD), which activate ions via vibrational excitation, typically result in few cleavages and abundant SO3 loss for highly sulfated GAGs such as heparin and heparan sulfate, hampering efforts to determine sites of modification. The recent application of electron activation techniques, specifically electron capture dissociation (ECD) and electron detachment dissociation (EDD), provides a marked improvement for the mass spectrometry characterization of GAGs. In this work, we compare ECD, EDD and IRMPD for the dissociation of the highly sulfated carbohydrate sucrose octasulfate (SOS). Both positive and negative multiply-charged ions are investigated. ECD, EDD and IRMPD of SOS produce abundant and reproducible fragmentation. The product ions produced by ECD are quite different than those produced by IRMPD of SOS positive ions, suggesting different dissociation mechanisms as a result of electronic versus vibrational excitation. The product ions produced by EDD and IRMPD of SOS negative ions also differ from each other. Evidence for SO3 rearrangement exists in the negative ion IRMPD data, complicating the assignment of product ions.

Epignathus is a rare, benign, congenital teratoma of the hard palate. Most of these teratomas are unidirectional and protrude through the mouth. Hence, the prognosis depends on the size of the tumor and the degree of face distortion and airway obstruction that it causes. However, some epignathi protrude bidirectionally, involving and destroying the brain tissue, resulting in a poor prognosis. This report presents a case of ultrasonographic detection of a bidirectional epignathus at 15 weeks of pregnancy.

Photoaffinity labeling is used to covalently attach ligands to macromolecules to determine their spatial arrangement and structure. Benzophenone (BP) groups are widely used for covalent photoaffinity labeling and for probing protein interactions. We developed bifunctional BP photoactivatable derivatives using three different general chemical approaches. In addition to the photoaffinity reactivity of the BP, these derivatives contain an additional group: A radioactive tracer for biological studies, or an N-ethylmaleimide group as an additional crosslinker, or a biotin group to be used during purification and characterization of probe-protein complexes using the high-affinity biotin-avidin interaction. A model series of photoaffinity labeling probes was synthesized based on the arbutin ligand. These compounds can be used as probes to study the arbutin binding site of microbial beta-glucoside transporters by photolabeling residues in its vicinity. The second functionality provides additional options for studying proteins and binding sites. The probes were developed using different methodologies: (i) a diazotation reaction; (ii) protecting group methodology; and (iii) solid-phase synthesis. These procedures are general and provide a simple and versatile approach for synthesizing bifunctional BP ligands, as demonstrated here on arbutin.

Chemical tagging of amino acids is an important tool in proteomics analysis, and has been used to introduce isotope labels and mass defect labels into proteolytic peptides by derivatization of cysteine or lysine residues. Here, we present a new reagent with chemical specificity for tryptophan residues. Previously, 2-nitrobenzenesulfenyl chloride has been used as a highly specific reagent for labeling tryptophan residues. We show that this tag undergoes UV dissociation during matrix assisted laser desorption/ionization (MALDI). The multiplicity of photofragments increases the difficulty of characterizing the derivatization products. To overcome this problem, we have synthesized a new reagent, 2-(trifluoromethyl)benzenesulfenyl chloride, which is shown to react quantitatively with tryptophan in peptides and proteins. Most significantly, it exhibits high photostability in MALDI-Fourier transform mass spectrometry analyses.

Epidemiologists have determined that in Mexico most persons with idiopathic pulmonary fibrosis will die within 2 to 3 years of their diagnosis. As physicians, we are left to do the only thing we ca...

This study was undertaken to elucidate whether eating a fermented milk containing Lactobacillus acidophilus La1 and bifidobacteria could induce changes in intestinal flora and modulate the immune response in man. Volunteers consumed a fermented milk containing L. acidophilus La1 and bifidobacteria over a period of three weeks during which an attenuated Salmonella typhi Ty21a was administered to mimic an enteropathogenic infection. A control group ate no fermented foods but received the S. typhi Ty21a. Faecal flora analyses showed an increase in L. acidophilus and bifidobacterial counts during fermented milk intake. The specific serum IgA titre rise to S. typhi Ty21a in the test group was > 4-fold and significantly higher (P = 0.04) than in the control group. An increase in total serum IgA was also observed. These results indicate that lactic acid bacteria which can persist in the gastrointestinal tract can act as adjuvants to the humoral immune response.

Objectives Our purpose was to conduct the first prospective evaluation of the incidence and neonatal outcome of fetuses with persistent right umbilical vein (PRUV). This condition had traditionally been considered to be extremely rare and to forebode grave consequences for the babies, but later evidence raised some doubt upon the veracity of these contentions. Methods Between August 1995 and November 1998, 8950 low-risk patients were prospectively evaluated at two medical centers. The ultrasonographic diagnosis of a persistent right umbilical vein was made in a transverse section of the fetal abdomen when the portal vein was curved toward the stomach and the fetal gallbladder was located medially to the umbilical vein. Results Seventeen cases of fetuses with PRUV were detected during the study period among the 8950 study participants. Four of them had additional malformations of which three had been detected antenatally. Conclusions We established that the incidence of PRUV in a low risk population is 1:526. We believe that the sonographic finding of this anomaly is an indication for conducting targeted fetal sonography and fetal echocardiography. When the PRUV is connected to the portal system and after other anomalies are ruled out, the prognosis can generally be expected to be favorable.