A genetic linkage map of human chromosome 21: analysis of recombination as a function of sex and age.

A genetic linkage map of human chromosome 21 has been constructed using 22 anonymous DNA markers and five complementary DNAs (cDNAs) encoding the amyloid beta protein precursor (APP), superoxide dismutase 1 (SOD1), the ets-2 proto-oncogene (ETS2), the estrogen inducible breast cancer locus (BCEI), and the leukocyte antigen, CD18 (CD18). Segregation of RFLPs detected by these DNA markers was traced in the Venezuelan Reference Pedigree (VRP). A comprehensive genetic linkage map consisting of the 27 DNA markers spans 102 cM on the long arm of chromosome 21. We have confirmed our initial findings of a dramatically increased rate of recombination at the telomere in both females and males and of significantly higher recombination in females in the pericentromeric region. By comparing patterns of recombination in specific regions of chromosome 21 with regard to both parental sex and age, we have now identified a statistically significant downward trend in the frequency of crossovers in the most telomeric portion of chromosome 21 with increasing maternal age. A less significant decrease in recombination with increasing maternal age was observed in the pericentromeric region of the chromosome. These results may help in ultimately understanding the physical relationship between recombination and nondisjunction in the occurrence of trisomy 21.     

Adherence of Bilophila wadsworthia to cultured human embryonic intestinal cells

Adherence of Bilophila wadsworthia to the cultured human embryonic intestinal cell line, Intestine 407 (Int 407), varied among the strains tested from strongly adherent (76-100% cells positive for one or more adherent bacteria) to non- or weakly adherent (0-25% positive cells). Although negative staining revealed that infrequent cells of an adherent strain, WAL 9077, the adherent type-strain, WAL 7959, and a non-adherent strain, WAL 8448, expressed loosely associated fimbrial structures, a role for these structures in adhesion could not be confirmed with either scanning or thin-section electron micrography. Ruthenium red staining of thin-section preparations and subsequent electron microscopy failed to reveal an extensive extracellular polysaccharide layer. SDS-PAGE analysis of crude outer membrane fractions of WAL 9077 and WAL 8448 demonstrated clear differences in their major and minor outer membrane protein components. Thus, we postulate that the adherence of B. wadsworthia to Int 407 cells is mediated by an outer membrane or cell wall component.     

Photoperiod-induced differences in uterine growth in Phodopus sungorus are evident at an early age when serum estradiol and uterine estrogen receptor levels are not different

Sexual development is inhibited in Siberian hamsters (Phodopus sungorus) in short days (SD), and a small uterus is an obvious indicator of photo-inhibition. The small uterus in SD is presumably due to the delayed onset of estrous cycles. However, in an earlier study, the investigators reported that serum estradiol (E2) concentration was significantly higher in young females raised in SD than in long days (LD), with the highest concentrations measured in SD at 4 weeks of age. These seemingly contradictory findings were investigated in the present study. First, uterine mass and body mass were measured in SD- and LD-reared hamsters from 1 to 12 weeks of age. Uterine mass was significantly greater in LD than in SD by 3 weeks of age and onward. Thereafter, our investigation focused on 4-week-old hamsters. Serum E2 concentrations in LD and in SD were not significantly different and there were no significant LD–SD differences in uterine estrogen receptors (ER), as measured by immunohistochemistry and quantitative real-time RT-PCR. Therefore, alternative explanations for the photoperiodic difference in uterine size in young Siberian hamsters are considered.     

A unified probabilistic model of the perception of three-dimensional structure from optic flow

Human observers can perceive the three- dimensional (3-D) structure of their environment using various cues, an important one of which is optic flow. The motion of any point’s projection on the retina depends both on the point’s movement in space and on its distance from the eye. Therefore, retinal motion can be used to extract the 3-D structure of the environment and the shape of objects, in a process known as structure-from-motion (SFM). However, because many combinations of 3-D structure and motion can lead to the same optic flow, SFM is an ill-posed inverse problem. The rigidity hypothesis is a constraint supposed to formally solve the SFM problem and to account for human performance. Recently, however, a number of psychophysical results, with both moving and stationary human observers, have shown that the rigidity hypothesis alone cannot account for human performance in SFM tasks, but no model is known to account for the new results. Here, we construct a Bayesian model of SFM based mainly on one new hypothesis, that of stationarity, coupled with the rigidity hypothesis. The predictions of the model, calculated using a new and powerful methodology called Bayesian programming, account for a wide variety of experimental findings.     

Multi-drug resistant Bacteroides fragilis recovered from blood and severe leg wounds caused by an improvised explosive device (IED) in Afghanistan

This report summarizes the case of a 23 year-old otherwise healthy male that was injured in an improvised explosive device (IED) blast in support of Operation Enduring Freedom (OEF). He sustained bilateral open tibia and fibula fractures in the setting of being exposed to water contaminated with raw sewage. Despite long-term carbapenem therapy, the patient's wounds were repeatedly noted to have purulent drainage during surgical debridement and cultures from these wounds were persistently positive for Bacteroides fragilis. Apparent clinical failure persisted despite the addition of metronidazole to his regimen and an eventual trial of tigecycline. Susceptibility testing of the B.?fragilis isolate was performed and resistance to penicillin, clindamycin,metronidazole, cefoxitin, meropenem, imipenem, piperacillin/tazobactam, and tigecycline was confirmed. The presence of a nimE gene on a potentially transferrable plasmid was also confirmed by plasmid sequencing. The only antibiotics that displayed in vitro susceptibility were moxifloxacin and linezolid. These antibiotics were initiated in combination with aggressive irrigation and serial surgical debridement. Conversion to left-sided internal fixation became feasible and his left lower extremity was salvaged without residual evidence of infection. The patient completed an eight week course of combination moxifloxacin and linezolid therapy without adverse event. This B.?fragilis isolate displayed simultaneous high-level resistance to multiple antibiotics routinely utilized in anaerobic infections. This was evidenced by clinical failure, in vitro susceptibility testing, and demonstration of genes associated with resistance mechanisms. This case warrants review not only due to the rarity of this event but also the potential implications regarding anaerobic infections in traumatic wounds and the success of a novel treatment regimen utilizing combination therapy with moxifloxacin and linezolid.     

Soil Bacterial Consortia and Previous Exposure Enhance the Biodegradation of Sulfonamides from Pig Manure

Persistence or degradation of synthetic antibiotics in soil is crucial in assessing their environmental risks. Microbial catabolic activity in a sandy loamy soil with pig manure using 12C- and 14C-labelled sulfamethazine (SMZ) respirometry showed that SMZ was not readily degradable. But after 100 days, degradation in sulfadiazine-exposed manure was 9.2%, far greater than soil and organic manure (0.5% and 0.11%, respectively, p < 0.05). Abiotic degradation was not detected suggesting microbial catabolism as main degradation mechanism. Terminal restriction fragment length polymorphism showed biodiversity increases within 1 day of SMZ spiking and especially after 200 days, although some species plummeted. A clone library from the treatment with highest degradation showed that most bacteria belonged to α, β and γ classes of Proteobacteria, Firmicutes, Bacteroidetes and Acidobacteria. Proteobacteria (α, β and γ), Firmicutes and Bacteroidetes which were the most abundant classes on day 1 also decreased most following prolonged exposure. From the matrix showing the highest degradation rate, 17 SMZ-resistant isolates biodegraded low levels of 14C-labelled SMZ when each species was incubated separately (0.2-1.5%) but biodegradation was enhanced when the four isolates with the highest biodegradation were incubated in a consortium (Bacillus licheniformis, Pseudomonas putida, Alcaligenes sp. and Aquamicrobium defluvium as per 16S rRNA gene sequencing), removing up to 7.8% of SMZ after 20 days. One of these species (B. licheniformis) was a known livestock and occasional human pathogen. Despite an environmental role of these species in sulfonamide bioremediation, the possibility of horizontal transfer of pathogenicity and resistance genes should caution against an indiscriminate use of these species as sulfonamide degraders.     

Expiration rate drives human airway design

Analyses of human airway architecture based on calculations of airflow resistance or energy dissipation suggest that the branching pattern is not optimized for minimizing energy loss by flow dissipation during respiration. Airway flow dissipates only a few percent of the total body work during normal breathing, so branching patterns deviate from minimum energy loss to also optimize other physiological needs. Studies of airway performance often record some measure of expiration, such as FEV1 (Forced Expiratory Volume in 1 s), because airway constriction during expiration limits the rate of rapid respiration. We posit that lung structure is optimized for the rate of expiration as well as minimum energy loss. By increasing the daughter-to-parent airway diameter ratio (h) from 0.794 (corresponding to the energy minimum for symmetrically branching airways) to 0.85 (the observed value in humans) luminal pressures at airway generations 4-15 were substantially increased during exercise (a 4.5 and 15 cmH₂O increase during moderate and heavy exercise, respectively). Values of h somewhat larger than 0.794 help airways remain open during expiration by increasing both viscous pressure drop and convective acceleration pressure drop. Asymmetric bifurcations also exhibit higher proximal airway pressures than symmetric ones, but the improvement was not large.     

Potent P1' biphenylmethyl substituted aggrecanase inhibitors.

A series of cis-1(S)2(R)-amino-2-indanol based compounds with a biphenylmethyl group at the P1' position was found to be potent aggrecanase inhibitors. Both compounds 2j and 2n possessed very high aggrecanase affinity (IC(50)=1.5nM), and showed excellent selectivity over MMP-1 and MMP-9, with moderate selectivity against MMP-2.     

5-Amidinobenzo[b]thiophenes as dual inhibitors of factors IXa and Xa

Syntheses and SAR studies of 5-amidinobenzo[b]thiophene analogs provided compounds with low submicromolar factor IXa activity and equal or slightly better selectivity relative to factor Xa.