Polarization and Charge Transfer in the Hydration of Chloride Ions

A theoretical study of the structural and electronic properties of the chloride ion and water molecules in the first hydration shell is presented. The calculations are performed on an ensemble of configurations obtained from molecular dynamics simulations of a single chloride ion in bulk water. The simulations utilize the polarizable AMOEBA force field for trajectory generation, and MP2-level calculations are performed to examine the electronic structure properties of the ions and surrounding waters in the external field of more distant waters. The ChelpG method is employed to explore the effective charges and dipoles on the chloride ions and first-shell waters. The Quantum Theory of Atoms in Molecules (QTAIM) is further utilized to examine charge transfer from the anion to surrounding water molecules. From the QTAIM analysis, 0.2 elementary charges are transferred from the ion to the first-shell water molecules. The default AMOEBA model overestimates the average dipole moment magnitude of the ion compared with the estimated quantum mechanical value. The average magnitude of the dipole moment of the water molecules in the first shell treated at the MP2 level, with the more distant waters handled with an AMOEBA effective charge model, is 2.67 D. This value is close to the AMOEBA result for first-shell waters (2.72 D) and is slightly reduced from the bulk AMOEBA value (2.78 D). The magnitude of the dipole moment of the water molecules in the first solvation shell is most strongly affected by the local water-water interactions and hydrogen bonds with the second solvation shell, rather than by interactions with the ion.Comment: Slight revision, in press at J. Chem. Phy

Database management and analysis of fisheries in Illinois: Final report, 1 March 1999-28 February 2002

Issued May 2002; F-69-RReport issued on: May 200

Examining \u3cem\u3eDSM\u3c/em\u3e Criteria for Trichotillomania in A Dimensional Framework: Implications for \u3cem\u3eDSM-5\u3c/em\u3e And Diagnostic Practice

Background: Diagnosis of Trichotillomania (TTM) requires meeting several criteria that aim to embody the core pathology of the disorder. These criteria are traditionally interpreted monothetically, in that they are all equally necessary for diagnosis. Alternatively, a dimensional conceptualization of psychopathology allows for examination of the relatedness of each criterion to the TTM latent continuum. Objectives: First, to examine the ability of recently removed criteria (B and C) to identify the latent dimensions of TTM psychopathology, such that they discriminate between individuals with low and high degrees of hair pulling severity. Second, to determine the impact of removing criteria B and C on the information content of remaining diagnostic criteria. Third, to determine the psychometric properties of remaining TTM diagnostic criteria that remain largely unchanged in DSM-5; that is, whether they measure distinct or overlapping levels of TTM psychopathology. Fourth, to determine whether information content derived from diagnostic criteria aid in the prediction of disease trajectory (i.e., can relapse propensity be predicted from criteria endorsement patterns). Method: Statistics derived from Item Response Theory were used to examine diagnostic criteria endorsement in 91 adults with TTM who underwent psychotherapy. Results: The removal of two criteria in DSM-5 and psychometric validity of remaining criteria was supported. Additionally, individual trait parameters were used to predict treatment progress, uncovering predictive power where none previously existed. Conclusions: Diagnostic criteria for TTM should be examined in dimensional models, which allow for nuanced and sensitive measurement of core symptomology in treatment contexts

Financing drug discovery for orphan diseases

Recently proposed ‘megafund’ financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10–20 projects in the portfolio.MIT Laboratory for Financial Engineerin

GCH1 haplotypes and cardiovascular risk in HIV

Heightened systemic inflammation contributes to cardiovascular (CVD) events in people living with HIV (PLWH), though not all PLWH develop CVD, thus suggesting a genetic modifying role. We examined GCH1 polymorphisms, which have been associated with reduced endothelial function in European populations with CVD and increased inflammation, in a racially diverse cohort of U.S. PLWH initiating antiretroviral therapy (ART). GCH1 polymorphisms differed by race and were not associated flow-mediated dilation or carotid intima media thickness before or after 48 weeks of ART

Light-dependent N-end rule-mediated disruption of protein function in Saccharomyces cerevisiae and Drosophila melanogaster

Here we describe the development and characterization of the photo-N-degron, a peptide tag that can be used in optogenetic studies of protein function in vivo. The photo-N-degron can be expressed as a genetic fusion to the amino termini of other proteins, where it undergoes a blue light-dependent conformational change that exposes a signal for the class of ubiquitin ligases, the N-recognins, which mediate the N-end rule mechanism of proteasomal degradation. We demonstrate that the photo-N-degron can be used to direct light-mediated degradation of proteins in Saccharomyces cerevisiae and Drosophila melanogaster with fine temporal control. In addition, we compare the effectiveness of the photo-N-degron with that of two other light-dependent degrons that have been developed in their abilities to mediate the loss of function of Cactus, a component of the dorsal-ventral patterning system in the Drosophila embryo. We find that like the photo-N-degron, the blue light-inducible degradation (B-LID) domain, a light-activated degron that must be placed at the carboxy terminus of targeted proteins, is also effective in eliciting light-dependent loss of Cactus function, as determined by embryonic dorsal-ventral patterning phenotypes. In contrast, another previously described photosensitive degron (psd), which also must be located at the carboxy terminus of associated proteins, has little effect on Cactus-dependent phenotypes in response to illumination of developing embryos. These and other observations indicate that care must be taken in the selection and application of light-dependent and other inducible degrons for use in studies of protein function in vivo, but importantly demonstrate that N- and C-terminal fusions to the photo-N-degron and the B-LID domain, respectively, support light-dependent degradation in vivo

Oligonucleotide compound and method for treating nidovirus infections

A method and oligonucleotide compound for inhibiting replication of a nidovirus in virus-infected animal cells are disclosed. The compound (i) has a nuclease-resistant backbone, (ii) is capable of uptake by the infected cells, (iii) contains between 8-25 nucleotide bases, and (iv) has a sequence capable of disrupting base pairing between the transcriptional regulatory sequences in the 5′ leader region of the positive-strand viral genome and negative-strand 3′ subgenomic region. In practicing the method, infected cells are exposed to the compound in an amount effective to inhibit viral replication

Chest Radiographs Are Valuable in Demonstrating Clinically Significant Pacemaker Complications That Require Reoperation

AbstractPurposeTo evaluate the utility of chest radiography in demonstrating clinically significant pacemaker complications that required reoperation.MethodsIn this retrospective case-controlled series, we identified 14 consecutive adults who required pacemaker reoperation and who had chest radiographs available for review (6 men, 8 women; mean age, 71 years [range, 43–95 years]). Ten patients had pacemakers implanted at our institution, and 4 were referred for reoperation. Forty-two controls, 3 for each patient, had postoperative chest radiographs and normal device function (25 men, 17 women; mean age 76 years [range, 37–96 years]). All postoperative chest radiographs, including 1-year follow-ups, were blindly reviewed by at least 2 of 4 radiologists for lead perforation and position of right atrial and right ventricular leads. Follow-up radiographs were assessed for lead perforation, lead displacement, and lead fracture. Data were analysed by using the Fisher exact test.ResultsOf the patients, 1.7% (10/581) required reoperation for pacemaker dysfunction (noncapture, oversensing, abnormal atrial and ventricular thresholds, failing impedance), extracardiac stimulation, and lead perforation and/or displacement. There were no lead fractures. Chest radiographs demonstrated pacemaker complications in 57% of patients (8/14) at a median of 2 days (<1–32 days) after implantation and in 5% of the controls (2/42) (P < .0001). None of the abnormalities were noted on the official reports. Among subgroups, chest radiographs were abnormal for the following indications: pacemaker dysfunction in 4 of 7 patients versus 0 of 21 controls (P = .0017), extracardiac stimulation in 1 of 3 patients vs 0 of 9 controls (P = .25), and lead perforation and/or displacement in 3 of 4 patients vs 2 of 12 controls (P = .06).ConclusionsChest radiographs are useful after pacemaker placement and demonstrate the majority of complications that require reoperation. Familiarity with the expected normal position of the leads, appearances of pacemaker complications, and comparison with prior radiographs is crucial in rendering a correct diagnosis that guides patient management

Natural History of the Porcine Bioprosthetic Heart Valve

The porcine bioprosthesis has been the prosthetic valve of choice at Henry Ford Hospital since October 1971. By 1979, 23 cases of degeneration had been seen, and the rate seven years after implantation was 16%. Now, with a ten-year follow-up, there are 41 degenerated valves. After seven years, the percent free of degeneration is 88%, (SE of 2% [standard error]); at eight years, 82% (SE of 2.9%,); at nine years, 80% (SE of 3.4%); and at ten years, the percent free of degeneration is 69% (SE of 6.5%,). There was no difference in degeneration between men and women, between aortic or mitral position, or between the valves which were or were not rinsed in antibiotics. The incidence of degeneration was significantly greater in patients under 35 years of age. Contrary to our expectations, the number of valves removed for degeneration has not increased linearly, although the number at risk has continued to rise. In 1977, we removed four valves for degeneration; in 1978, eight valves; in 1979, 77 valves; in 1980, five valves; and in 1981, ten valves. The duration of implantation for degenerated valves has increased from 56 months (SD [standard deviation] of 11 months) in 1977-78 to 77 months (SD of 19 months) in 1981. Analysis of cohorts from 1972,1973, 1974, all now followed for seven years, reveals that at seven years the percent free of degeneration for 1972 is 88% (SE of 4.4%,); for 1973, 83% (SE of 4.8%); and for 1974, 95% (SE of 2.6%). Although a difference is suggested, it is not yet statistically significant (p = .48) due to the small number of valves degenerating. The incidence of porcine bioprosthetic degeneration appears to be decreasing, possibly because valves manufactured later in the series are more durable