Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix.

The refinement of biomolecular crystallographic models relies on geometric restraints to help to address the paucity of experimental data typical in these experiments. Limitations in these restraints can degrade the quality of the resulting atomic models. Here, an integration of the full all-atom Amber molecular-dynamics force field into Phenix crystallographic refinement is presented, which enables more complete modeling of biomolecular chemistry. The advantages of the force field include a carefully derived set of torsion-angle potentials, an extensive and flexible set of atom types, Lennard-Jones treatment of nonbonded interactions and a full treatment of crystalline electrostatics. The new combined method was tested against conventional geometry restraints for over 22 000 protein structures. Structures refined with the new method show substantially improved model quality. On average, Ramachandran and rotamer scores are somewhat better, clashscores and MolProbity scores are significantly improved, and the modeling of electrostatics leads to structures that exhibit more, and more correct, hydrogen bonds than those refined using traditional geometry restraints. In general it is found that model improvements are greatest at lower resolutions, prompting plans to add the Amber target function to real-space refinement for use in electron cryo-microscopy. This work opens the door to the future development of more advanced applications such as Amber-based ensemble refinement, quantum-mechanical representation of active sites and improved geometric restraints for simulated annealing

Protecting the Brand: Evaluating the Cost of Security Breach from a Marketer’s Perspective

Cyberattacks have increased over the years both at the individual and firm level. Yet, the organizational budgets directed toward information security remains low. One reason is that the ramifications of information breach, such as increased consumer perception of risk and brand equity erosion remain, to the senior executives and board of directors in organizations, almost invisible. The second reason is that managers are required to justify budgets. The cost of system breach is often difficult to quantify. There are direct and enduring costs of information breach. As such, it has implications that impact not just the downtime during a data breach but loss of customers, trust, loyalty and brand equity, all of great concern to marketing managers. This paper analyzes the impact of a breach announcement on the market valuation of the company. Such an analysis using the event study methodology provides a clear indication of how the market reacts to the firm’s breach in information. The results of the study indicate that the market punishes the firm with a small but significant negative abnormal return on the announcement of the breach, and this trend persists. This result, together with the indirect or enduring costs related to brand erosion, provides a good justification to senior executives for protecting the integrity of information, and by so doing, protecting the equity of the brand

Singular limit of Hele-Shaw flow and dispersive regularization of shock waves

We study a family of solutions to the Saffman-Taylor problem with zero surface tension at a critical regime. In this regime, the interface develops a thin singular finger. The flow of an isolated finger is given by the Whitham equations for the KdV integrable hierarchy. We show that the flow describing bubble break-off is identical to the Gurevich-Pitaevsky solution for regularization of shock waves in dispersive media. The method provides a scheme for the continuation of the flow through singularites.Comment: Some typos corrected, added journal referenc

Unstable fingering patterns of Hele-Shaw flows as a dispersionless limit of the KdV hierarchy

We show that unstable fingering patterns of two dimensional flows of viscous fluids with open boundary are described by a dispersionless limit of the KdV hierarchy. In this framework, the fingering instability is linked to a known instability leading to regularized shock solutions for nonlinear waves, in dispersive media. The integrable structure of the flow suggests a dispersive regularization of the finite-time singularities.Comment: Published versio

Age, Growth, Mortality, and Reproduction of Roughtongue Bass, Pronotogrammus martinicensis (Serranidae), in the Northeastern Gulf of Mexico

The inaccessibility of outer continental shelf reefs has made it difficult to investigate the biology of Pronotogrammus martinicensis, a small sea bass known to be numerous and widely distributed in such habitat. This study takes advantage of a series of cruises in the northeastern Gulf of Mexico that collected 1,485 individuals. Fish were collected over or in the vicinity of reef habitats with hook and line, otter trawl, and rotenone. We present a preliminary validation of an otolith ageing method and report that P. martinicensis reached a maximum size of 143 mm standard length (SL), grew to about 50% of this size within their first year, and lived to a maximum age of 15 yr. Size at age data (n = 490) fitted to the von Bertalanffy growth model yielded the predictive equation: SLt = 106.3(1 - e[-0.641{t-0.646}]), where t = age in years. Gonad histology (n = 333) was examined to confirm that P. martinicensis is a protogynous, monandric hermaphrodite. We found no evidence of simultaneous hermaphroditism, which had been tentatively proposed in a previous study. Most P. martinicensis matured as females in their second year (age 1), primary oocytes developed asynchronously into secondary oocytes, and females were batch spawners. Males were postmaturational. Seminiferous tissue formed as early as age 1, but, although the rate of sex change is unknown, most fish did not function as a male until age 3 or age 4. These data provide age-based benchmarks of a common reef fish species living on the outer continental shelf of the tropical western North Atlantic Ocean

Characterization of an electron conduit between bacteria and the extracellular environment

A number of species of Gram-negative bacteria can use insoluble minerals of Fe(III) and Mn(IV) as extracellular respiratory electron acceptors. In some species of Shewanella, deca-heme electron transfer proteins lie at the extracellular face of the outer membrane (OM), where they can interact with insoluble substrates. To reduce extracellular substrates, these redox proteins must be charged by the inner membrane/periplasmic electron transfer system. Here, we present a spectro-potentiometric characterization of a trans-OM icosa-heme complex, MtrCAB, and demonstrate its capacity to move electrons across a lipid bilayer after incorporation into proteoliposomes. We also show that a stable MtrAB subcomplex can assemble in the absence of MtrC; an MtrBC subcomplex is not assembled in the absence of MtrA; and MtrA is only associated to the membrane in cells when MtrB is present. We propose a model for the modular organization of the MtrCAB complex in which MtrC is an extracellular element that mediates electron transfer to extracellular substrates and MtrB is a trans-OM spanning ß-barrel protein that serves as a sheath, within which MtrA and MtrC exchange electrons. We have identified the MtrAB module in a range of bacterial phyla, suggesting that it is widely used in electron exchange with the extracellular environment

Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease.

ObjectiveTo understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.MethodsFifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes.ResultsMRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life.InterpretationNovel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714

Cerebral perfusion in chronic stroke: Implications for lesion-symptom mapping and functional MRI

Lesion-symptom mapping studies are based upon the assumption that behavioral impairments are directly related to structural brain damage. Given what is known about the relationship between perfusion deficits and impairment in acute stroke, attributing specific behavioral impairments to localized brain damage leaves room for speculation, as impairments could also reflect abnormal neurovascular function in brain regions that appear structurally intact on traditional CT and MRI scans. Compared to acute stroke, the understanding of cerebral perfusion in chronic stroke is far less clear. Utilizing arterial spin labeling (ASL) MRI, we examined perfusion in 17 patients with chronic left hemisphere stroke. The results revealed a decrease in left hemisphere perfusion, primarily in peri-infarct tissue. There was also a strong relationship between increased infarct size and decreased perfusion. These findings have implications for lesion-symptom mapping studies as well as research that relies on functional MRI to study chronic stroke

M32+/-1

WFPC-2 images are used to study the central structure of M31, M32, and M33. The dimmer peak, P2, of the M31 double nucleus is centered on the bulge to 0.1", implying that it is the dynamical center of M31. P2 contains a compact source discovered by King et al. (1995) at 1700 A. This source is resolved, with r_{1/2} approx0.2 pc. It dominates the nucleus at 3000 A, and is consistent with late B-early A stars. This probable cluster may consist of young stars and be an older version of the cluster of hot stars at the center of the Milky Way, or it may consist of heavier stars built up from collisions in a possible cold disk of stars orbiting P2. In M32, the central cusp rises into the HST limit with gamma approx0.5, and the central density rho_0>10^7M_sol pc^-3. The V-I and U-V color profiles are flat, and there is no sign of an inner disk, dust, or any other structure. This total lack of features seems at variance with a nominal stellar collision time of 2 X 10^10 yr, which implies that a significant fraction of the light in the central pixel should come from blue stragglers. InM33, the nucleus has an extremely steep gamma=1.49 power-law profile for 0.05"<r<0.2" that becomes shallower as the HST resolution limit is approached. The profile for r<0.04" has either a gamma approx 0.8 cusp or a small core with r_c ~<0.13 pc. The central density is rho_0 > 2 10^6M_sol pc^-3, and the implied relaxation time is only ~3 X 10^6 yr, indicating that the nucleus is highly relaxed. The accompanying short collision time of 7 X 10^9 yr predicts a central blue straggler component quantitatively consistent with the strong V-I and B-R color gradients seen with HST and from the ground.Comment: 44 pages, 22 figures (7 as separate JPEG images), submitted to The Astronomical Journal. Full postscript image available at http://www.noao.edu/noao/staff/lauer/lauer_paper