Allosteric Activation of the Par-6 PDZ Via a Partial Unfolding Transition

Proteins exist in a delicate balance between the native and unfolded states, where thermodynamic stability may be sacrificed to attain the flexibility required for efficient catalysis, binding, or allosteric control. Partition-defective 6 (Par-6) regulates the Par polarity complex by transmitting a GTPase signal through the Cdc42/Rac interaction binding PSD-95/Dlg/ZO-1 (CRIB-PDZ) module that alters PDZ ligand binding. Allosteric activation of the PDZ is achieved by local rearrangement of the L164 and K165 side chains to stabilize the interdomain CRIB:PDZ interface and reposition a conserved element of the ligand binding pocket. However, microsecond to millisecond dynamics measurements revealed that L164/K165 exchange requires a larger rearrangement than expected. The margin of thermodynamic stability for the PDZ domain is modest (∼3 kcal/mol) and further reduced by transient interactions with the disordered CRIB domain. Measurements of local structural stability revealed that tertiary contacts within the PDZ are disrupted by a partial unfolding transition that enables interconversion of the L/K switch. The unexpected participation of partial PDZ unfolding in the allosteric mechanism of Par-6 suggests that native-state unfolding may be essential for the function of other marginally stable proteins

Social Determinants of Health: Underreported Heterogeneity in Systematic Reviews of Caregiver Interventions.

BACKGROUND AND OBJECTIVES:Although most people have some experience as caregivers, the nature and context of care are highly variable. Caregiving, socioeconomic factors, and health are all interrelated. For these reasons, caregiver interventions must consider these factors. This review examines the degree to which caregiver intervention research has reported and considered social determinants of health. RESEARCH DESIGN AND METHODS:We examined published systematic reviews and meta-analyses of interventions for older adults with age-related chronic conditions using the PRISMA and AMSTAR 2 checklists. From 2,707 papers meeting search criteria, we identified 197 potentially relevant systematic reviews, and selected 33 for the final analysis. RESULTS:We found scant information on the inclusion of social determinants; the papers lacked specificity regarding race/ethnicity, gender, sexual identity, socioeconomic status, and geographic location. The majority of studies focused on dementia, with other conditions common in later life vastly underrepresented. DISCUSSION AND IMPLICATIONS:Significant gaps in evidence persist, particularly for interventions targeting diverse conditions and populations. To advance health equity and improve the effectiveness of interventions, research should address caregiver heterogeneity and improve assessment, support, and instruction for diverse populations. Research must identify aspects of heterogeneity that matter in intervention design, while recognizing opportunities for common elements and strategies

Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma.

The standard of care for newly diagnosed glioblastoma (GBM) is surgery, then radiotherapy (RT) with concurrent temozolomide (TMZ), followed by adjuvant TMZ. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT+TMZ, prior to adjuvant TMZ, would have a significantly shorter progression-free (PFS) and overall survival (OS). To test this hypothesis we evaluated 120 patients with newly diagnosed GBM receiving RT+TMZ followed by adjuvant TMZ. MRI was performed after completion of RT+TMZ, prior to initiation of adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 um2/ms and ADCH value of 1.6 um2/ms were used to stratify patients into high and low risk categories. Results suggest patients with low ADCL had significantly shorter PFS (Cox Hazard Ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 vs. 644 days (Cox Hazard Ratio = 0.31, P = 0.047). ADCH was not predictive of PFS or OS when accounting for age and ADCL. In summary, newly diagnosed glioblastoma patients with low ADCL after completion of RT+TMZ are likely to progress and die earlier than patients with higher ADCL. Results suggest ADC histogram analysis may be useful for patient risk stratification following completion of RT+TMZ

Form factor for a family of quantum graphs: An expansion to third order

For certain types of quantum graphs we show that the random-matrix form factor can be recovered to at least third order in the scaled time $\tau$ from periodic-orbit theory. We consider the contributions from pairs of periodic orbits represented by diagrams with up to two self-intersections connected by up to four arcs and explain why all other diagrams are expected to give higher-order corrections only. For a large family of graphs with ergodic classical dynamics the diagrams that exist in the absence of time-reversal symmetry sum to zero. The mechanism for this cancellation is rather general which suggests that it may also apply at higher-orders in the expansion. This expectation is in full agreement with the fact that in this case the linear-$\tau$ contribution, the diagonal approximation, already reproduces the random-matrix form factor for $\tau<1$. For systems with time-reversal symmetry there are more diagrams which contribute at third order. We sum these contributions for quantum graphs with uniformly hyperbolic dynamics, obtaining $+2\tau^{3}$, in agreement with random-matrix theory. As in the previous calculation of the leading-order correction to the diagonal approximation we find that the third order contribution can be attributed to exceptional orbits representing the intersection of diagram classes.Comment: 23 pages (including 4 fig.) - numerous typos correcte

Consecutive wildfires affect stream biota in cold- and warmwater dryland river networks

Citation: Whitney, J. E., Gido, K. B., Pilger, T. J., Propst, D. L., & Turner, T. F. (2015). Consecutive wildfires affect stream biota in cold- and warmwater dryland river networks. Freshwater Science, 34(4), 1510-1526. doi:10.1086/683391Climate change and fire suppression have altered fire regimes globally, leading to larger, more frequent, and more severe wildfires. Responses of coldwater stream biota to single wildfires are well studied, but measured responses to consecutive wildfires in warmwater systems that often include mixed assemblages of native and nonnative taxa are lacking. We quantified changes in physical habitat, resource availability, and biomass of cold- and warmwater oligochaetes, insects, crayfish, fishes, and tadpoles following consecutive megafires (covering >100 km(2)) in the upper Gila River, New Mexico, USA. We were particularly interested in comparing responses of native and nonnative fishes that might have evolved under different disturbance regimes. Changes in habitat and resource availability were related to cumulative fire effects, fire size, and postfire precipitation. The 2nd of 2 consecutive wildfires in the basin was larger and, coupled with moderate postfire discharge, resulted in increased siltation and decreased algal biomass. Several insect taxa responded to these fires with reduced biomass, whereas oligochaete biomass was unaffected. Biomass of 6 of 7 native fish species decreased after the fires, and decreases were associated with site proximity to fire. Nonnative fish decreases after fire were most pronounced for coldwater salmonids, and warmwater nonnative fishes exhibited limited responses. All crayfish and tadpoles collected were nonnative and were unresponsive to fire disturbance. More pronounced responses of native insects and fishes to fires indicate that increasing fire size and frequency threatens the persistence of native fauna and suggests that management activities promoting ecosystem resilience might help ameliorate wildfire effects

Simulator sickness when performing gaze shifts within a wide field of view optic flow environment: preliminary evidence for using virtual reality in vestibular rehabilitation

BACKGROUND: Wide field of view virtual environments offer some unique features that may be beneficial for use in vestibular rehabilitation. For one, optic flow information extracted from the periphery may be critical for recalibrating the sensory processes used by people with vestibular disorders. However, wide FOV devices also have been found to result in greater simulator sickness. Before a wide FOV device can be used in a clinical setting, its safety must be demonstrated. METHODS: Symptoms of simulator sickness were recorded by 9 healthy adult subjects after they performed gaze shifting tasks to locate targets superimposed on an optic flow background. Subjects performed 8 trials of gaze shifting on each of the six separate visits. RESULTS: The incidence of symptoms of simulator sickness while subjects performed gaze shifts in an optic flow environment was lower than the average reported incidence for flight simulators. The incidence was greater during the first visit compared with subsequent visits. Furthermore, the incidence showed an increasing trend over the 8 trials. CONCLUSION: The performance of head unrestrained gaze shifts in a wide FOV optic flow environment is tolerated well by healthy subjects. This finding provides rationale for testing these environments in people with vestibular disorders, and supports the concept of using wide FOV virtual reality for vestibular rehabilitation

Pittsburgh\u27s Mt. Lebanon Tunnels- Case History

Discussions of basic design philosophy and comparison of alternative contract bid options are presented. Also discussed are descriptions of field monitoring activities with respect to the construction methods, ground response, installation of materials and their performance. Finally, conclusions are reached relative to the NATM philosophy as applied to this project and its place as a design process within the context of United States underground construction practice

October 1964

Turf and Lawn Grass Association Better turf through research and Educatio

Form factor for large quantum graphs: evaluating orbits with time-reversal

It has been shown that for a certain special type of quantum graphs the random-matrix form factor can be recovered to at least third order in the scaled time \tau using periodic-orbit theory. Two types of contributing pairs of orbits were identified, those which require time-reversal symmetry and those which do not. We present a new technique of dealing with contribution from the former type of orbits. The technique allows us to derive the third order term of the expansion for general graphs. Although the derivation is rather technical, the advantages of the technique are obvious: it makes the derivation tractable, it identifies explicitly the orbit configurations which give the correct contribution, it is more algorithmical and more system-independent, making possible future applications of the technique to systems other than quantum graphs.Comment: 25 pages, 14 figures, accepted to Waves in Random Media (special issue on Quantum Graphs and their Applications). Fixed typos, removed an overly restrictive condition (appendix), shortened introductory section

Space Environmental Effects on the Optical Properties of Selected Transparent Polymers

Transparent polymer films are currently considered for use as solar concentrating lenses for spacecraft power and propulsion systems. These polymer films concentrate solar energy onto energy conversion devices such as solar cells and thermal energy systems. Conversion efficiency is directly related to the polymer transmission. Space environmental effects will decrease the transmission and thus reduce the conversion efficiency. This investigation focuses on the effects of ultraviolet and charged particle radiation on the transmission of selected transparent polymers. Multiple candidate polymer samples were exposed to near ultraviolet (NUV) radiation to screen the materials and select optimum materials for further study. All materials experienced transmission degradation of varying degree. A method was developed to normalize the transmission loss and thus rank the materials according to their tolerance of NUV. Teflon(Tm) FEP and Teflon(Tm) PFA were selected for further study. These materials were subjected to a combined charged particle dose equivalent to 5 years in a typical geosynchronous Earth orbit (GEO). Results from these NUV screening tests and the 5 year GEO equivalent dose are presented