The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation.

Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+-conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+-conductance as the unbound channel. Further, activation kinetics are more sigmoidal, indicating that multiple conformational changes coupled to opening are modulated. Single-channel current amplitudes reveal that each channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1 channels by GxTx results from decreased open probability due to increased occurrence of long-lived closed states; the time constant of the final pore opening step itself is not impacted by GxTx. When intracellular potential is less than 0 mV, GxTx traps the gating charges on Kv2.1's voltage sensors in their most intracellular position. Gating charges translocate at positive voltages, however, indicating that GxTx stabilizes the most intracellular conformation of the voltage sensors (their resting conformation). Kinetic modeling suggests a modulatory mechanism: GxTx reduces the probability of voltage sensors activating, giving the pore opening step less frequent opportunities to occur. This mechanism results in K+-conductance activation kinetics that are voltage-dependent, even if pore opening (the rate-limiting step) has no inherent voltage dependence. We conclude that GxTx stabilizes voltage sensors in a resting conformation, and inhibits K+ currents by limiting opportunities for the channel pore to open, but has little, if any, direct effect on the microscopic kinetics of pore opening. The impact of GxTx on channel gating suggests that Kv2.1's pore opening step does not involve movement of its voltage sensors

A frictionless microswimmer

We investigate the self-locomotion of an elongated microswimmer by virtue of the unidirectional tangential surface treadmilling. We show that the propulsion could be almost frictionless, as the microswimmer is propelled forward with the speed of the backward surface motion, i.e. it moves throughout an almost quiescent fluid. We investigate this swimming technique using the special spheroidal coordinates and also find an explicit closed-form optimal solution for a two-dimensional treadmiler via complex-variable techniques.Comment: 6 pages, 4 figure

Electron impact ionization loading of a surface electrode ion trap

We demonstrate a method for loading surface electrode ion traps by electron impact ionization. The method relies on the property of surface electrode geometries that the trap depth can be increased at the cost of more micromotion. By introducing a buffer gas, we can counteract the rf heating assocated with the micromotion and benefit from the larger trap depth. After an initial loading of the trap, standard compensation techniques can be used to cancel the stray fields resulting from charged dielectric and allow for the loading of the trap at ultra-high vacuum.Comment: 4 pages, 5 eps figures. Shift in focus, minor correction

Building a successful fertility preservation program at a major cancer center

Over 150,000 reproductive age individuals face fertility-threatening cancer treatments each year. Improved detection and treatment of cancer in reproductive-age patients have greatly increased the long-term survival and made it possible for these individuals to consider their long-term quality-of-life after cancer including having biologic offspring. Various methods of fertility preservation (FP) are now available for both males and females. In order to maximize FP options available to patients facing imminent gonadotoxic therapies, it is crucial that women have quick access to FP care and that providers expedite FP strategies. The overarching goal of a clinical FP program is to help patients and their physicians consider the impact of treatment on future fertility and facilitate FP efforts in what is often a limited time period before cancer treatment begins

Does the Robotic Platform Reduce Morbidity Associated With Combined Radical Surgery and Adjuvant Radiation for Early Cervical Cancers?

Open radical hysterectomy followed by adjuvant radiation for cervical cancer has been associated with significant rates of morbidity. Radical hysterectomy is now often performed robotically. We sought to examine if the robotic platform decreased the morbidity associated with radical hysterectomy followed by adjuvant radiation

The effects of radicular dentine treated with double antibiotic paste and ethylenediaminetetraacetic acid on the attachment and proliferation of dental pulp stem cells

Aim This study explored the effects of dentine treated with two concentrations of double antibiotic paste (DAP) and ethylenediaminetetraacetic acid (EDTA) on the attachment and proliferation of dental pulp stem cells (DPSCs). Materials and Methods Radicular dentine samples were prepared with identical dimensions and randomized into six groups (n = 4). Four groups were treated with double antibiotic paste (DAP) at concentrations of 500 mg ml−1 or 1 mg ml−1 with or without EDTA. The other two groups were treated with EDTA only or received no treatment. DPSCs were seeded on each dentine sample (10 000 cells per sample). Lactate dehydrogenase activity assays were used to calculate the attached DPSCs after 1 day of incubation. Water soluble tetrazolium assays were performed to investigate DPSCs proliferation on the treated dentine samples after three additional days of incubation. Two-way anova followed by Tukey–Kramer tests was used for statistical analyses (α = 0.05). Results Dentine treated with 1 or 500 mg ml−1 of DAP followed by EDTA caused significant increases in DPSCs attachment compared to the dentine treated with the DAP alone. The 500 mg ml−1 of DAP with or without EDTA caused significant reductions in DPSCs proliferation. However, the treatment of dentine with 1 mg ml−1 of DAP did not have significant negative effects on DPSCs proliferation regardless of the use of EDTA. Conclusion The use of 1 mg ml−1 of DAP followed by 10 min of irrigation with EDTA in endodontic regeneration procedure may have no negative effects on the attachment and proliferation of DPSCs

Cervical Cancer in Women Aged 35 Years and Younger

AbstractPurposeAge has been evaluated as a prognostic factor in cervical cancer in both hospital- and population-based studies. Results regarding the relation of age and cervical cancer prognosis are conflicting. This study pursued a contemporary assessment of the association of extreme young age at the time of a cervical cancer diagnosis on survival.MethodsInstitutional review board approval was obtained, and retrospective data collection at 2 academic institutions was performed. Inclusion criteria involved women ≤35 years diagnosed with cervical cancer between 1990 and 2012. Data included demographic and prognostic information pertinent to survival and progression. Characteristics of very young (≤25 years) and young (>25–35 years) women were compared. Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards modeling were used to assess the association of age, tumor histology, grade, stage, and parametrial involvement with progression-free survival (PFS) and overall survival (OS).FindingsIncident cases (n = 126) of cervical cancer in patients ≤35 years of age were identified of which complete clinical information was available for 114 women. Fifteen percent (17 of 114) were ≤25 years, with the remaining 85% (97 of 114) being 26 to 35 years of age. Race, smoking status, and marital status were comparable between the 2 groups. Squamous histology dominated overall (77 of 114; 68%) with adenocarcinoma contributing ~25% (30 of 114; 26%) of cases. The majority (96 of 114, 84%) had either stage 1A (31 of 114, 27%) or 1B (65 of 114, 57%) disease. A log-rank test revealed no evidence to infer a difference in either PFS or OS among the age groups (P = 0.511 and P = 0.340). In a univariate analysis, grade and stage significantly affected OS (P < 0.0001, P = 0.045), and stage significantly affected PFS (P < 0.0001). In multivariate modeling, presence of parametrial involvement and histologic cancer type significantly affected both PFS (P = 0.002, P = 0.001) and OS (P = 0.001, P = 0.001).ImplicationsTumor histology, parametrial involvement, and stage continue to be strong prognosticators for PFS and OS. Progression and survival outcomes are age independent in women with cervical cancer ≤35 years of age. Further study of a larger young cohort may potentially yield different outcomes

Predicting Risk of Potentially Preventable Hospitalization in Older Adults with Dementia

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151826/1/jgs16030_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151826/2/jgs16030.pd

Modeling of Tunable Elastic Ultralight Aircraft

Aircraft weight is one of the most critical factors in the design and operation of modern vehicles. The ability to integrate ultra-light materials into the primary load bearing structures has the potential to reduce aircraft weight significantly. Ultralight materials tend to be lattice-based meta-materials that are difficult and computationally expensive to model. One of the advantages of meta-materials is to be able to tune or "program" their bulk material properties through the placement of heterogeneous components in the material. A large amount of time devoted to the simulation in the development time for the tuning of the material can be a barrier to the adoption of large scale lattice materials. In this paper, we present a workflow and analysis tool-set to provide first-order estimates for rapid development of engineered lattice materials for aerospace applications. We present results for estimating the displacement and maximum structural stresses

A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13

A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Rapid Communication. We performed a genome-wide linkage analysis search for a genetic locus responsible for kidney dysfunction in a large family. This inherited condition, characterized by proteinuria, progressive renal insufficiency, and focal segmental glomerulosclerosis, follows autosomal dominant inheritance. We show with a high degree of certainty (maximum 2-point lod score 12.28) that the gene responsible for this condition is located on chromosome 19q13