Microscopic mass estimations

The quest to build a mass formula which have in it the most relevant microscopic contributions is analyzed. Inspired in the successful Duflo-Zuker mass description, the challenges to describe the shell closures in a more transparent but equally powerful formalism are discussed.Comment: 14 pages, 6 figures, submitted to Journal of Physics G, Focus issue on Open Problems in Nuclear Structure Theor

Structural Analysis of the Voltage-Dependent Calcium Channel β Subunit Functional Core and Its Complex with the α1 Interaction Domain

AbstractVoltage-dependent calcium channels (VDCC) are multiprotein assemblies that regulate the entry of extracellular calcium into electrically excitable cells and serve as signal transduction centers. The α1 subunit forms the membrane pore while the intracellular β subunit is responsible for trafficking of the channel to the plasma membrane and modulation of its electrophysiological properties. Crystallographic analyses of a β subunit functional core alone and in complex with a α1 interaction domain (AID) peptide, the primary binding site of β to the α1 subunit, reveal that β represents a novel member of the MAGUK protein family. The findings illustrate how the guanylate kinase fold has been fashioned into a protein-protein interaction module by alteration of one of its substrate sites. Combined results indicate that the AID peptide undergoes a helical transition in binding to β. We outline the mechanistic implications for understanding the β subunit's broad regulatory role of the VDCC, particularly via the AID

HAT-P-11: Discovery of a Second Planet and a Clue to Understanding Exoplanet Obliquities

HAT-P-11 is a mid-K dwarf that hosts one of the first Neptune-sized planets found outside the solar system. The orbit of HAT-P-11b is misaligned with the star's spin --- one of the few known cases of a misaligned planet orbiting a star less massive than the Sun. We find an additional planet in the system based on a decade of precision radial velocity (RV) measurements from Keck/HIRES. HAT-P-11c is similar to Jupiter in its mass ($M_P \sin{i} = 1.6\pm0.1$ $M_J$) and orbital period ($P = 9.3^{+1.0}_{-0.5}$ year), but has a much more eccentric orbit ($e=0.60\pm0.03$). In our joint modeling of RV and stellar activity, we found an activity-induced RV signal of $\sim$7 m s$^{-1}$, consistent with other active K dwarfs, but significantly smaller than the 31 m s$^{-1}$ reflex motion due to HAT-P-11c. We investigated the dynamical coupling between HAT-P-11b and c as a possible explanation for HAT-P-11b's misaligned orbit, finding that planet-planet Kozai interactions cannot tilt planet b's orbit due to general relativistic precession; however, nodal precession operating on million year timescales is a viable mechanism to explain HAT-P-11b's high obliquity. This leaves open the question of why HAT-P-11c may have such a tilted orbit. At a distance of 38 pc, the HAT-P-11 system offers rich opportunities for further exoplanet characterization through astrometry and direct imaging.Comment: 16 pages, 11 figures, 4 tables. Accepted to A

The role of KCNQ1 mutations and maternal beta blocker use during pregnancy in the growth of children with long QT syndrome

Synnynnäinen ionikanavasairaus pitkä QT -oireyhtymä (long QT syndrome, LQTS) on perinnöllinen hengen-vaarallisia rytmihäiriöitä aiheuttava sairaus. LQTS johtuu sydänlihassolujen ionikanavien rakenteita koodaa-vien geenien mutaatioista. Yleisimmät mutaatiot ovat KCNQ1-geenissä, ja ne aiheuttavat sairauden alamuo-don LQT1. KCNQ1 sijaitsee kromosomin 11p15.5 leimautuneella alueella, ja se koodittaa jänniteriippuvaista kaliumkanavaa, Kv7.1:a. Kaksi KCNQ1:n aktivoivaa mutaatiota aiheuttavat autosomaalisesti dominantisti periytyvän kasvuhormonin vajauksen ja äidiltä perittynä ienfibromatoosin. Tutkimuksen tarkoituksena oli analysoida LQTS -potilaiden, joilla on toiminnan hävittävä mutaatio (loss-of-function mutaatio) KCNQ1-geenissä, kasvua ja endokriinisia ominaisuuksia. Keskityimme erityisesti varhaisen kasvun ja parent-of-origin -mutaation suhteeseen. Tutkimuksessa analysoitiin LQT1-potilaiden (n=104) syntymäpituutta ja -painoa, syntymän jälkeistä kasvua ensimmäisen vuoden osalta sekä potilaiden endokriinisia ominaisuuksia. Tutkimuksessa havaittiin, että poti-laat, jotka olivat perineet KCNQ1-mutaation äidiltään, olivat syntymässä lyhyempiä kuin potilaat, jotka olivat perineet mutaation isältään. Jatkoanalyysit osoittivat, että vain potilaat, joiden äidit olivat saaneet beetasal-paajaa raskaana ollessaan, olivat lyhyempiä ja kevyempiä kuin ne potilaat, jotka olivat perineet mutaation isältään. Äidin beetasalpaajan käyttö raskauden aikana oli myös yhteydessä matalampiin napa-TSH-pitoisuuksiin sekä merkittävään saavutuskasvuun ensimmäisen elinvuoden aikana. Myöhemmin eroa ei ha-vaittu. Tutkimuksemme mukaan KCNQ1:n loss-of-function -mutaatiot eivät ole yhteydessä epänormaaliin kasvuun. Sen sijaan analyysiemme mukaan äidin raskauden aikainen beetasalpaajan käyttö näyttää rajoittavan ras-kaudenaikaista LQT1-potilaiden kasvua, mitä seuraa nopea saavutuskasvu ensimmäisen elinvuoden aikaan

Focal Plane Alignment Utilizing Optical CMM

In many applications, an optical detector has to be located relative to mechanical reference points. One solution is to specify stringent requirements on (1) mounting the optical detector relative to the chip carrier, (2) soldering the chip carrier onto the printed circuit board (PCB), and (3) installing the PCB to the mechanical structure of the subsystem. Figure 1 shows a sketch of an optical detector mounted relative to mechanical reference with high positional accuracy. The optical detector is typically a fragile wafer that cannot be physically touched by any measurement tool. An optical coordinate measuring machine (CMM) can be used to position optical detectors relative to mechanical reference points. This approach will eliminate all requirements on positional tolerances. The only requirement is that the PCB is manufactured with oversized holes. An exaggerated sketch of this situation is shown in Figure 2. The sketch shows very loose tolerances on mounting the optical detector in the chip carrier, loose tolerance on soldering the chip carrier to the PCB, and finally large tolerance on where the mounting screws are located. The PCB is held with large screws and oversized holes. The PCB is mounted loosely so it can move freely around. The optical CMM measures the mechanical reference points. Based on these measurements, the required positions of the optical detector corners can be calculated. The optical CMM is commanded to go to the position where one detector corner is supposed to be. This is indicated with the cross-hairs in Figure 2(a). This figure is representative of the image of the optical CMM monitor. Using a suitable tapping tool, the PCB is manually tapped around until the corner of the optical detector is at the crosshairs of the optical CMM. The CMM is commanded to another corner, and the process is repeated a number of times until all corners of the optical detector are within a distance of 10 to 30 microns of the required position. The situation is sketched in Figure 2(b) (the figure also shows the tapping tool and where to tap). At this point the fasteners for the PCB are torqued slightly so the PCB can still move. The PCB location is adjusted again with the tapping tool. This process is repeated 3 to 4 times until the final torque is achieved. The oversized mounting holes are then filled with a liquid bonding agent to secure the board in position (not shown in the sketch). A 10- to 30-micron mounting accuracy has been achieved utilizing this method.

APP Homodimers Transduce an Amyloid-β-Mediated Increase in Release Probability at Excitatory Synapses

SummaryAccumulation of amyloid-β peptides (Aβ), the proteolytic products of the amyloid precursor protein (APP), induces a variety of synaptic dysfunctions ranging from hyperactivity to depression that are thought to cause cognitive decline in Alzheimer’s disease. While depression of synaptic transmission has been extensively studied, the mechanisms underlying synaptic hyperactivity remain unknown. Here, we show that Aβ40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. Aβ40 binds to the APP, increases the APP homodimer fraction at the plasma membrane, and promotes APP-APP interactions. The APP activation induces structural rearrangements in the APP/Gi/o-protein complex, boosting presynaptic calcium flux and vesicle release. The APP growth-factor-like domain (GFLD) mediates APP-APP conformational changes and presynaptic enhancement. Thus, the APP homodimer constitutes a presynaptic receptor that transduces signal from Aβ40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer’s disease

PatientExploreR: an extensible application for dynamic visualization of patient clinical history from electronic health records in the OMOP common data model.

MotivationElectronic health records (EHRs) are quickly becoming omnipresent in healthcare, but interoperability issues and technical demands limit their use for biomedical and clinical research. Interactive and flexible software that interfaces directly with EHR data structured around a common data model (CDM) could accelerate more EHR-based research by making the data more accessible to researchers who lack computational expertise and/or domain knowledge.ResultsWe present PatientExploreR, an extensible application built on the R/Shiny framework that interfaces with a relational database of EHR data in the Observational Medical Outcomes Partnership CDM format. PatientExploreR produces patient-level interactive and dynamic reports and facilitates visualization of clinical data without any programming required. It allows researchers to easily construct and export patient cohorts from the EHR for analysis with other software. This application could enable easier exploration of patient-level data for physicians and researchers. PatientExploreR can incorporate EHR data from any institution that employs the CDM for users with approved access. The software code is free and open source under the MIT license, enabling institutions to install and users to expand and modify the application for their own purposes.Availability and implementationPatientExploreR can be freely obtained from GitHub: https://github.com/BenGlicksberg/PatientExploreR. We provide instructions for how researchers with approved access to their institutional EHR can use this package. We also release an open sandbox server of synthesized patient data for users without EHR access to explore: http://patientexplorer.ucsf.edu.Supplementary informationSupplementary data are available at Bioinformatics online

Characterization of the C-Terminal Nuclease Domain of Herpes Simplex Virus pUL15 as a Target of Nucleotidyltransferase Inhibitors

The natural product α-hydroxytropolones manicol and β-thujaplicinol inhibit replication of herpes simplex viruses 1 and 2 (HSV-1 and HSV-2, respectively) at nontoxic concentrations. Because these were originally developed as divalent metal-sequestering inhibitors of the ribonuclease H activity of HIV-1 reverse transcriptase, α-hydroxytropolones likely target related HSV proteins of the nucleotidyltransferase (NTase) superfamily, which share an “RNase H-like” fold. One potential candidate is pUL15, a component of the viral terminase molecular motor complex, whose C-terminal nuclease domain, pUL15C, has recently been crystallized. Crystallography also provided a working model for DNA occupancy of the nuclease active site, suggesting potential protein–nucleic acid contacts over a region of ∼14 bp. In this work, we extend crystallographic analysis by examining pUL15C-mediated hydrolysis of short, closely related DNA duplexes. In addition to defining a minimal substrate length, this strategy facilitated construction of a dual-probe fluorescence assay for rapid kinetic analysis of wild-type and mutant nucleases. On the basis of its proposed role in binding the phosphate backbone, studies with pUL15C variant Lys700Ala showed that this mutation affected neither binding of duplex DNA nor binding of small molecule to the active site but caused a 17-fold reduction in the turnover rate (kcat), possibly by slowing conversion of the enzyme–substrate complex to the enzyme–product complex and/or inhibiting dissociation from the hydrolysis product. Finally, with a view of pUL15-associated nuclease activity as an antiviral target, the dual-probe fluorescence assay, in combination with differential scanning fluorimetry, was used to demonstrate inhibition by several classes of small molecules that target divalent metal at the active site