Direct detection of bound ammonium ions in the selectivity filter of ion channels by solid-state NMR.

The flow of ions across cell membranes facilitated by ion channels is an important function for all living cells. Despite the huge amount of structural data provided by crystallography, elucidating the exact interactions between the selectivity filter atoms and bound ions is challenging. Here, we detect bound 15 N-labeled ammonium ions as a mimic for potassium ions in ion channels using solid-state NMR under near-native conditions. The non-selective ion channel NaK showed two ammonium peaks corresponding to its two ion binding sites, while its potassium-selective mutant NaK2K that has a signature potassium- selective selectivity filter with four ion binding sites gave rise to four ammonium peaks. Ions bound in specific ion binding sites were identified based on magnetization transfer between the ions and carbon atoms in the selectivity filters. Magnetization transfer between bound ions and water molecules revealed that only one out of four ions in the selectivity filter of NaK2K is in close contact with water, which is in agreement with the direct knock-on ion conduction mechanism where ions are conducted through the channel by means of direct interactions without water molecules in between. Interestingly, the potassium-selective ion channels investigated here (NaK2K and, additionally, KcsA-Kv1.3) showed remarkably different chemical shifts for their bound ions, despite having identical amino acid sequences and crystal structures of their selectivity filters. Molecular dynamics simulations show similar ion binding and conduction behavior between ammonium and potassium ions and identify the origin of the differences between the investigated potassium channel

Proposta de metodologia para análise dos grupos econômicos

Este artigo discute importantes questões metodológicas relacionadas ao projeto "Grupos econômicos da indústria brasileira e a política econômica: estrutura, estratégias e desafios", pesquisa conjunta entre o Instituto de Economia da Universidade Estadual de Campinas e a Escola de Administração de Empresas de São Paulo da Fundação Getúlio Vargas (EAESP/FGV). Analisa as estratégias corporativas dos grupos econômicos baseando-se nos conceitos de sinergia, competências básicas e produtos básicos. Aborda também a possibilidade de se construir tipologias úteis para o estudo do controle corporativo e das estratégias de diversificação, tendo como premissa que a gestão dos recursos humanos é um elemento relevante para a compreensão do comportamento estratégico dos grupos

Teleportation of a quantum state of a spatial mode with a single massive particle

Mode entanglement exists naturally between regions of space in ultra-cold atomic gases. It has, however, been debated whether this type of entanglement is useful for quantum protocols. This is due to a particle number superselection rule that restricts the operations that can be performed on the modes. In this paper, we show how to exploit the mode entanglement of just a single particle for the teleportation of an unknown quantum state of a spatial mode. We detail how to overcome the superselection rule to create any initial quantum state and how to perform Bell state analysis on two of the modes. We show that two of the four Bell states can always be reliably distinguished, while the other two have to be grouped together due to an unsatisfied phase matching condition. The teleportation of an unknown state of a quantum mode thus only succeeds half of the time.Comment: 12 pages, 1 figure, this paper was presented at TQC 2010 and extends the work of Phys. Rev. Lett. 103, 200502 (2009

On defining the Hamiltonian beyond quantum theory

Energy is a crucial concept within classical and quantum physics. An essential tool to quantify energy is the Hamiltonian. Here, we consider how to define a Hamiltonian in general probabilistic theories, a framework in which quantum theory is a special case. We list desiderata which the definition should meet. For 3-dimensional systems, we provide a fully-defined recipe which satisfies these desiderata. We discuss the higher dimensional case where some freedom of choice is left remaining. We apply the definition to example toy theories, and discuss how the quantum notion of time evolution as a phase between energy eigenstates generalises to other theories.Comment: Authors' accepted manuscript for inclusion in the Foundations of Physics topical collection on Foundational Aspects of Quantum Informatio

FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.

CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion

Babo1, formerly Vop1 and Cop1/2, is no eyespot photoreceptor but a basal-body protein illuminating cell division in Volvox carteri.

von der Heyde EL, Hallmann A. Babo1, formerly Vop1 and Cop1/2, is no eyespot photoreceptor but a basal-body protein illuminating cell division in Volvox carteri. The Plant journal : for cell and molecular biology. 2020;102(2):276-298.In photosynthetic organisms many processes are light-dependent and sensing of light requires light-sensitive proteins. The supposed eyespot-photoreceptor protein Babo1 (formerly Vop1) has previously been classified as an opsin due to the capacity for binding retinal. Here, we analyze Babo1 and provide evidence that it is no opsin. Due to the localization at the basal bodies, the former Vop1 and Cop1/2 proteins were renamed V.c. Babo1 and C.r. Babo1. We reveal a large family of more than sixty Babo1-related proteins from a wide range of species. The detailed subcellular localization of fluorescence-tagged Babo1 shows that it accumulates at the basal apparatus. More precisely, it is located predominantly at the basal bodies and to a lesser extent at the four strands of rootlet microtubules. We trace Babo1 during basal body separation and cell division. Dynamic structural rearrangements of Babo1 particularly occur right before the first cell division. In four-celled embryos Babo1 was exclusively found at the oldest basal bodies of the embryo and on the corresponding d-roots. The unequal distribution of Babo1 in four-celled embryos could be an integral part of a geometrical system in early embryogenesis, which establishes the anterior-posterior polarity and influences the spatial arrangement of all embryonic structures and characteristics. Due to its retinal-binding capacity, Babo1 could also be responsible for the unequal distribution of retinoids, knowing that such concentration gradients of retinoids can be essential for the correct patterning during embryogenesis of more complex organisms. Thus, our findings push the Babo1 research in another direction. © 2019 The Authors The Plant Journal © 2019 John Wiley & Sons Ltd

ReveaLLAGN 0: First Look at JWST MIRI data of Sombrero and NGC 1052

We present the first results from the Revealing Low-Luminosity Active Galactic Nuclei (ReveaLLAGN) survey, a JWST survey of seven nearby LLAGN. We focus on two observations with the Mid-Infrared Instrument's (MIRI) Medium Resolution Spectrograph (MRS) of the nuclei of NGC 1052 and Sombrero (NGC 4594 / M104). We also compare these data to public JWST data of a higher-luminosity AGN, NGC 7319. JWST clearly resolves the AGN component even in Sombrero, the faintest target in our survey; the AGN components have very red spectra. We find that the emission-line widths in both NGC 1052 and Sombrero increase with increasing ionization potential, with FWHM > 1000 km/s for lines with ionization potential > 50 eV. These lines are also significantly blue-shifted in both LLAGN. The high ionization potential lines in NGC 7319 show neither broad widths or significant blue shifts. Many of the lower ionization potential emission lines in Sombrero show significant blue wings extending > 1000 km/s. These features and the emission-line maps in both galaxies are consistent with outflows along the jet direction. Sombrero has the lowest luminosity high-ionization potential lines ([Ne V] and [O IV]) ever measured in the mid-IR, but the relative strengths of these lines are consistent with higher luminosity AGN. On the other hand, the [Ne V] emission is much weaker relative to the [Ne III}] and [Ne II] lines of higher-luminosity AGN. These initial results show the great promise that JWST holds for identifying and studying the physical nature of LLAGN.Comment: Submitted to Ap

FAN1 modifies Huntington's disease progression by stabilising the expanded HTT CAG repeat

Huntington's disease (HD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the HTT gene. CAG repeat length explains around half of the variation in age-at-onset, but genetic variation elsewhere in the genome accounts for a significant proportion of the remainder. Genome-wide association studies have identified a bidirectional signal on chromosome 15, likely underlain by FAN1 (FANCD2 and FANCI Associated Nuclease 1), a nuclease involved in DNA interstrand cross link repair. Here we show that increased FAN1 expression is significantly associated with delayed age-at-onset and slower progression of HD suggesting FAN1 is protective in the context of an expanded HTT CAG repeat. FAN1 overexpression in human cells reduces CAG repeat expansion in exogenously expressed mutant HTT exon 1, and in patient-derived stem cells and differentiated medium spiny neurons, FAN1 knockdown increases CAG repeat expansion. The stabilising effect is FAN1 concentration and CAG repeat length dependent. We show that FAN1 binds to the expanded HTT CAG repeat DNA and its nuclease activity is not required for protection against CAG repeat expansion. These data shed new mechanistic insights into how the genetic modifiers of HD act to alter disease progression, and show that FAN1 affects somatic expansion of the CAG repeat through a nuclease-independent mechanism. This provides new avenues for therapeutic interventions in HD and potentially other triplet repeat disorders

Attitudes toward cost-conscious care among U.S. physicians and medical students: analysis of national cross-sectional survey data by age and stage of training

Abstract Background The success of initiatives intended to increase the value of health care depends, in part, on the degree to which cost-conscious care is endorsed by current and future physicians. This study aimed to first analyze attitudes of U.S. physicians by age and then compare the attitudes of physicians and medical students. Methods A paper survey was mailed in mid-2012 to 3897 practicing physicians randomly selected from the American Medical Association Masterfile. An electronic survey was sent in early 2015 to all 5,992 students at 10 U.S. medical schools. Survey items measured attitudes toward cost-conscious care and perceived responsibility for reducing healthcare costs. Physician responses were first compared across age groups (30–40 years, 41–50 years, 51–60 years, and > 60 years) and then compared to student responses using Chi square tests and logistic regression analyses (controlling for sex). Results A total of 2,556 physicians (65%) and 3395 students (57%) responded. Physician attitudes generally did not differ by age, but differed significantly from those of students. Specifically, students were more likely than physicians to agree that cost to society should be important in treatment decisions (p < 0.001) and that physicians should sometimes deny beneficial but costly services (p < 0.001). Students were less likely to agree that it is unfair to ask physicians to be cost-conscious while prioritizing patient welfare (p < 0.001). Compared to physicians, students assigned more responsibility for reducing healthcare costs to hospitals and health systems (p < 0.001) and less responsibility to lawyers (p < 0.001) and patients (p < 0.001). Nearly all significant differences persisted after controlling for sex and when only the youngest physicians were compared to students. Conclusions Physician attitudes toward cost-conscious care are similar across age groups. However, physician attitudes differ significantly from medical students, even among the youngest physicians most proximate to students in age. Medical student responses suggest they are more accepting of cost-conscious care than physicians and attribute more responsibility for reducing costs to organizations and systems rather than individuals. This may be due to the combined effects of generational differences, new medical school curricula, students’ relative inexperience providing cost-conscious care within complex healthcare systems, and the rapidly evolving U.S. healthcare system.https://deepblue.lib.umich.edu/bitstream/2027.42/146517/1/12909_2018_Article_1388.pd

The Emergence and Evolution of the Multidimensional Organization

The article discusses multidimensional organizations and the evolution of complex organizations. The six characteristics of multidimensional organizations, disadvantages of the successful organizational structure that is categorized as a multidivisional, multi-unit or M-form, research by the Foundation for Management Studies which suggests that synergies across business divisions can be exploited by the M-form, a team approach to creating economic value, examples of multidimensional firms such as PricewaterhouseCoopers, and a comparison of various organization types including the matrix form are mentioned