Identification of transmembrane domains that regulate spatial arrangements and activity of prokineticin receptor 2 dimers

The chemokine prokineticin 2 (PK2) activates its cognate G protein-coupled receptor (GPCR) PKR2 to elicit various downstream signaling pathways involved in diverse biological processes. Many GPCRs undergo dimerization that can modulate a number of functions including membrane delivery and signal transduction. The aim of this study was to elucidate the interface of PKR2 protomers within dimers by analyzing the ability of PKR2 transmembrane (TM) deletion mutants to associate with wild type (WT) PKR2 in yeast using co-immunoprecipitation and mammalian cells using bioluminescence resonance energy transfer. Deletion of TMs 5-7 resulted in a lack of detectable association with WT PKR2, but could associate with a truncated mutant lacking TMs 6-7 (TM1-5). Interestingly, TM1-5 modulated the distance, or organization, between protomers and positively regulated Gαs signaling and surface expression of WT PKR2. We propose that PKR2 protomers form type II dimers involving TMs 4 and 5, with a role for TM5 in modulation of PKR2 function

Quantum spin Hall effect in bound states in continuum

Moving the polarization of the incident wave along a meridian of the Poincaré sphere, experimentally we show that the coupling with the fundamental Bloch's surface waves of the mode, provide a spatially coherent, macroscopic spinmomentum locked propagation along the symmetry axes of the PhCM. This novel mechanism of light-spin manipulation enables a versatile implementation of spin-optical structures that may pave the way to novel strategies for light spin technology and photonic multiplatform implementations

The rate of CD4 decline as a determinant of progression to AIDS independent of the most recent CD4 count

The data of two cohort studies of HIV-infected individuals were used to examine whether the rate of CD4 decline is a determinant of HIV progression, independent of the most recent CD4 count. Time from seroconversion to clinical AIDS was the main outcome measure. Rates of CD4 decline were estimated using the ordinary least squares regression method. AIDS incidences were compared in individuals who had previously experienced either a steeper or a less steep rate of CD4 decline. Cox proportional hazards model including a time-dependent covariate for the rate of CD4 decline was performed. The rate of prior CD4 decline was significantly associated with the risk of developing AIDS independently from the most recent CD4 count, with a 2 % increase in hazard of AIDS (P < 0.01) for a difference of 10 cells/mm(3) in the estimated yearly drop in CD4 count. This finding gives scientific credit to the belief that individuals with a prior steeper CD4 decline consistently have a higher subsequent risk of developing AIDS than those with a less steep prior decline

Soft X-ray emission lines from a relativistic accretion disk in MCG-6-30-15 and Mrk 766

XMM-Newton Reflection Grating Spectrometer (RGS) spectra of the Narrow Line Seyfert 1 galaxies MCG -6-30-15 and Mrk 766 are physically and spectroscopically inconsistent with standard models comprising a power-law continuum absorbed by either cold or ionized matter. We propose that the remarkably similar features detected in both objects in the 5-35 Angstrom band are H-like oxygen, nitrogen, and carbon emission lines, gravitationally redshifted and broadened by relativistic effects in the vicinity of a Kerr black hole. We discuss the implications of our interpretation, and demonstrate that the derived parameters can be physically self-consistent

Association of drusen deposition with choroidal intercapillary pillars in the aging human eye

PURPOSE. To determine the pattern of drusen accumulation with age and to investigate the initial sites of deposition and their relationship to choroidal capillaries in human donor eyes from the eye bank of Moorfields Eye Hospital.METHODS. Wholemounted, hydrated preparations of the choriocapillaris and Bruch's membrane from donor eyes ranging from 42 to 95 years, with or without retinal pigment epithelium (RPE), were examined by conventional and confocal microscopy. Drusen were visualized by their autofluorescence.RESULTS. In all age groups studied autofluorescent drusen were present at the equator but were not found centrally where the vascular architecture is different, being tubular rather than a honeycomb pattern. Autofluorescing drusen were strongly associated with the lateral walls of the choriocapillaris (an area commonly known as the intercapillary pillars of the choriocapillaris (P = 0.028; Wilcoxon signed ranks test). Nonfluorescing drusen were occasionally seen centrally, but were not easily identified, and because of their large size, their localization with respect to capillary walls was not possible.CONCLUSIONS. These results strongly support the notion that autofluorescent drusen are not randomly distributed and have a specific spatial relationship to choroidal vessel walls. That equatorial drusen fluoresce, whereas central drusen do not, suggests that they may have different chemical compositions at the two sites and possibly different significance in age-related macular disease

Altered expression of the voltage-gated calcium channel subunit α2δ-1: a comparison between two experimental models of epilepsy and a sensory nerve ligation model of neuropathic pain.

The auxiliary α2δ-1 subunit of voltage-gated calcium channels is up-regulated in dorsal root ganglion neurons following peripheral somatosensory nerve damage, in several animal models of neuropathic pain. The α2δ-1 protein has a mainly presynaptic localization, where it is associated with the calcium channels involved in neurotransmitter release. Relevant to the present study, α2δ-1 has been shown to be the therapeutic target of the gabapentinoid drugs in their alleviation of neuropathic pain. These drugs are also used in the treatment of certain epilepsies. In this study we therefore examined whether the level or distribution of α2δ-1 was altered in the hippocampus following experimental induction of epileptic seizures in rats, using both the kainic acid model of human temporal lobe epilepsy, in which status epilepticus is induced, and the tetanus toxin model in which status epilepticus is not involved. The main finding of this study is that we did not identify somatic overexpression of α2δ-1 in hippocampal neurons in either of the epilepsy models, unlike the upregulation of α2δ-1 that occurs following peripheral nerve damage to both somatosensory and motor neurons. However, we did observe local reorganisation of α2δ-1 immunostaining in the hippocampus only in the kainic acid model, where it was associated with areas of neuronal cell loss, as indicated by absence of NeuN immunostaining, dendritic loss, as identified by areas where microtubule-associated protein-2 immunostaining was missing, and reactive gliosis, determined by regions of strong OX42 staining

Modulation of iron metabolism in response to infection: Twists for all tastes

Iron is an essential nutrient for almost all living organisms, but is not easily made available. Hosts and pathogens engage in a fight for the metal during an infection, leading to major alterations in the host’s iron metabolism. Important pathological consequences can emerge from the mentioned interaction, including anemia. Several recent reports have highlighted the alterations in iron metabolism caused by different types of infection, and several possible therapeutic strategies emerge, based on the targeting of the host’s iron metabolism. Here, we review the most recent literature on iron metabolism alterations that are induced by infection, the consequent development of anemia, and the potential therapeutic approaches to modulate iron metabolism in order to correct iron-related pathologies and control the ongoing infection.This work is a result of the project Norte-01-0145-FEDER-000012-Structured program on bioengineered therapies for infectious diseases and tissue regeneration, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project PTDC/IMI-MIC/1683/2014 (POCI-01-0145-FEDER-016590). A.C.M. receives the individual fellowship SFRH/BPD/101405/2014 from FCT

Coreness of Cooperative Games with Truncated Submodular Profit Functions

Coreness represents solution concepts related to core in cooperative games, which captures the stability of players. Motivated by the scale effect in social networks, economics and other scenario, we study the coreness of cooperative game with truncated submodular profit functions. Specifically, the profit function $f(\cdot)$ is defined by a truncation of a submodular function $\sigma(\cdot)$: $f(\cdot)=\sigma(\cdot)$ if $\sigma(\cdot)\geq\eta$ and $f(\cdot)=0$ otherwise, where $\eta$ is a given threshold. In this paper, we study the core and three core-related concepts of truncated submodular profit cooperative game. We first prove that whether core is empty can be decided in polynomial time and an allocation in core also can be found in polynomial time when core is not empty. When core is empty, we show hardness results and approximation algorithms for computing other core-related concepts including relative least-core value, absolute least-core value and least average dissatisfaction value

How Do We Understand Depression in People with Persistent Pain?

Depression and depressed mood are common in people with persistent (chronic) pain, exacerbating disability and worsening quality of life. Yet the relationship between persistent pain and depression remains unclear, despite its importance for designing or adapting interventions to address both pain and depression. Meta-analysis of cognitive and behavioral interventions designed for rehabilitation of persistent pain shows small benefits for distress. However, substantial variation between studies in patients’ baseline levels of depression and in quality of treatments militates against any clear conclusions. Apart from these interventions, longitudinal studies on chronic pain and depression in adults from clinical populations provide weak evidence that depression worsens pain outcomes. We systematically searched for and reviewed 14 longitudinal studies that explored the association between persistent pain and depression, aiming to identify: (1) the effects on pain of baseline depression; (2) the effects on depression of baseline pain; and (3) possible mediating variables, with particular attention to methodology. Unfortunately, most studies used unsuitable instruments to measure depression, and we could draw only tentative conclusions about effects over time. Better models and clearer measurement strategies are required for a next generation of clinically useful treatment trials and, meanwhile, some implications for treatment are explored

Model of host-pathogen Interaction dynamics links In vivo optical imaging and immune responses

Tracking disease progression in vivo is essential for the development of treatments against bacterial infection. Optical imaging has become a central tool for in vivo tracking of bacterial population development and therapeutic response. For a precise understanding of in vivo imaging results in terms of disease mechanisms derived from detailed postmortem observations, however, a link between the two is needed. Here, we develop a model that provides that link for the investigation of Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli (EPEC). We connect in vivo disease progression of C57BL/6 mice infected with bioluminescent bacteria, imaged using optical tomography and X-ray computed tomography, to postmortem measurements of colonic immune cell infiltration. We use the model to explore changes to both the host immune response and the bacteria and to evaluate the response to antibiotic treatment. The developed model serves as a novel tool for the identification and development of new therapeutic interventions