Oxysterol-binding protein related-proteins (ORPs) 5 and 8 regulate calcium signaling at specific cell compartments

Oxysterol-binding protein related-protein 5 and 8 (ORP5/8) localize to the membrane contact sites (MCS) of the endoplasmic reticulum (ER) and the mitochondria, as well as to the ER-plasma membrane (PM) MCS. The MCS are emerging as important regulators of cell signaling events, including calcium (Ca2+) signaling. ORP5/8 have been shown to interact with phosphatidylinositol-4,5-bisphosphate (PIP2) in the PM, and to modulate mitochondrial respiration and morphology. PIP2 is the direct precursor of inositol trisphosphate (IP3), a key second messenger responsible for Ca2+-release from the intracellular Ca2+ stores. Further, mitochondrial respiration is linked to Ca2+ transfer from the ER to the mitochondria. Hence, we asked whether ORP5/8 would affect Ca2+ signaling in these cell compartments, and employed genetically engineered aequorin Ca2+ probes to investigate the effect of ORP5/8 in the regulation of mitochondrial and caveolar Ca2+. Our results show that ORP5/8 overexpression leads to increased mitochondrial matrix Ca2+ as well as to increased Ca2+ concentration at the caveolar subdomains of the PM during histamine stimulation, while having no effect on the cytoplasmic Ca2+. Also, we found that ORP5/8 overexpression increases cell proliferation. Our results show that ORP5/8 regulate Ca2+ signaling at specific MCS foci. These local ORP5/8-mediated Ca2+ signaling events are likely to play roles in processes such as mitochondrial respiration and cell proliferation.Peer reviewe

Scheduling access to shared space in multi-robot systems

Through this study, we introduce the idea of applying scheduling techniques to allocate spatial resources that are shared among multiple robots moving in a static environment and having temporal constraints on the arrival time to destinations. To illustrate this idea, we present an exemplified algorithm that plans and assigns a motion path to each robot. The considered problem is particularly challenging because: (i) the robots share the same environment and thus the planner must take into account overlapping paths which cannot happen at the same time; (ii) there are time deadlines thus the planner must deal with temporal constraints; (iii) new requests arrive without a priori knowledge thus the planner must be able to add new paths online and adjust old plans; (iv) the robot motion is subject to noise thus the planner must be reactive to adapt to online changes. We showcase the functioning of the proposed algorithm through a set of agent-based simulations

Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid

Alzheimer’s disease is linked to amyloid β (Aβ) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of Aβ aggregation may lead to improved diagnostics and therapeutics. While previous studies have been performed in pure buffer, we approach the mechanism in vivo using cerebrospinal fluid (CSF). We investigated the aggregation mechanism of Aβ42 in human CSF through kinetic experiments at several Aβ42 monomer concentrations (0.8–10 µM). The data were subjected to global kinetic analysis and found consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface. A mechanism only including primary nucleation was ruled out. We find that the aggregation process is composed of the same microscopic steps in CSF as in pure buffer, but the rate constant of secondary nucleation is decreased. Most importantly, the autocatalytic amplification of aggregate number through catalysis on the fibril surface is prevalent also in CSF

Mechanism of Pion Production in alphaalphap Scattering at 1 GeV/nucleon

The one-pion and two-pion production in the p(alpha, alpha prime)X reaction at an energy of E{alpha} = 4.2 GeV has been studied by simultaneous registration of the scattered alpha particles and the secondary pion or proton. The obtained results demonstrate that the inelastic alpha-particle scattering on the proton at the energy of the experiment proceeds either through excitation and decay of Delta resonance in the projectile or through excitation in the target proton of the Roper resonance, which decays mainly on a nucleon and a pion or a nucleon and a sigma meson - system of two pions in the isospin I = 0, S-wave.Comment: 16 pages, 10 figures. Submitted to Proceedings of the XX International Baldin Seminar on High - Energy Physics Problems, Dubna, October 4 - 9, 201

Demokrasi di Atas Pasir: Kemajuan dan Kemunduran Demokratisasi di Indonesia

Buku ini didasarkan atas survei yang menunjukkan bahwa demokrasi Indonesia, selain memperlihatkan kemajuan-kemajuan juga memperlihatkan beberapa kemunduran. Adalah benar bahwa rakyat yang sudah bebeas menggunakan hak suara mereka dalam pemilu, akan tetapi kaum perempuan (yang kebanyakan tidak memiliki jaringan yang bagus), kaum miskin dan kelompok marjinal, secara de facto terhalang untuk maju sebagai kandidat dan bahkan kadangkala untuk memilih. Upaya untuk mengembangkan representasi popular menjadi terhambat. Isu-isu mendasar seperti persamaan hak-hak sipil dan politik, serta pemenuhan hak-hak sosial, ekonomi, dan budaya juga menghadapi tantangan serupa. Oleh karena itu, ada kebutuhan mendesak untuk mengembangkan blok politik demokratis yang terorganisasikan dengan baik dan tidak didominasi atau dipengaruhi oleh partai. Upaya ini perlu dilakukan untuk mengingkatkan pengaruh masyarakat (demos) yang independen ke dalam aktivitas-aktivitas politik yang terorganisir; untuk mengubah relasi-relasi kekuasaan yang ada melalui representasi dan partisipasi yang lebih merakyat; untuk meningkatkan posisi-tawar yang mengarahkan pada tercapainya kompromi-kompromi yang lebih baik untuk pembangunan berkelanjutan berdasarkan prinsip-prinsip hak asasi manusia

Pharmacokinetic aspects of retinal drug delivery

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.Peer reviewe

Increasing the power of the poor? NGO-led social accountability initiatives and political capabilities in rural Uganda

Social accountability has become an important new buzzword among development actors seeking to understand the forms of state-society synergy that may be supportive of better public services. Advocates suggest demand-side initiatives are key to increasing the power of the poor in service provision, while sceptics question the application of technical fixes to complex political challenges. This article reports findings from qualitative research into the political capabilities outcomes achieved among local health and education stakeholders through the social accountability interventions of a non-governmental organisation (NGO) in Western Uganda. It argues that NGOs are unlikely to generate substantive advances for social accountability in agrarian contexts characterised by patronage politics without organising marginalised groups themselves to tackle the causes of their disadvantage