Spatial Planning System in Transitional Indonesia

This paper discusses the interaction between institutional-cultural forces and globalizing neo-liberal ideas in the discussion on the formulation of the draft of new Spatial Planning Act in Indonesia. Although the neo-liberal ideas cannot change the whole nature of the planning system, this paper shows that they fragment the system and conflict with the existing institutional-cultural forces. It argues that the ideas of rule of law and decentralization, as promoted by the neo-liberalism, should be encouraged in order to develop a more effective planning system in Indonesia.     

Human Milk Oligosaccharide 2′-Fucosyllactose Modulates Local Viral Immune Defense by Supporting the Regulatory Functions of Intestinal Epithelial and Immune Cells

Human milk contains bioactive components that provide protection against viral infections in early life. In particular, intestinal epithelial cells (IEC) have key regulatory roles in the prevention of enteric viral infections. Here we established an in vitro model to study the modulation of host responses against enteric viruses mimicked by poly I:C (pIC). The effects of 2′-fucosyllactose (2′FL), abundantly present in human milk, were studied on IEC and/or innate immune cells, and the subsequent functional response of the adaptive immune cells. IEC were pre-incubated with 2′FL and stimulated with naked or Lyovec™-complexed pIC (LV-pIC). Additionally, monocyte-derived dendritic cells (moDC) alone or in co-culture with IEC were stimulated with LV-pIC. Then, conditioned-moDC were co-cultured with naïve CD4⁺ T helper (Th)-cells. IEC stimulation with naked or LV-pIC promoted pro-inflammatory IL-8, CCL20, GROα and CXCL10 cytokine secretion. However, only exposure to LV-pIC additionally induced IFNβ, IFNλ1 and CCL5 secretion. Pre-incubation with 2′FL further increased pIC induced CCL20 secretion and LV-pIC induced CXCL10 secretion. LV-pIC-exposed IEC/moDC and moDC cultures showed increased secretion of IL-8, GROα, IFNλ1 and CXCL10, and in the presence of 2′FL galectin-4 and -9 were increased. The LV-pIC-exposed moDC showed a more pronounced secretion of CCL20, CXCL10 and CCL5. The moDC from IEC/moDC cultures did not drive T-cell development in moDC/T-cell cultures, while moDC directly exposed to LV-pIC secreted Th1 driving IL-12p70 and promoted IFNγ secretion by Th-cells. Hereby, a novel intestinal model was established to study mucosal host-defense upon a viral trigger. IEC may support intestinal homeostasis, regulating local viral defense which may be modulated by 2′FL. These results provide insights regarding the protective capacity of human milk components in early life.     

Bis(Benzofuran–1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus

The yellow fever virus (YFV) is an emerging RNA virus and has caused large outbreaks in Africa and Central and South America. The virus is often transmitted through infected mosquitoes and spreads from area to area because of international travel. Being an acute viral hemorrhagic disease, yellow fever can be prevented by an effective, safe, and reliable vaccine, but not be eliminated. Currently, there is no antiviral drug available for its cure. Thus, two series of novel bis(benzofuran–1,3-imidazolidin-4-one)s and bis(benzofuran–1,3-benzimidazole)s were designed and synthesized for the development of anti-YFV lead candidates. Among 23 new bis-conjugated compounds, 4 of them inhibited YFV strain 17D (Stamaril) on Huh-7 cells in the cytopathic effect reduction assays. These conjugates exhibited the most compelling efficacy and selectivity with an EC₅₀ of <3.54 μM and SI of >15.3. The results are valuable for the development of novel antiviral drug leads against emerging diseases.     

Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability

Integrin αIIbβ3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The αIIbβ3 integrin is highly expressed on platelets and requires an activation step for binding to fibrinogen, fibrin or von Willebrand factor (VWF). A current model assumes that the process of integrin activation relies on actomyosin force-dependent molecular changes from a bent-closed and extended-closed to an extended-open conformation. In this paper we review the pathways that point to a functional reversibility of platelet αIIbβ3 activation and transient aggregation. Furthermore, we refer to mouse models indicating that genetic defects that lead to reversible platelet aggregation can also cause instable thrombus formation. We discuss the platelet agonists and signaling pathways that lead to a transient binding of ligands to integrin αIIbβ3. Our analysis points to the (autocrine) ADP P2Y₁ and P2Y₁₂ receptor signaling via phosphoinositide 3-kinases and Akt as principal pathways linked to reversible integrin activation. Downstream signaling events by protein kinase C, CalDAG-GEFI and Rap1b have not been linked to transient integrin activation. Insight into the functional reversibility of integrin activation pathways will help to better understand the effects of antiplatelet agents.     

Coagulation Factor XIIIa and Activated Protein C Activate Platelets via GPVI and PAR1

Platelet and coagulation activation are highly reciprocal processes driven by multi-molecular interactions. Activated platelets secrete several coagulation factors and expose phosphatidylserine, which supports the activation of coagulation factor proteins. On the other hand, the coagulation cascade generates known ligands for platelet receptors, such as thrombin and fibrin. Coagulation factor (F)Xa, (F)XIIIa and activated protein C (APC) can also bind to platelets, but the functional consequences are unclear. Here, we investigated the effects of the activated (anti)coagulation factors on platelets, other than thrombin. Multicolor flow cytometry and aggregation experiments revealed that the ‘supernatant of (hirudin-treated) coagulated plasma’ (SCP) enhanced CRP-XL-induced platelet responses, i.e., integrin α_IIbβ₃ activation, P-selectin exposure and aggregate formation. We demonstrated that FXIIIa in combination with APC enhanced platelet activation in solution, and separately immobilized FXIIIa and APC resulted in platelet spreading. Platelet activation by FXIIIa was inhibited by molecular blockade of glycoprotein VI (GPVI) or Syk kinase. In contrast, platelet spreading on immobilized APC was inhibited by PAR1 blockade. Immobilized, but not soluble, FXIIIa and APC also enhanced in vitro adhesion and aggregation under flow. In conclusion, in coagulation, factors other than thrombin or fibrin can induce platelet activation via GPVI and PAR receptors.     

Mucoadhesive Electrospun Nanofiber-Based Hybrid System with Controlled and Unidirectional Release of Desmopressin

The sublingual mucosa is an attractive route for drug delivery, although challenged by a continuous flow of saliva that leads to a loss of drug by swallowing. It is of great benefit that drugs absorbed across the sublingual mucosa avoid exposure to the harsh environment of the gastro-intestinal lumen; this is especially beneficial for drugs of low physicochemical stability such as therapeutic peptides. In this study, a two-layered hybrid drug delivery system was developed for the sublingual delivery of the therapeutic peptide desmopressin. It consisted of peptide-loaded mucoadhesive electrospun chitosan/polyethylene oxide-based nanofibers (mean diameter of 183 ± 20 nm) and a saliva-repelling backing film to promote unidirectional release towards the mucosa. Desmopressin was released from the nanofiber-based hybrid system (approximately 80% of the loaded peptide was released within 45 min) in a unidirectional manner in vitro. Importantly, the nanofiber–film hybrid system protected the peptide from wash-out, as demonstrated in an ex vivo flow retention model with porcine sublingual mucosal tissue. Approximately 90% of the loaded desmopressin was retained at the surface of the ex vivo porcine sublingual mucosa after 15 min of exposure to flow rates representing salivary flow.     

Recombination luminescence from defects in boron-ion implantation-doped diamond using low fluences

 Two identical, high purity, natural type IIa diamonds, which displayed the ubiquitous blue cathodoluminescence (CL) band at ≈ 2.9 eV, as well as an indication of the corresponding green band at ≈ 2.4 eV, have been equivalently doped by using extremely low dose B⁺- and C⁺-ion CIRA-implantations respectively. Comparative CL measurements showed changes in the intensities of the 2.9 and 2.4 eV bands and the generation of bands at ≈ 4 eV, as well as at ≈ 3.5 and ≈ 4.6 eV (the latter two in the B⁺-CIRA diamond). The results are commensurate with the model (proposed previously) in which the 2.9 and 4 eV bands are generated respectively by electron-hole recombinations at negatively charged acceptor- and positively charged donor-like, intrinsic defects. The present results indicate that Coulomb interactions between the latter defects and (at least partially) compensated, negatively charged, boron acceptors, generate the 3.5 and 4.6 eV bands, which may be considered as higher energy (≈ 0.6 eV) replicas of the 2.9 and 4 eV bands. In both cases, two electrons and a hole interact just before the hole combines with an electron. Such a configuration of charges seems related to, and could possibly be described as, a type of ”ionised exciton molecule”, where the ”bonding” of two negative ”nuclei” is facilitated by the presence of the hole. The CL measurements further indicate that the 2.4 eV band forms when a high enough density of, in this case, neutral acceptors are present. These neutral acceptors compete with the valence band to supply holes for recombination at the negatively charged, acceptor-type, intrinsic defects which are, in the absence of the boron, responsible for the generation of the blue, 2.9 eV band. Received: 5 December 1997 / Accepted: 13 December 1997     

Study of the Transit-Time Limitations of the Impulse Response in Mid-Wave Infrared HgCdTe Avalanche Photodiodes

The impulse response in frontside-illuminated mid-wave infrared HgCdTe electron avalanche photodiodes (APDs) has been measured with localized photoexcitation at varying positions in the depletion layer. Gain measurements have shown an exponential gain, with a maximum value of M = 5000 for the diffusion current at a reverse bias of V _b = 12 V. When the light was injected in the depletion layer, the gain was reduced as the injection approached the N+ edge of the junction. The impulse response was limited by the diode series resistance–capacitance product, RC, due to the large capacitance of the diode metallization. Hence, the fall time is given by the RC constant, estimated as RC = 270 ps, and the rise time is due to the charging of the diode capacitance via the transit and multiplication of carriers in the depletion layer. The latter varies between t _10–90 = 20 ps (at intermediate gains M < 500) and t _10–90 = 70 ps (at M = 3500). The corresponding RC-limited bandwidth is BW = 600 MHz, which yields a new absolute record in gain–bandwidth product of GBW = 2.1 THz. The increase in rise time at high gains indicates the existence of a limit in the transit-time-limited gain–bandwidth product, GBW = 19 THz. The impulse response was modeled using a one-dimensional deterministic model, which allowed a quantitative analysis of the data in terms of the average velocity of electrons and holes. The fitting of the data yielded a saturation of the electron and hole velocity of v _e = 2.3 × 10⁷ cm/s and v _h = 1.0 × 10⁷ cm/s at electric fields E > 1.5 kV/cm. The increase in rise time at high bias is consistent with the results of Monte Carlo simulations and can be partly explained by a reduction of the electron saturation velocity due to frequent impact ionization. Finally, the model was used to predict the bandwidth in diodes with shorter RC = 5 ps, giving BW = 16 GHz and BW = 21 GHz for x _j = 4 μm and x _j = 2 μm, respectively, for a gain of M = 100.     

Dynamic Monte Carlo Simulations of Oscillatory Reactions

The dynamic Monte Carlo method has been used to simulate the 2 A + B₂ → 2 AB reaction catalyzed by a reconstructing substrate. Oscillatory behavior and spatio-temporal is studied as a function of grid size. Spatio-temporal pattern formation has been simulated in various forms: cellular patterns, target patterns, rotating spirals, and turbulent patterns. Cellular patterns are a manifestation of a local synchronization mechanism in which all reaction fronts periodically extinguish each other. This illustrates that dynamic Monte Carlo simulations form a promising technique and can be used to predict macroscopic kinetic phenomena on a molecular basis.