Characterization and phylogenetic analysis of multidrug-resistant protein-encoding genes in Trypanosoma evansi isolated from buffaloes in Ngawi district, Indonesia

Background and Aim: Excessive use of trypanocidal drugs can lead to cases of drug resistance. Multiple cases of resistance have been widely reported for drugs such as isometamidium chloride and diminazene aceturate. These cases deserve serious attention, especially in Indonesia, where the first case was recorded and where the molecular basis of trypanocidal drug resistance has never been evaluated. This study aimed to analyze the multidrug resistance protein (MRP) gene in Trypanosoma evansi isolates, sampled from Indonesia, by focusing on the phylogenetic relationship between these isolates and other Trypanosoma spp. Materials and Methods: A total of 88 blood samples were drawn from buffaloes in the Ngawi district, Indonesia. Animals infected with T. evansi were detected through the microhematocrit technique and Giemsa blood smear methods. Positive blood samples were used to inoculate in male mice (Mus musculus BALB-C strain) as an animal model for culturing the T. evansi. The genomic DNA of the blood taken from the T. evansi-infected mice was used for polymerase chain reaction amplification, sequencing, and phylogenetic analysis. Results: Two genes were analyzed; the first gene detected for T. evansi corresponded to Trypanosoma brucei with a homology of 99% and the second gene to Trypanosoma brucei gambiense, with a homology of 100%. These two genes of the MRP from T. evansi showed clear similarity to the MRPE and MRPA genes of the T. brucei ssp. Conclusion: The MRP gene is conserved on the subspecies level of T. brucei. Only few point mutations were found between various sequences, which mean that the proteins have the same structure. This is important to treat the parasite with the appropriate drugs in the future

Principles of Small-Molecule Transport through Synthetic Nanopores

Synthetic nanopores made from DNA replicate the key biological processes of transporting molecular cargo across lipid bilayers. Understanding transport across the confined lumen of the nanopores is of fundamental interest and of relevance to their rational design for biotechnological applications. Here we reveal the transport principles of organic molecules through DNA nanopores by synergistically combining experiments and computer simulations. Using a highly parallel nanostructured platform, we synchronously measure the kinetic flux across hundreds of individual pores to obtain rate constants. The single-channel transport kinetics are close to the theoretical maximum, while selectivity is determined by the interplay of cargo charge and size, the pores' sterics and electrostatics, and the composition of the surrounding lipid bilayer. The narrow distribution of transport rates implies a high structural homogeneity of DNA nanopores. The molecular passageway through the nanopore is elucidated via coarse-grained constant-velocity steered molecular dynamics simulations. The ensemble simulations pinpoint with high resolution and statistical validity the selectivity filter within the channel lumen and determine the energetic factors governing transport. Our findings on these synthetic pores' structure-function relationship will serve to guide their rational engineering to tailor transport selectivity for cell biological research, sensing, and drug delivery

Coexistence of 'alpha+ 208Pb' cluster structures and single-particle excitations in 212Po

Excited states in 212Po have been populated by alpha transfer using the 208Pb(18O,14C) reaction at 85MeV beam energy and studied with the EUROBALL IV gamma multidetector array. The level scheme has been extended up to ~ 3.2 MeV excitation energy from the triple gamma coincidence data. Spin and parity values of most of the observed states have been assigned from the gamma angular distributions and gamma -gamma angular correlations. Several gamma lines with E(gamma) < 1 MeV have been found to be shifted by the Doppler effect, allowing for the measurements of the associated lifetimes by the DSAM method. The values, found in the range [0.1-0.6] ps, lead to very enhanced E1 transitions. All the emitting states, which have non-natural parity values, are discussed in terms of alpha-208Pb structure. They are in the same excitation-energy range as the states issued from shell-model configurations.Comment: 21 pages, 19 figures, corrected typos, revised arguments in Sect. III

Selective liposomal transport through blood brain barrier disruption in ischaemic stroke reveals two distinct therapeutic opportunities

The development of effective therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many blood-borne therapies and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischaemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5h and 4h) and delayed (24h and 48h) timepoints, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains long-term liposomal co-localisation within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischaemic region late after experimental stroke (2-3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages towards brain repair. These findings demonstrate the capability of liposomes to maximise selective translocation into the brain after stroke and identify two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of stroke treatments

Dye molecules in electrolytes: new approach for suppression of dye-desorption in dye-sensitized solar cells

The widespread commercialization of dye-sensitized solar cells remains limited because of the poor long-term stability. We report on the influence of dye-molecules added in liquid electrolyte on long-term stability of dye-sensitized solar cells. Dye-desorption from the TiO2 surface during long-term cycling is one of the decisive factors that degrade photocurrent densities of devices which in turn determine the efficiencies of the devices. For the first time, desorption of dye from the TiO2 surface could be suppressed by controlling thermodynamic equilibrium; by addition of dye molecules in the electrolyte. The dye molecules in the electrolyte can suppress the driving forces for the adsorbed dye molecules to be desorbed from TiO2 nanoparticles. As a result, highly enhanced device stabilities were achieved due to the reduction of dye-desorption although there was a little decrease in the initial efficiencies.open4

A cobalt complex redox shuttle for dye-sensitized solar cells with high open-circuit potentials

Dye-sensitized solar cells are a promising alternative to traditional inorganic semiconductor-based solar cells. Here we report an open-circuit voltage of over 1,000 mV in mesoscopic dye-sensitized solar cells incorporating a molecularly engineered cobalt complex as redox mediator. Cobalt complexes have negligible absorption in the visible region of the solar spectrum, and their redox properties can be tuned in a controlled fashion by selecting suitable donor/acceptor substituents on the ligand. This approach offers an attractive alternate to the traditional I3−/I− redox shuttle used in dye-sensitized solar cells. A cobalt complex using tridendate ligands [Co(bpy-pz)2]3+/2+(PF6)3/2 as redox mediator in combination with a cyclopentadithiophene-bridged donor-acceptor dye (Y123), adsorbed on TiO2, yielded a power conversion efficiency of over 10% at 100 mW cm−2. This result indicates that the molecularly engineered cobalt redox shuttle is a legitimate alternative to the commonly used I3−/I− redox shuttle

Inelastic excitation of new high-spin yrast isomers in 180Ta

For the first time, six-quasiparticle isomers have been observed in the meta-stable nucleus 18073Ta107. Two new high-spin isomers were populated following deep-inelastic reactions with a pulsed 23892U beam incident on a thick 18072Hf target. Out-of-beam γ-ray events were collected using the Gammasphere germanium detector array. In addition to the known four-quasiparticle isomers, yrast Kπ = (22-) and K≥23 six-quasiparticle isomers have been observed with microsecond half-lives. These are the highest-spin isomers observed using the technique of deep-inelastic excitation. The assignments are compared to predictions made by BCS and Lipkin-Nogami multiquasiparticle calculations

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

Nf2/Merlin controls spinal cord neural progenitor function in a Rac1/ErbB2-dependent manner

Objective: Individuals with the neurofibromatosis type 2 (NF2) cancer predisposition syndrome develop spinal cord glial tumors (ependymomas) that likely originate from neural progenitor cells. Whereas many spinal ependymomas exhibit indolent behavior, the only treatment option for clinically symptomatic tumors is surgery. In this regard, medical therapies are unfortunately lacking due to an incomplete understanding of the critical growth control pathways that govern the function of spinal cord (SC) neural progenitor cells (NPCs). Methods: To identify potential therapeutic targets for these tumors, we leveraged primary mouse Nf2-deficient spinal cord neural progenitor cells. Results: We demonstrate that the Nf2 protein, merlin, negatively regulates spinal neural progenitor cell survival and glial differentiation in an ErbB2-dependent manner, and that NF2-associated spinal ependymomas exhibit increased ErbB2 activation. Moreover, we show that Nf2-deficient SC NPC ErbB2 activation results from Rac1-mediated ErbB2 retention at the plasma membrane. Significance: Collectively, these findings establish ErbB2 as a potential rational therapeutic target for NF2-associated spinal ependymoma

Yrast three-quasiparticle K isomers in neutron-rich 181Hf

New high-K orbitals have been identified in the neutron-rich 181Hf nucleus via one-neutron transfer from a pulsed 238U beam onto a stable 180Hf target. Yrast three-quasiparticle high-K isomers, with half-lives as long as 1.5 ms, have been populated. The decay scheme of 181Hf has been extended to (25/2-). Blocked BCS calculations, including residual interactions, compare well with the experimental results