Controlling Optomechanical Libration with the Degree of Polarization.

Control of the potential energy and free evolution lie at the heart of levitodynamics as key requirements for sensing, wave function expansion, and mechanical squeezing protocols. Here, we experimentally demonstrate versatile control over the optical potential governing the libration motion of a levitated anisotropic nanoparticle. This control is achieved by introducing the degree of polarization as a new tool for rotational levitodynamics. We demonstrate thermally driven free rotation of a levitated anisotropic scatterer around its short axis and we use the rotational degrees of freedom to probe the local spin of a strongly focused laser beam.

Levitodynamics: Levitation and control of microscopic objects in vacuum.

The control of levitated nano- and micro-objects in vacuum­which capitalizes on scientific achievements in the fields of atomic physics, control theory, and optomechanics­is of considerable interest. The ability to couple the motion of levitated systems to internal degrees of freedom, as well as to external forces and systems, provides opportunities for science and technology. Attractive research directions, ranging from fundamental quantum physics to commercial sensors, have been unlocked by the many recent experimental achievements, including motional ground-state cooling of an optically levitated nanoparticle. Here we review the status, challenges, and prospects of levitodynamics, the multidisciplinary research area devoted to understanding, controlling, and using levitated nano- and micro-objects in vacuum.

Escape dynamics of active particles in multistable potentials.

Rare transitions between long-lived metastable states underlie a great variety of physical, chemical and biological processes. Our quantitative understanding of reactive mechanisms has been driven forward by the insights of transition state theory and in particular by Kramers' dynamical framework. Its predictions, however, do not apply to systems that feature non-conservative forces or correlated noise histories. An important class of such systems are active particles, prominent in both biology and nanotechnology. Here, we study the active escape dynamics of a silica nanoparticle trapped in a bistable potential. We introduce activity by applying an engineered stochastic force that emulates self-propulsion. Our experiments, supported by a theoretical analysis, reveal the existence of an optimal correlation time that maximises the transition rate. We discuss the origins of this active turnover, reminiscent of the much celebrated Kramers turnover. Our work establishes a versatile experimental platform to study single particle dynamics in non-equilibrium settings.

Redirecting the immune response towards immunoprotective domains of a DNABII protein resolves experimental otitis media.

The chronicity and recurrence of many bacterial diseases is largely attributable to the presence of a biofilm, and eradication of these structures is confounded by an extracellular DNA-rich matrix. DNABII proteins, including integration host factor (IHF), are critical components of the matrix formed by all human pathogens tested to date. Whereas the natural adaptive immune response to IHF is against non-protective epitopes within the carboxyl-terminal region, antibodies against the DNA-binding "tips" induce biofilm collapse. We designed a "tip-chimer" immunogen to mimic the DNA-binding regions within the α-subunit and ß-subunit of IHF from nontypeable Haemophilus influenzae (IHFNTHi). Re-direction of the natural adaptive immune response toward immunoprotective domains disrupted NTHi biofilms in vitro and in an experimental model of otitis media. Our data support the rational design of a powerful therapeutic approach, and also that of a DNABII-directed vaccine antigen that would avoid augmentation of any pre-existing natural, but nonprotective, immune response.

Optically levitated nanoparticle as a model system for stochastic bistable dynamics.

Nano-mechanical resonators have gained an increasing importance in nanotechnology owing to their contributions to both fundamental and applied science. Yet, their small dimensions and mass raises some challenges as their dynamics gets dominated by nonlinearities that degrade their performance, for instance in sensing applications. Here, we report on the precise control of the nonlinear and stochastic bistable dynamics of a levitated nanoparticle in high vacuum. We demonstrate how it can lead to efficient signal amplification schemes, including stochastic resonance. This work contributes to showing the use of levitated nanoparticles as a model system for stochastic bistable dynamics, with applications to a wide variety of fields.

Stimulated scintillation emission depletion X-ray imaging.

X-ray microtomography is a widely applied tool for noninvasive structure investigations. The related detectors are usually based on a scintillator screen for the fast in situ conversion of an X-ray image into an optical image. Spatial resolution of the latter is fundamentally diffraction limited. In this work, we introduce stimulated scintillation emission depletion (SSED) X-ray imaging where, similar to stimulated emission depletion (STED) microscopy, a depletion beam is applied to the scintillator screen to overcome the diffraction limit. The requirements for the X-ray source, the X-ray flux, the scintillator screen, and the STED beam were evaluated. Fundamental spatial resolution limits due to the spread of absorbed X-ray energy were estimated with Monte Carlo simulations. The SSED proof-of-concept experiments demonstrated 1) depletion of X-ray excited scintillation, 2) partial confinement of scintillating regions to sub-diffraction sized volumes, and 3) improvement of the imaging contrast by applying SSED.

STED properties of Ce3+, Tb3+, and Eu3+ doped inorganic scintillators.

Scintillator-based X-ray imaging is a powerful technique for noninvasive real-space microscopic structural investigation such as synchrotron-based computed tomography. The resolution of an optical image formed by scintillation emission is fundamentally diffraction limited. To overcome this limit, stimulated scintillation emission depletion (SSED) X-ray imaging, based on stimulated emission depletion (STED) microscopy, has been recently developed. This technique imposes new requirements on the scintillator material: efficient de-excitation by the STED-laser and negligible STED-laser excited luminescence. In this work, luminescence depletion was measured in several commonly-used Ce3+, Tb3+, and Eu3+ - doped scintillators using various STED lasers. The depletion of Tb3+ and Eu3+ via 4f-4f transitions was more efficient (Ps = 8…19 mW) than Ce3+ depletion via 5d-4f transitions (Ps = 43…45 mW). Main origins of STED-laser excited luminescence were one- and two-photon excitation, and scintillator impurities. LSO:Tb scintillator and a 628 nm cw STED-laser is the most promising combination for SSED satisfying the above-mentioned requirements.

Efficacy and safety of human mesenchymal stromal cells in healing of critical-size bone defects in immunodeficient rats.

To evaluate the preclinical efficacy and safety of human mesenchymal stem cells (hMSC) rapidly expanded in growth medium for clinical use with human serum and recombinant growth factors, we conducted a controlled, randomized trial of plasma clots with hMSC vs. plasma clots only in critical segmental femoral defects in rnu/rnu immunodeficient rats. X-ray, microCT and histomorphometrical evaluation were performed at 8 and 16 weeks. MSC were obtained from healthy volunteers and patients with lymphoid malignancy. Human MSC survived in the defect for the entire duration of the trial. MSC from healthy volunteers, in contrast to hMSC from cancer patients, significantly improved bone healing at 8, but not 16 weeks. However, at 16 weeks, hMSC significantly improved vasculogenesis in residual defect. We conclude that hMSC from healthy donors significantly contributed to the healing of bone defects at 8 weeks and to the vascularisation of residual connective tissue for up to 16 weeks. We found the administration of hMSC to be safe, as no adverse reaction to human cells at the site of implantation and no evidence of migration of hMSC to distant organs was detected.

Protein synthesis inhibitors of natural origin for CML therapy: semisynthetic homoharringtonine (Omacetaxine mepesuccinate).

Omacetaxine mepesuccinate is a drug approved in 2014 by FDA for the use in CML therapy in patients resistant to at least two thymidine kinase inhibitors (TKIs). It possesses unique mechanism of anticancer activity that is principally different from mechanism of activity of TKIs. Omacetaxine mepesuccinate inhibits protein translation through prevention of the initial elongation step of protein synthesis and its use benefits CML patients possessing the BCR-ABL oncogene. Because of the superior activity of Omacetaxine in patients who became resistant to therapy with TKIs, FDA decided on the accelerated approval of this drug taking its consideration not only its activity as such but also a favorable benefit-to-risk profile in patients included into clinical studies.

Antenna-coupled photon emission from hexagonal boron nitride tunnel junctions.

The ultrafast conversion of electrical signals to optical signals at the nanoscale is of fundamental interest for data processing, telecommunication and optical interconnects. However, the modulation bandwidths of semiconductor light-emitting diodes are limited by the spontaneous recombination rate of electron-hole pairs, and the footprint of electrically driven ultrafast lasers is too large for practical on-chip integration. A metal-insulator-metal tunnel junction approaches the ultimate size limit of electronic devices and its operating speed is fundamentally limited only by the tunnelling time. Here, we study the conversion of electrons (localized in vertical gold-hexagonal boron nitride-gold tunnel junctions) to free-space photons, mediated by resonant slot antennas. Optical antennas efficiently bridge the size mismatch between nanoscale volumes and far-field radiation and strongly enhance the electron-photon conversion efficiency. We achieve polarized, directional and resonantly enhanced light emission from inelastic electron tunnelling and establish a novel platform for studying the interaction of electrons with strongly localized electromagnetic fields.

TH-9 (a theophylline derivative) induces long-lasting enhancement in excitatory synaptic transmission in the rat hippocampus that is occluded by frequency-dependent plasticity in vitro.

Dementia, especially Alzheimer's disease, is a rapidly increasing medical condition that presents with enormous challenge for treatment. It is characterized by impairment in memory and cognitive function often accompanied by changes in synaptic transmission and plasticity in relevant brain regions such as the hippocampus. We recently synthesized TH-9, a conjugate racetam-methylxanthine compound and tested if it had potential for enhancing synaptic function and possibly, plasticity, by examining its effect on hippocampal fast excitatory synaptic transmission and plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 hippocampal area of naïve juvenile male Sprague-Dawley rats using conventional electrophysiological recording techniques. TH-9 caused a concentration-dependent, long-lasting enhancement in fEPSPs. This effect was blocked by adenosine A1, acetylcholine (muscarinic and nicotinic) and glutamate (N-methyl-d-aspartate) receptor antagonists but not by a γ-aminobutyric acid receptor type B (GABA(B)) receptor antagonist. The TH-9 effect was also blocked by enhancing intracellular cyclic adenosine monophosphate and inhibiting protein kinase A. Pretreatment with TH-9 did not prevent the induction of long-term potentiation (LTP) or long-term depression (LTD). Conversely, induction of LTP or LTD completely occluded the ability of TH-9 to enhance fEPSPs. Thus, TH-9 utilizes cholinergic and adenosinergic mechanisms to cause long-lasting enhancement in fEPSPs which were occluded by LTP and LTD. TH-9 may therefore employ similar or convergent mechanisms with frequency-dependent synaptic plasticities to produce the observed long-lasting enhancement in synaptic transmission and may thus, have potential for use in improving memory.

Biofilms can be dispersed by focusing the immune system on a common family of bacterial nucleoid-associated proteins.

Bacteria that cause chronic and/or recurrent diseases often rely on a biofilm lifestyle. The foundation of the biofilm structure is the extracellular polymeric substance (EPS) that acts as a barrier to both effectors of the immune system and antimicrobial agents. Recent work has highlighted extracellular DNA (eDNA) as a key component common to many pathogenic biofilms. Here, we show that the DNABII family of proteins, well known for their strong structural influences on intracellular DNA, was also critical for the integrity of the EPS matrix of biofilms that contain eDNA. In fact, antisera derived against a purified Escherichia coli DNABII family member rapidly disrupts the biofilm EPS formed by multiple human pathogens in vitro. In addition, when a member of this family of proteins was used as an immunogen in an animal model in which the bacteria had already formed a robust biofilm at the site of infection, the resultant targeted immune response strongly ameliorated this biofilm disease in vivo. Finally, this methodology to debulk the biofilm of EPS was shown to work synergistically with otherwise ineffective traditional anti-microbial approaches in vitro. We discuss the prospects for targeting DNABII family members as a potential universal strategy for treating biofilm diseases.

Transcutaneous immunization as preventative and therapeutic regimens to protect against experimental otitis media due to nontypeable Haemophilus influenzae.

We have developed three nontypeable Haemophilus influenzae (NTHI) adhesin-derived immunogens that are significantly efficacious against experimental otitis media (OM) due to NTHI when delivered parenterally. We now expanded our preventative immunization strategies to include transcutaneous immunization (TCI) as a less invasive, but potentially equally efficacious, regimen to prevent OM due to NTHI. Additionally, we examined the potential of TCI as a therapeutic immunization regimen to resolve ongoing experimental OM. Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone. Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls. These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM.

Cytotoxicity and antileukaemic activity of new duplexes linking 3-C-ethynylcytidine and 5-fluorodeoxyuridine.

The cytotoxic and antineoplastic potential of two new duplex drugs, ECyd-5-FdU and ECyd- lipid- 5-FdU, were compared with the activity of the parent single-nucleoside analogues, 3-C-ethynylcytidine (ECyd) and 5-fluorodeoxyuridine (5-FdU), either applied as monotherapy or simultaneously in equimolar concentrations simulating their ratio in a duplex drug. Murine leukaemia L1210 cells were used for comparative in vitro tests of the duplex and the single drugs. The tested substances were evaluated for their cytotoxicity, combinatory potential and revitalisation properties. Additionally, an in vivo model of leukaemia L1210-bearing mice of the DBA/2J strain was used for testing of acute toxicity and antileukaemic activity using various chemotherapeutic regimes. Based on the results of this study, the suitability of ECyd and 5-FdU for forming a duplex drug was discussed from the perspective of their expected synergistic anticancer activities. We found an improvement of chemotherapy outcomes of the new duplex drugs tested by comparing their in vitro cytotoxicity and an increase of the time of survival of experimental leukaemia-bearing mice in a statistically significant manner.

Morphology and distribution of granulomatous inflammation in freshwater ornamental fish infected with mycobacteria.

Mycobacteriosis in fish is a chronic progressive ubiquitous disease caused by Mycobacterium marinum, M. gordonae and M. fortuitum in most cases. The aim of this study was to describe the morphology and distribution of lesions in 322 freshwater ornamental fish across 36 species. Granulomatous inflammation was diagnosed by gross examination and histopathology testing in 188 fish (58.4%); acid-fast rods (AFR) were determined in only 96 (51.1%) fish from 19 species after Ziehl-Neelsen staining. The most often affected organs with AFR were the kidney (81.2%), digestive tract (54.1%), liver (48.2%), spleen (45.9%) and skin (21.2%); sporadically, AFR were found in the branchiae (9.4%) and gonads (4.7%). In 14 randomly selected fish originating from four different fish tanks, the distribution of mycobacterial infection was studied by culture examination of the skin, gills, muscle tissue, digestive tract, liver, spleen and kidney. In 12 fish, the species M. marinum, M. gordonae, M. fortuitum, M. triviale, and M. avium subsp. hominissuis (serotypes 6 and 8 and genotype IS901- and IS1245+) were detected; mixed infection caused by different mycobacterial species was documented in five of them.

Selenium as a chemoprotective anti-cancer agent: reality or wishful thinking?

It is generally accepted that selenium (Se) plays an important role in maintaining equilibrium of a healthy organism. It also participates in processes related to carcinogenesis such as inhibition of tumor formation and regression. Scientific data accumulated so far using experimental animal models and from clinical studies devoted to investigating the effects of Se confirm strong relationship or correlation between Se supplementation and tumor frequency of prostate, lungs, liver and colon. However, details of mechanisms of action of Se in modulation of carcinogenesis and cancer prevention are not yet fully elucidated. It is not clear yet whether Se deficiency itself is a cancer risk factor or whether it helps an already present cancer to progress. Additionally, the effects of other factors such as age, gender, life style, geographic location, comorbidities and use of drugs, are not clear. Despite the fact that some positive results were obtained with Se supplementation, it is necessary to verify these findings in more controlled experimental models including clinical studies. At the present time, data related to Se supplementation are not convincing enough as to allow general recommendation for using Se as an effective agent for chemoprevention of cancer. The goal of this minireview is to highlight present level of understanding of Se biological and prospects of its future clinical use. Information regarding Se, its effectiveness in various experimental models and in clinical tests, including combinations with other bioactive agents and anticancer drugs, is evaluated and summarized.

Mechanism of near-field Raman enhancement in one-dimensional systems.

We develop a theory of near-field Raman enhancement in one-dimensional systems, and report supporting experimental results for carbon nanotubes. The enhancement is established by a laser-irradiated nanoplasmonic structure acting as an optical antenna. The near-field Raman intensity is inversely proportional to the 10th power of the separation between the enhancing structure and the one-dimensional system. Experimental data obtained from single-wall carbon nanotubes indicate that the Raman enhancement process is not significantly influenced by the specific phonon eigenvector, and is mainly defined by the properties of the nanoplasmonic structure.

[Treatment of trochanteric fractures by percutaneous compression plate]. / Osetrení trochanterických zlomenin PC.C.P. dlahou.

PURPOSE OF THE STUDY: To present a new type of percutaneous compression plate (PCP) for a minimally invasive method of treating trochanteric hip fractures. MATERIAL: Between September 2004 and December 2006, a total of 66 patients with hip fractures were treated by minimally invasive percutaneous osteosynthesis involving a PCP. The average age of the patients was 74.5 years (range, 27-95 years). The fractures were classified as pertrochanteric (AO31, A1.1-A2.3) in 73%, femoral neck fracture (AO31, B2) in 20%, and intertrochanteric fracture (AO31, A3.1) in 7% of the patients. METHODS: Reduction was performed under conduction or general anaesthesia on a traction table, using an X-ray image intensifier system. Reduction and intra-operative temporary stabilisation of the fracture was facilitated by a posterior reduction device. Access was gained and a PCP was inserted through two incisions at the lateral side of the proximal femur. RESULTS: The patients were followed up for at least 6 months. Radiographic union was found on average at 3 months post-operatively. No pseudoarthrosis or implant failure was recorded. At 6-month follow-up, 81% of the patients were able to walk without walking aid or with one walking cane only. Two crutches were used by 8% of the patients.To walk without help was impossible for 11% of the patients whose mobility had already been limited before the injury. DISCUSSION: PCP osteosynthesis for trochanteric fractures is a novel minimally invasive approach providing a better treatment of the fracture. Compared to dynamic hip screw osteosynthesis used before, PCP allows for earlier weight bearing and noticeably reduces blood loss. Implant construction as well as post-operative controlled impaction of the fracture minimize the risk of osteosynthesis failure. The simple instrumentation construction enables us to reduce operative time. CONCLUSIONS: The percutaneous compression plate is a contribution to minimally invasive osteosynthesis of trochanteric fractures. An increase in rotational stability of the implant due to its biaxial telescopic construction allows for earlier weight-bearing of the extremity, thus facilitating the patient's earlier return to everyday life activities. It also reduces operative trauma, blood loss and post-operative complications.

Tip-enhanced near-field optical microscopy of carbon nanotubes.

We review recent experimental studies on single-walled carbon nanotubes on substrates using tip-enhanced near-field optical microscopy (TENOM). High-resolution optical and topographic imaging with sub 15 nm spatial resolution is shown to provide novel insights into the spectroscopic properties of these nanoscale materials. In the case of semiconducting nanotubes, the simultaneous observation of Raman scattering and photoluminescence (PL) is possible, enabling a direct correlation between vibrational and electronic properties on the nanoscale. So far, applications of TENOM have focused on the spectroscopy of localized phonon modes, local band energy renormalizations induced by charge carrier doping, the environmental sensitivity of nanotube PL, and inter-nanotube energy transfer. At the end of this review we discuss the remaining limitations and challenges in this field.

Cytarabine conjugates with biologically active molecules and their potential anticancer activity.

The presented review article deals with various conjugates of arabinosylcytosine (araC). This powerful drug that is routinely used in therapy of hematological malignancies has some shortcomings, which limit its use and therapeutic effects. These are low lipophilicity, low stability to degrading enzymes and need for biological activation through phosphorylation. Conjugating araC to another molecule is done with the intention of increasing araC stability and lipophilicity and possibly avoiding rate-limiting araC phosphorylation. An attachment of that another molecule, possessing its own biological activity, may result in formation of a conjugated molecule with new biological activities and better therapeutic potential. The review deals with various araC conjugates formed at the positions N(4), 2, 2', 3' and 5'. Biological activities and differences from araC of compounds formed by conjugation are also discussed.