Pharmacogenetics, adverse drug reactions and public health

Adverse drug reactions (ADRs) are a major public health problem. Pharmacogenetic testing prior to drug treatment is supposed to considerably alleviate this problem. The state of pharmacogenetic development was assessed by a systematic literature review, supplemented by expert interviews. Analysis of three case examples revealed that - with the exception of thiopurine methyltransferase (TPMT) - studies are lacking which unambiguously prove the clinical value of pharmacogenetic testing. Testing can prevent some, but by far not all ADRs. Since it does not compensate for clinical monitoring, pharmacogenetics can be regarded as add-on technology, applied in addition to established methods. A non-representative, explorative survey conducted amongst members of the German Society of Laboratory Medicine revealed that the demand for testing is limited and has not increased much, although a certain increase is expected in the future.     

Teil III. Edelgasdetektoren,Indirekter Elektron-Mobility-Detektor und Schlußfolgerungen

Die Multiplikation von Ladungsträgern durch feldbeschleunigte Elektronen erfolgt im Bereich der unselbständigen Entladung. Sie wurde von Lovelock [1] erstmals für β-Argondetektoren zur Steigerung der Empfindlichkeit E_N angewandt. Detektoren im Bereich der selbständigen Entladung [2] haben sich nicht bewährt.     

Ethynylphosphonamidates for the Rapid and Cysteine‐Selective Generation of Efficacious Antibody–Drug Conjugates

Requirements for novel bioconjugation reactions for the synthesis of antibody–drug conjugates (ADCs) are exceptionally high, since conjugation selectivity as well as the stability and hydrophobicity of linkers and payloads drastically influence the performance and safety profile of the final product. We report Cys‐selective ethynylphosphonamidates as new reagents for the rapid generation of efficacious ADCs from native non‐engineered monoclonal antibodies through a simple one‐pot reduction and alkylation. Ethynylphosphonamidates can be easily substituted with hydrophilic residues, giving rise to electrophilic labeling reagents with tunable solubility properties. We demonstrate that ethynylphosphonamidate‐linked ADCs have excellent properties for next‐generation antibody therapeutics in terms of serum stability and in vivo antitumor activity.     

Strong signal suppression in single-pump optical parametric amplifiers

We show that the combined action of parametric gain and Raman scattering can lead to the complete suppression of an input optical signal in a single-pump parametric amplifier. This suppression is due to an interference between the two parametric gain modes. The interference occurs only at a set of discrete combinations of pump power, phase mismatch, and frequency detuning. Experimentally we are able to demonstrate over 95% (13 dB) suppression of an input signal in an amplifier with a peak parametric gain of only 6 dB.     

Nanobodies: Chemical Functionalization Strategies and Intracellular Applications

Nanobodies can be seen as next‐generation tools for the recognition and modulation of antigens that are inaccessible to conventional antibodies. Due to their compact structure and high stability, nanobodies see frequent usage in basic research, and their chemical functionalization opens the way towards promising diagnostic and therapeutic applications. In this Review, central aspects of nanobody functionalization are presented, together with selected applications. While early conjugation strategies relied on the random modification of natural amino acids, more recent studies have focused on the site‐specific attachment of functional moieties. Such techniques include chemoenzymatic approaches, expressed protein ligation, and amber suppression in combination with bioorthogonal modification strategies. Recent applications range from sophisticated imaging and mass spectrometry to the delivery of nanobodies into living cells for the visualization and manipulation of intracellular antigens.     

Monitoring FET flow control and wall adsorption of charged fluorescent dye molecules in nanochannels integrated into a multiple internal reflection infrared waveguide

Using Si as the substrate, we have fabricated multiple internal reflection infrared waveguides embedded with a parallel array of nanofluidic channels. The channel width is maintained substantially below the mid-infrared wavelength to minimize infrared scattering from the channel structure and to ensure total internal reflection at the channel bottom. A Pyrex slide is anodically bonded to the top of the waveguide to seal the nanochannels, while simultaneously enabling optical access in the visible range from the top. The Si channel bottom and sidewalls are thermally oxidized to provide an electrically insulating barrier, and the Si substrate surrounding the insulating SiO(2) layer is selectively doped to function as a gate. For fluidic field effect transistor (FET) control, a DC potential is applied to the gate to manipulate the surface charge on SiO(2) channel bottom and sidewalls and therefore their zeta-potential. Depending on the polarity and magnitude, the gate potential can accelerate, decelerate, or reverse the flow. Here, we demonstrate that this nanofluidic infrared waveguide can be used to monitor the FET flow control of charged, fluorescent dye molecules during electroosmosis by multiple internal reflection Fourier transform infrared spectroscopy. Laser scanning confocal fluorescence microscopy is simultaneously used to provide a comparison and verification of the IR analysis. Using the infrared technique, we probe the vibrational modes of dye molecules, as well as those of the solvent. The observed infrared absorbance accounts for the amount of dye molecules advancing or retracting in the nanochannels, as well as adsorbing to and desorbing from the channel bottom and sidewalls.     

Synthesis,Structure, and Properties of the High‐Pressure Modification of CePdSn – a 5 K Antiferromagnet

The high‐pressure (HP) modification of CePdSn was synthesized under multianvil high‐pressure (10.5 GPa) high‐temperature (1100 °C) conditions from the normal‐pressure (NP) modification. The structures of both modifications were studied by X‐ray powder and single crystal diffraction: TiNiSi type, Pnma, a = 754.1(2), b = 470.6(1), c = 798.4(3) pm, wR2 = 0.0333, 945 F² values, 20 variables for NP‐CePdSn and ZrNiAl type, , a = 760.03(5), c = 416.06(3) pm, wR2 = 0.0443, 248 F² values, 13 variables for HP‐CePdSn. The structural chemistry of both modifications is goverened by platinum centered trigonal prisms. The platinum and tin atoms in NP‐CePdSn and HP‐CePdSn build up a three‐dimensional [PdSn] network in which the cerium atoms fill channels. Susceptibility measurements on HP‐CePdSn reveal an experimental magnetic moment of 2.55(1) μ_B/Ce atom in the paramagnetic region. At 5 K a paramagnetic‐to‐antiferromagnetic transition is evident from magnetization and specific heat measurements.     

A thin film analog of the corneal mucus layer of the tear film: an enigmatic long range non-classical DLVO interaction in the breakup of thin polymer films

We present experimental results on the instability and dewetting of thin liquid polydimethylsiloxane (PDMS) films intercalated between an aqueous medium and a silicon wafer grafted with PDMS ‘brushes’. This is a thin film analog of the precorneal thin mucus coating sandwiched between the aqueous tear film and the glycocalyx carrying corneal epithelial surface. Lowering of the PDMS–water interfacial tension by a surfactant results in dewetting even of micrometer thick films within a few minutes. The instability appears to be induced by a long range non-classical DLVO force which has the same decay behavior as the nonretarded van der Waals force, but a magnitude which is about 2–3 orders higher. Implications for the breakup of the precorneal mucus layer and the tear film are discussed.