High-Contrast Interference of Ultracold Fermions.

Many-body interference between indistinguishable particles can give rise to strong correlations rooted in quantum statistics. We study such Hanbury Brown-Twiss-type correlations for number states of ultracold massive fermions. Using deterministically prepared ^{6}Li atoms in optical tweezers, we measure momentum correlations using a single-atom sensitive time-of-flight imaging scheme. The experiment combines on-demand state preparation of highly indistinguishable particles with high-fidelity detection, giving access to two- and three-body correlations in fields of fixed fermionic particle number. We find that pairs of atoms interfere with a contrast close to 80%. We show that second-order density correlations arise from contributions from all two-particle pairs and detect intrinsic third-order correlations.

Usefulness of an Implantable Loop Recorder to Detect Clinically Relevant Arrhythmias in Patients With Advanced Fabry Cardiomyopathy.

Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holter electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holter ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 ± 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses ≥3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter-defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holter ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder.

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice.

Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention.

A randomized trial comparing two cuffed emergency cricothyrotomy devices using a wire-guided and a catheter-over-needle technique.

BACKGROUND: According to different algorithms of airway management, emergency cricothyrotomy is the final step in managing the otherwise inaccessible airway. As an alternative to an open surgical procedure, minimally invasive approaches exist. Various sets for different methods are commercially available. QuickTrach™ (VBM Medizintechnik GmbH, Sulz am Neckar, Germany) contains a plastic cannula over a metal needle for direct placement in the trachea, whereas a guide-wire is used for the actual placement of the cannula in the Melker Set™ (Cook Group Incorporated, Bloomington, IN). OBJECTIVE: We hypothesize that the direct puncture involving less discrete steps is faster to perform. However, it will lead to more complications due to the higher force needed to place the relatively thick needle. METHOD: After approval of the local ethics committee, the study was performed on cadavers of 16 adult sheep. A wire-guided cricothyrotomy was compared with a catheter-over-needle technique. Successful placement and performance time were compared. Complication rate and maximal achieved airway pressure were evaluated. Data is given as mean and interquartile range, and Mann-Whitney U-test (p < 0.05) for significant differences. RESULTS: With the wire-guided technique, successful placement was possible in all attempts. The catheter-over-needle method was successful in 63% and had a higher complication rate (75% vs. 13%). The cannula-over-needle method allowed a faster cricothyrotomy (32 [2-34] vs. 53 [52-56] s). Both methods allowed the delivery of similar maximal airway pressures (50 [44-51] vs. 48 [43-53] mbar). CONCLUSION: The wire-guided method proved to be the more reliable technique, leading to fewer complications. However, the direct puncture was faster to perform. Placed accurately, both devices allowed sufficient ventilation.

Cytosine-arabinoside-induced keratopathy: a model of corneal proliferation kinetics.

AIMS: The use of the chemotherapeutic cytosine arabinoside (Ara-C) causes an ocular toxic reaction, characterized by aspecific keratopathy. We examined the pathway of the damaged cells by in vivo confocal microscopy. METHODS: Prospective study of 11 patients with acute myeloic leukemia treated with high-dose Ara-C. Ten eyes developed fluorescein-negative punctate keratopathy, and were examined by slit lamp and in vivo confocal biomicroscopy at days 1, 3-4 and 9-14 after the beginning of ocular symptoms. RESULTS: In vivo confocal microscopy revealed disseminated highly reflective granular irregular intraepithelial elements in the central cornea, which affected about 3% of epithelial cells. At day 1 of symptoms, these elements were present only in the basal epithelial layer (median 275.5/mm(2)), at days 3-4 they were mainly found in the basal (187.5/mm(2)) but also in the apical layers (96/mm(2)), at days 9-14 they mainly presented in more superficial layers (115/mm(2) apically vs. 15.5/mm(2) in the basal layers). DISCUSSION: The intraepithelial distribution of cells with a granular cytosolic signal evolved over time, reflecting the migration of the necrotic basal cells to the wing cell layer and finally to apical epithelial layers. The desquamation of the necrotic cells is related to the resolution of symptoms, according to the period of the epithelial cell turnover. By confocal microscopy, we could follow the intraepithelial route of cells damaged by Ara-C in vivo.

Device-based impedance measurement is a useful and accurate tool for direct assessment of intrathoracic fluid accumulation in heart failure.

AIMS: Heart failure patients are often equipped with implanted devices and are frequently hospitalized due to volume overload. Reliable prediction of imminent fluid congestion has the potential to provide early detection of cardiac decompensation and therefore might be capable of enhancing therapy management. We investigated whether implant-based impedance (Z) measurement is closely correlated with directly assessed extravascular lung water and might thus be useful for patient monitoring. METHODS AND RESULTS: In sheep, pulmonary fluid congestion was induced. Continuous haemodynamic monitoring was performed and extravascular lung water index (EVLWI) assessed. An implanted device with a right ventricular lead measured Z using different electrode configurations. All animals developed gradual pulmonary fluid accumulation leading to inclining lung oedema: EVLWI did increase from 9.5 +/- 1 to 21.1 +/- 5.1 mL/kg (+127%). A concomitant decrease of Z by up to 23%, depending on the electrode configuration, was observed and regression analysis between Z and EVLWI yielded a significant inverse correlation. CONCLUSION: Changes of Z show a strong inverse correlation with changes of directly measured EVLWI. This allows the application of Z as a measure of intrathoracic fluid status and has the potential to optimize patient care, especially in the context of evolving telemedicine concepts.

Surface pressure induced charge transfer between fullerene and tetrathiafulvalene derivative in Langmuir-Blodgett films.

Structures and electronic states of a 1:1 mixture of bis-tetrathiafulvalene annulated macrocycle (1) and C60 in Langmuir films at the air-water interface and Langmuir-Blodgett (LB) films on solid substrates were examined. Compression of the Langmuir films induced for the first time a phase transition from a weakly interacting state without charge transfer (CT) to a neutral CT state. The scanning force microscope images of LB films transferred onto mica by a single withdrawal showed quite different spatial patterns depending on the CT states. When deposited at around 1 mNm(-1), a domain structure with 3 nm height was obtained, which corresponded to the state without CT interaction. Contrastingly, once the CT interaction was induced by applying surface pressure, a network structure was observed with a height of 6 nm. The CT band, whose transition moment was almost parallel to the substrate surface, was observed at 11.5 x 10(3) cm(-1) in the polarized UV-VIS-NIR spectra of the films deposited at 9 mNm(-1). The phase transition was irreversible, although the surface pressure-area isotherm showed a reversible behavior below 9 mNm(-1). The morphology and electronic state of the film was controllable merely by changing the surface pressure at the air-water interface.

Targeted proteolysis sustains calcineurin activation.

BACKGROUND: Calcineurin (CnA) is important in the regulation of myocardial hypertrophy. We demonstrated that targeted proteolysis of the CnA autoinhibitory domain under pathological myocardial workload leads to increased CnA activity in human myocardium. Here, we investigated the proteolytic mechanism leading to activation of CnA. METHODS AND RESULTS: In patients with diseased myocardium, we found strong nuclear translocation of CnA. In contrast, in normal human myocardium, there was a cytosolic distribution of CnA. Stimulation of rat cardiomyocytes with angiotensin (Ang) II increased calpain activity significantly (433+/-11%; P<0.01; n=6) and caused proteolysis of the autoinhibitory domain of CnA. Inhibition of calpain by a membrane-permeable calpain inhibitor prevented proteolysis. We identified the cleavage site of calpain in the human CnA sequence at amino acid 424. CnA activity was increased after Ang II stimulation (310+/-29%; P<0.01; n=6) and remained high after removal of Ang II (214+/-17%; P<0.01; n=6). Addition of a calpain inhibitor to the medium decreased CnA activity (110+/-19%; P=NS; n=6) after removal of Ang II. Ang II stimulation of cardiomyocytes also translocated CnA into the nucleus as demonstrated by immunohistochemical staining and transfection assays with GFP-tagged CnA. Calpain inhibition and therefore suppression of calpain-mediated proteolysis of CnA enabled CnA exit from the nucleus. CONCLUSIONS: Ang II stimulation of cardiomyocytes increased calpain activity, leading to proteolysis of the autoinhibitory domain of CnA. This causes an increase in CnA activity and results in nuclear translocation of CnA. Loss of the autoinhibitory domain renders CnA constitutively nuclear and active, even after removal of the hypertrophic stimulus.

Tetra-TTF calix[4]pyrrole: a rationally designed receptor for electron-deficient neutral guests.

A calix[4]pyrrole incorporating four appended tetrathiafulvalene (TTF) units has been synthesized, and its receptor abilities toward neutral electron-deficient guests, such as 1,3,5-trinitrobenzene, tetrafluoro-p-benzoquinone, and tetrachloro-p-benzoquinone, have been studied in solution by UV-vis and 1H NMR spectroscopies as well as in the solid-state by X-ray crystallography. In its 1,3-alternate conformation a 1:2 sandwich-like complex-stabilized by charge transfer and hydrogen bonding interactions-is formed between the tetra-TTF calix[4]pyrrole and the guest molecules. However, upon addition of chloride ions to the complex the 1,3-alternate conformation is changed in favor of a cone conformation which serves to effect a release of the guests from the tetra-TTF calix[4]pyrrole.

Langmuir-Blodgett films of amphiphilic bis(tetrathiafulvalene) macrocycles with four alkyl chains.

Amphiphilic bis(tetrathiafulvalene) [bis(TTF)] macrocycles with four alkyl chains were fabricated as novel electrically active Langmuir-Blodgett (LB) films. Two TTF units were linked via [24]crown-8, [21]crown-7, and [18]crown-6 macrocycles, forming charge-transfer (CT) salts with 2,3,5,6-tetrafluoro-7,7,8,8-tetracyano-p-quinodimethane (F4-TCNQ) at the air-water interface and on solid substrates. The CT salt of the amphiphilic bis(TTF)-macrocycle having a [24]crown-8 ring system formed a uniform surface morphology on mica. Using single-crystal X-ray structural analysis, the layer structure between the hydrophobic chains and the one-dimensional pi-pi stack of the CT salt was confirmed. Our results show that the bis(TTF)-macrocycle was folded at the flexible [24]crown-8 moiety, forming intramolecular pi-pi dimer structures and one-dimensional intermolecular pi-pi stacks with F4-TCNQ dimers. The open-shell electronic structure of the LB films was determined by electronic spectra, electrical conductivity, and electron spin resonance analyses. Asymmetry was introduced into the bis(TTF)-macrocycle by changing the ring size from [24]crown-8 to [21]crown-7. The surface morphology of the CT salts with F4-TCNQ was established as two-dimensional round-shape domains on mica. Further reduction of the macrocyclic ring from [21]crown-7 to [18]crown-6 resulted in a CT salt of the bis(TTF)-macrocycle with F4-TCNQ with a leaf-shape domain morphology and a typical dimension of approximately 1 microm2 on mica. In general, decreasing the macrocyclic ring size from [24]crown-8 to [21]crown-7 or [18]crown-6 affected the inter- and intramolecular interactions and the surface morphologies of LB films.

New strategies and building blocks for functionalised 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene derivatives, including pyrrolo-annelated derivatives and pi-extended systems with intramolecular charge-transfer.

A range of new functionalised 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene (TTFAQ) derivatives have been synthesised from the key di(halomethyl) building blocks, 10-[4,5-bis(bromomethyl)-1,3-dithiol-2-ylidene]-anthracene-9(10H)-one 10, 10-[4,5-bis(chloromethyl)-1,3-dithiol-2-ylidene]anthracene-9(10H)-one 11 and 9-[4,5-bis(chloromethyl)-1,3-dithiol-2-ylidene]-10-[4,5-bis(hexylsulfanyl)- 1,3-dithiol-2-ylidene]-9,10-dihydroanthracene 18. A Diels-Alder strategy comprising trapping of the transient exocyclic diene 19, which is derived from 18, with 1,4-naphthoquinone leads to the aromatised TTFAQ anthraquinone system 21. Horner-Wadsworth-Emmons olefination of 21 with the anion generated from reagent 22 gave the fused bis(TTFAQ) structure 23. Pyrrolo-annelated derivatives 30-34 have been obtained in a sequence of reactions from compound 10. Mono-formylation of the pyrrole ring of 32 and 33 under Vilsmeier conditions gave 35 and 36 which upon reaction with 2,4,5,7-tetranitrofluorene gave the donor-pi-acceptor diads 38 and 39. Cyclic voltammetry (CV) in solution for all the TTFAQ derivatives shows the typical quasi-reversible two-electron oxidation wave of the TTFAQ core at potentials which vary slightly depending on the substituents. For example, the value of Eox is raised by the electron withdrawing anthraquinone and tetranitrofluorene units of 21 and 38, respectively. The CV of the conjugated TTFAQ dimer 23 showed two, two-electron oxidation waves corresponding to the sequential formation of 23(2+) and 23(4+) (delta Eox = 130 mV) providing evidence for a significant intramolecular electronic interaction, i.e. the dication 23(2+) acts as a conjugated donor-pi-acceptor diad, thereby raising the oxidation potential of its partner TTFAQ unit. Spectroelectrochemical studies on 23 support this explanation. A strong intramolecular charge transfer band at lambda max 538 nm is seen in the UV-Vis spectra of the TTFAQ-pi-tetranitrofluorene diads 38 and 39. The X-ray crystal structures are reported for compounds 30, 33 and 34. The pyrrolo-TTFAQ moiety adopts a saddle-shape with the central ring of the dihydroanthracene moiety folded along the C(9) ... C(10) vector in each case. Significant intermolecular interactions are observed in the structures.

A mono-TTF-annulated porphyrin as a fluorescence switch.

Annulation of one TTF unit directly to the porphyrin chromophore produces an almost nonfluorescent species which can be transformed into a fluorescent species by oxidation of the TTF unit.

A pyrrolo-tetrathiafulvalene cage: synthesis and X-ray crystal structure.

[reaction: see text] A novel type of tetrathiafulvalene-cage 4 containing three monopyrrolo-tetrathiafulvalene units has been prepared employing a general and efficient synthetic approach. X-ray crystal structure analysis revealed that the cage is able to accommodate solvent molecules within a cavity in the solid state.

Coupling of metal-based light-harvesting antennas and electron-donor subunits: trinuclear ruthenium(II) complexes containing tetrathiafulvalene-substituted polypyridine ligands.

Three new tetrathiafulvalene-substituted 2,2'-bipyridine ligands, cis-bpy-TTF(1), trans-bpy-TTF(1), and cis-bpy-TTF(2) have been prepared and characterized. X-ray analysis of trans-bpy-TTF(1) is also reported. Such ligands have been used to prepare two new trinuclear Ru(II) complexes, namely, [[(bpy)(2)Ru(micro-2,3-dpp)](2)Ru(bpy-TTF(1))](PF(6))(6) (9; bpy=2,2'-bipyridine; 2,3-dpp=2,3-bis(2'-pyridyl)pyrazine) and [[(bpy)(2)Ru(micro-2,3-dpp)](2)Ru(bpy-TTF(2))](PF(6))(6) (10). These compounds can be viewed as coupled antennas and charge-separation systems, in which the multichromophoric trinuclear metal subunits act as light-harvesting antennas and the tetrathiafulvalene electron donors can induce charge separation. The absorption spectra, redox behavior, and luminescence properties (both at room temperature in acetonitrile and at 77 K in a rigid matrix of butyronitrile) of the trinuclear metal complexes have been studied. For the sake of completeness, the mononuclear compounds [(bpy)(2)Ru(bpy-TTF(1))](PF(6))(2) (7) and [(bpy)(2)Ru(bpy-TTF(2))](PF(6))(2) (8) were also synthesized and studied. The properties of the tetrathiafulvalene-containing species were compared to those of the model compounds [Ru(bpy)(2)(4,4'-Mebpy)](2+) (4,4'-Mebpy=4,4'-dimethyl-2,2'-bipyridine) and [[(bpy)(2)Ru(micro-2,3-dpp)](2)Ru(bpy)](6+). The absorption spectra and redox behavior of all the new metal compounds can be interpreted by a multicomponent approach, in which specific absorption features and redox processes can be assigned to specific subunits of the structures. The luminescence properties of the complexes in rigid matrices at 77 K are very similar to those of the corresponding model compounds without TTF moieties, whereas the new species are nonluminescent, or exhibit very weak emissions relative to those of the model compounds in fluid solution at room temperature. Time-resolved transient absorption spectroscopy confirmed that the potentially luminescent MLCT states of 7-10 are significantly shorter lived than the corresponding states of the model species. Photoinduced electron-transfer processes from the TTF moieties to the (excited) MLCT chromophore(s) are held responsible for the quenching processes.

Electrochemical recognition of cations by bis(pyrrolo)tetrathiafulvalene macrocycles.

[structure: see text] Tetrathiafulvalene redox-responsive ligands devoid of cis/trans isomerism containing the electroactive bis(pyrrolo[3,4-d])tetrathiafulvalene moiety and polyether subunits have been synthesized. One ligand exhibits high binding affinities for Pb2+ and Ba2+ cations as shown by independent methods (1H NMR, UV-vis spectroscopy, and cyclic voltammetry). The ability of this receptor to electrochemically recognize Pb2+ and Ba2+ is shown by cyclic voltammetry.