Atom Interferometry with Coherent Enhancement of Bragg Pulse Sequences.

We report here on the realization of light-pulse atom interferometers with large-momentum-transfer atom optics based on a sequence of Bragg transitions. We demonstrate momentum splitting up to 200 photon recoils in an ultracold atom interferometer. We highlight a new mechanism of destructive interference of the losses leading to a sizable efficiency enhancement of the beam splitters. We perform a comprehensive study of parasitic interferometers due to the inherent multiport feature of the quasi-Bragg pulses. Finally, we experimentally verify the phase shift enhancement and characterize the interferometer visibility loss.

Immuno-oncology-101: overview of major concepts and translational perspectives.

Cancer immunotherapy is demonstrating impressive clinical benefit in different malignancies and clinical oncologists are increasingly turning their attention to immune-oncology. It is now well recognized that innate and adaptive immune cells infiltrating tumors are associated with clinical outcomes and responses to treatments, and can be harnessed to patients' benefit. Considerable advances have also been made in understanding how cancers escape from immune attack. Targeting of immunological escape processes regulated by the expression of immune checkpoint receptors and ligands and the down-modulation of tumor antigen presentation is the basis of immuno-oncology treatments. Despite recent achievements, there remain a number of unresolved issues in order to successfully implement cancer immunotherapy in many cancers. Importantly, clinical biomarkers are still needed for better optimization of emerging combination immunotherapies and better treatment tailoring. In this review, we summarize the function of innate and adaptive immune cells in anti-tumor immunity and the general mechanisms exploited by tumor cells to escape and inhibit immune responses as well as therapeutic strategies developed to overcome these mechanisms and discuss emerging biomarkers in immuno-oncology.

Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial.

Background: CD73 is an ecto-enzyme that promotes tumor immune escape through the production of immunosuppressive extracellular adenosine in the tumor microenvironment. Several CD73 inhibitors and adenosine receptor antagonists are being evaluated in phase I clinical trials. Patients and methods: Full-face sections from formalin-fixed paraffin-embedded primary breast tumors from 122 samples of triple-negative breast cancer (TNBC) from the BIG 02-98 adjuvant phase III clinical trial were included in our analysis. Using multiplex immunofluorescence and image analysis, we assessed CD73 protein expression on tumor cells, tumor-infiltrating leukocytes and stromal cells. We investigated the associations between CD73 protein expression with disease-free survival (DFS), overall survival (OS) and the extent of tumor immune infiltration. Results: Our results demonstrated that high levels of CD73 expression on epithelial tumor cells were significantly associated with reduced DFS, OS and negatively correlated with tumor immune infiltration (Spearman's R= -0.50, P < 0.0001). Patients with high levels of CD73 and low levels of tumor-infiltrating leukocytes had the worse clinical outcome. Conclusions: Taken together, our study provides further support that CD73 expression is associated with a poor prognosis and reduced anti-tumor immunity in human TNBC and that targeting CD73 could be a promising strategy to reprogram the tumor microenvironment in this BC subtype.

Second Toe Systolic Pressure Measurements are Valid Substitutes for First Toe Systolic Pressure Measurements in Diabetic Patients: A Prospective Study.

OBJECTIVE: Toe systolic pressure is a component of the standard vascular and diabetic foot assessment. Until now,clinicians have measured only first toe pressure given a lack of evidence for measurements of the other toes. In diabetic patients, first toe measurements are often not possible because of ulceration or amputation. It was hypothesized that the adjacent second toe systolic pressure measurements would be interchangeable with those of the first toe. METHODS: A prospective study was performed on 100 participants with diabetes mellitus. Duplicate systolic toe pressures were measured in the first toe and adjacent second toe using the Systoe Automated Toe Pressure System, Systoe Photophlethysmograph Sensor Cuff, and occlusion cuffs measuring 120 x 25 mm for the first toe and 90 x 15 mm for the second toe. Correlation analysis was followed by Ordinary Least Products regression to detect and distinguish fixed and proportional bias between the two toe measurements. The acceptable limits of interchangeable results were defined as 5-10 mmHg. RESULTS: Correlation coefficient r » 0.908; p < 0.001. Eighty-two percent of the variations in the second toe measurements were accounted for by knowing the first toe measurements and vice versa. Ordinary Least Products regression showed no fixed or proportional bias between the two methods of measurement: second toe systolic pressure = (-0.579) + (1.038) * first toe systolic pressure. Repeatability analysis showed a 0.5%variation between duplicate measurements. CONCLUSIONS: This is the first study which demonstrates that second toe systolic pressures are interchangeable with those of the first toe. Second toe pressures can be used in diabetic patients whose first toe pressures cannot be assessed.

Why Are We Frequently Ordering Urinalyses in Patients without Symptoms of Urinary Tract Infections in the Emergency Department?

(1) Background: In the emergency department (ED), ordering urine tests in patients without symptoms of a urinary tract infection can lead to inappropriate antimicrobial treatment. We aimed to identify factors contributing to the unnecessary ordering of urinalyses in the ED. (2) Methods: An online survey study among nurses and physicians working in the EDs of five hospitals in the Netherlands was conducted. (3) Results: The overall response rate was 26% (221/850; 85 nurses and 136 physicians). The vast majority of the respondents reported knowing when to order urine tests (197/221; 90%). Almost two-thirds of the respondents (145/221; 66%) agreed that they ordered urinalyses because it is rapid and non-invasive to patients. Most nurses (66/86; 78%) said they informed the doctor if they thought the urine test would not contribute to the patient's diagnosis, but only one-third of the physicians agreed with this statement (44/136; 32%). Most respondents (160/221; 72%) thought guidelines or protocols about urinalyses in the ED would be functional. (4) Conclusions: These results suggest urinalyses were frequently ordered in the ED to achieve a fast work process. Nurses and physicians could improve their communication about the indications for urine tests. Developing diagnostic guidelines for urine testing may be convenient.

Retention of 2,4,6-trinitrotoluene and heavy metals from industrial waste water by using the low cost adsorbent pine bark in a batch experiment.

Pine bark is a low cost sorbent originating from the forest industry. In recent years, it has been found to show promise as an adsorbent for metals and organic substances in contaminated water, especially landfill leachates and storm water. This study aims to investigate if pine bark can replace commercial adsorbents such as active carbon. An industrial effluent, collected from a treatment plant of a demilitarization factory, was diluted to form concentration ranges of contaminants and shaken with pine bark for 24 hours. Metals (e.g. Pb, Zn, Cd, As and Ni) and explosives, e.g., 2,4,6-trinitrotoluene (TNT), were analysed before and after treatment. The aim of the experiment was twofold; firstly, it was to investigate whether metals are efficiently removed in the presence of explosives and secondly, if adsorption of explosive substances to pine bark was possible. Langmuir and Freundlich isotherms were used to describe the adsorption process where this was possible. It was found that metal uptake was possible in the presence of TNT and other explosive contaminants. The uptake of TNT was satisfactory with up to 80% of the TNT adsorbed by pine bark.

Anisotropic 2D diffusive expansion of ultracold atoms in a disordered potential.

We study the horizontal expansion of vertically confined ultracold atoms in the presence of disorder. Vertical confinement allows us to realize a situation with a few coupled harmonic oscillator quantum states. The disordered potential is created by an optical speckle at an angle of 30° with respect to the horizontal plane, resulting in an effective anisotropy of the correlation lengths of a factor of 2 in that plane. We observe diffusion leading to non-gaussian density profiles. Diffusion coefficients, extracted from the experimental results, show anisotropy and strong energy dependence, in agreement with numerical calculations.

A millimeter magnetic trap for a dual (85Rb and 87Rb) species atom interferometer.

We present a magnetic trap for cold atoms near a surface of a millimeter-sized atom chip. The trap allows us to capture a large number of atoms with modest electrical currents (40 A) and to generate large magnetic gradients (>300 G cm-1). Here we report a mixture containing 6 × 109 atoms for the two rubidium isotopes 87Rb and 85Rb. This device does not require cleanroom facilities nor micro-machining technologies which makes its construction easier. In addition our design allows the implementation of an optical dipole trap with a laser beam passing through the chip.

NF-kappaB inducing kinase activates NF-kappaB transcriptional activity independently of IkappaB kinase gamma through a p38 MAPK-dependent RelA phosphorylation pathway.

Molecular and biochemical analysis indicates that nuclear transcription factor kappaB (NF-kappaB)-inducing kinase (NIK) mediates IKK activation and NF-kappaB transcriptional activity. However, gene deletion studies suggest that NIK triggers gene expression without affecting IkappaBalpha degradation and NF-kappaB DNA binding activity. In order to investigate the role of NIK in NF-kappaB transcriptional activity, we used mouse embryonic fibroblasts (MEF) derived from wild-type (wt) and IkappaB kinase gamma (IKKgamma) gene deficient (IKKgamma(-/-)) mice. We report that although TNF-induced NF-kappaB transcriptional activity is abolished in IKKgamma(-/-) cells, adenoviral gene delivery of NIK (Ad5NIK) still enhanced transcriptional activity and IL-6 mRNA accumulation. Moreover, NIK targets the transactivation function of NF-kappaB through stimulation of the transactivation domain (TAD) of RelA (S536) in IKKgamma(-/-) cells. Interestingly, Ad5NIK, but not TNF, induces RelA S536 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in IKKgamma(-/-) cells. Functional analysis demonstrated that Ad5NIK-induced NF-kappaB transcriptional activity, IL-6 mRNA expression and RelA phosphorylation are inhibited by the p38 inhibitor SB203580, suggesting a role for this MAPK in NIK signaling to NF-kappaB. These data demonstrate for the first time the presence of an IKKgamma-independent NIK/p38 MAPK-dependent signaling pathway that activates NF-kappaB and induces pro-inflammatory gene expression through RelA phosphorylation.

BisG10, a K+ channel blocker, affects the calcium release channel from skeletal muscle sarcoplasmic reticulum.

The action of bisG10, a potent K+ channel inhibitor, was tested on the Ca2+ release from isolated sarcoplasmic reticulum vesicles of rabbit skeletal muscle. Using a rapid filtration technique, we found that the drug inhibited Ca(2+)-induced Ca2+ release elicited in the presence of extravesicular K+ as counter-ion. This inhibition was not reversed by the addition of valinomycin and still occurred when Cl- was used as co-ion, indicating that not only K+ channels are involved in the inhibiting effect. We found that bisG10 decreased the binding of ryanodine to sarcoplasmic reticulum vesicles, showing that bisG10 is able to block the sarcoplasmic reticulum Ca2+ release channel.

Dose-dependent activation and block by bisG10, a K+ channel blocker, of mouse and frog skeletal muscle KATP channels.

The effects of a K+ channel blocker, bisG10, were examined on ATP-sensitive K+ (KATP) channels in membrane patches excised from mammalian and amphibian skeletal muscle fibres using the patch-clamp technique. At micromolar concentrations, bisG10, added on the intracellular side, induced a strong, reversible, flickery block of KATP channels. BisG10, added on the extracellular side, was about 100-fold less potent at inhibiting channel activity. At 10 nM, intracellular bisG10 increased KATP channel activity. This activation was independent of the presence of internal ATP or Mg2+. The inhibitory effect of bisG10 most likely arose from open-channel block whereas activation could result from more complex, indirect interactions.

Action of heptaminol hydrochloride on contractile properties in frog isolated twitch muscle fibre.

1. Heptaminol stopped or delayed the progressive decline in tension which characterizes the phenomenon of fatigue in frog isolated twitch muscle fibre. 2. Heptaminol had no action on the sodium, potassium and calcium voltage-dependent ionic conductances. 3. The hypothesis of an action via an internal alkalinization was tested by comparison with the action of NH4Cl. Both substances increased the tension. 4. The action of heptaminol was suppressed in sodium-free (TRIS) solution or in the presence of amiloride while the action of NH4Cl was always observed. 5. These results could be explained by a stimulation of the Na/H antiport by heptaminol.

Lipid peroxidation and alpha-tocopherol during an acute respiratory failure after near drowning.

We compare two patients admitted after near drowning. Both presented a severe metabolic acidosis, but only one of them developed an acute pulmonary edema with hypoxemia. An increase of lipid peroxides associated with a reduction of vitamin E concentration has been observed in this later patient. Lipid peroxidation, one of the important causes of disruption of cellular membranes after some injuries, could be implicated in the pathogenesis of lung edema in this patient.

Pharmacological properties of ATP-sensitive K+ channels in mammalian skeletal muscle cells.

The patch-clamp technique (single-channel recordings) was used to study the effects of glibenclamide and some channel openers on the KATP channel in mouse skeletal muscle. In outside/out membrane patches, glibenclamide reversibly inhibited KATP channel activity in a dose-dependent manner with an apparent Ki of 190 nM. In inside/out membrane patches, RP 61419 increased KATP channel activity both in the absence and in the presence of internal ATP while other K+ channel openers such as nicorandil and cromakalim required the presence of internal ATP to evoke channel activation. The half-maximal activity effect for cromakalim, with 0.5 mM ATP at the cytoplasmic face, was observed at about 220 microM. Pinacidil was unable to activate the KATP channel in the absence of internal ATP and could even reduce channel opening in situations where activity was high in the control. In the presence of internal Mg2+, activation by pinacidil occurred when ATP or low and weakly activating concentrations of ADP were present at the cytoplasmic side. Pinacidil activation could also be observed in the presence of ATP or ADP when Mg2+ was absent from the internal solution. The mechanism of action of pinacidil is discussed in terms of interactions between the different nucleotide regulatory sites and the K+ channel opener binding site of the KATP channel. Half-maximum activation of the KATP channel in the presence of 0.5 mM ATP at the cytoplasmic face was observed at 125 microM pinacidil.

High molecular weight lipids from the trilaminar outer wall (TLS)-containing microalgae Chlorella emersonii, Scenedesmus conmmunis and Tetraedron minimum.

High molecular weight lipids were isolated from Chlorella emersonii, Scenedesmus communis and Tetraedron minimum, thin trilaminar outer wall (TLS)-containing freshwater microalgae producing an insoluble non-hydrolysable biopolymer (i.e. algaenan). Molecular weight determination by gel permeation chromatography indicated that their molecular weights range from ca. 400 to 2000 Da. Flash pyrolysis with in situ methylation using tetramethylammonium hydroxide (TMAH) and alkaline hydrolysis showed that the high molecular weight lipids isolated from C. emersonii and S. communis are mainly composed of saturated n-C26 and n-C28 fatty acids and alcohols and of saturated n-C30 and n-C32 alpha,omega-diols and omega-hydroxy acids. In contrast the high molecular weight lipids isolated from T. minimum are predominantly composed of long-chain fatty acids and omega-hydroxy acids. Aromatic moieties were also identified in small amounts in the thermochemolysate and in the hydrolysate. Chemical structural models containing long-chain mono- and polyesters were proposed for the high molecular weight lipids isolated from the three microalgae in agreement with analytical and spectroscopic data. Structural similarity between the outer cell wall of these microalgae and the cuticular membrane of higher plants is suggested.

Comparison of neutral lipid profile of various trilaminar outer cell wall (TLS)-containing microalgae with emphasis on algaenan occurrence.

The neutral lipid profiles of nine species of thin trilaminar outer wall (TLS)-containing freshwater and marine microalgae from the class of Chlorophyceae were studied with emphasis on the relationship between the lipid content and the occurrence of insoluble non-hydrolysable biopolymer (i.e. algaenan). All the freshwater microalgae produce a highly aliphatic algaenan. In sharp contrast, no algaenan was isolated from the two marine microalgae, Chlorella marina and Chlorella minutissima marina, supporting the absence of a close relationship between the presence of TLS and the occurrence of algaenan. High molecular weight straight-chain hydrocarbons (C23-C29) were identified in most of the algaenan-producing microalgae and in the algaenan-devoid C. minutissima marina, whereas only low molecular weight hydrocarbons were detected in algaenan-producing Scenedesmus subspicatus and in algaenan-devoid C. marina. Sterols, phytol and fatty alcohols were the major constituents of the polar fraction of the neutral lipids of all the microalgae investigated. High molecular weight saturated or mono-unsaturated alcohols were detected in C. emersonii and in all the microalgae belonging to the genus Scenedesmus. High amounts of saturated C30 and C32 alpha,omega-diols were also detected in S. subspicatus, S. armatus and S. pannonicus. Three classes of lipids were encountered in very small amounts in the medium polarity fraction of the neutral lipids of the microalgae investigated: (i) Monoesters composed predominantly of saturated C16 or C18 fatty acids and saturated C8, C16 or C18 alcohols and (ii) long-chain methyl ketones from C25 to C31 were detected in several species and (iii) methyl esters of fatty acids ranging from C16 to C28 were identified in all the microalgae. Attempts to use the neutral lipid composition and particularly the unusual long-chain lipids, as specific indicators of the occurrence of algaenan in TLS-containing microalgae were unsuccessful.

Influence of growth status on composition of extra-cellular polysaccharides from two Chlamydomonas species.

The extracellular polysaccharides released by Chlamydomonas augustae at the beginning of growth contain mainly arabinose, glucose and galactose. Methylation analysis revealed that the major fraction of these extracellular polysaccharides can be described as a highly branched polymer composed of (1, 3, 4)-linked glucose and terminal arabinose and galactose units. The chemical composition of these extracellular polysaccharides varies during growth and in the stationary phase of growth glucose and glucuronic acid are the main components. The major fraction of the extracellular polysaccharides can be then described as a linear polymer composed of (1, 4)-linked glucose and (1, 4)-linked glucuronic acid. In sharp contrast, the extracellular polysaccharides from C. corrosa are independent of growth status and contain arabinose and galactose as major sugars. Methylation analysis indicated a highly branched polysaccharide composed of arabinose as unique branch point units and of terminal galactose residues.

The binding of strontium and europium by an aquatic fulvic acid--ion exchange distribution and ultrafiltration studies.

The complexation of an aquatic fulvic acid, FA, with Sr(2+) and Eu(3+) was studied at 0.10 and O1.O1M NaClO(4) using trace levels of metal ([Sr(2+)] = 10(-9)M and [Eu(3+)] = 10(-11)M) and a constant FA concentration (0.12 g/l) by an ultrafiltration technique (UF) and an ion exchange distribution method (IEDS). The overall complex formation function, beta(OV) for the two metals was calculated and its dependence on pH, ionic strength and method was investigated. The absolute value of log beta(OV), the pH dependence and the influence of the ionic strength on the complexation differed depending on the metal ion and experimental technique employed. By considering the functional group heterogeneity of the FA molecule, it was possible to predict the most predominantly bound site (keto-enol) and resolve the complex formation function for this site and EU(3+) (IEDS: 9.43 +/- 0.29 l/eq at 0.10M and 10.58 +/- 0.72 l/eq at 0.01M; UF: 7.19 +/- 1.51 l/eq at 0.01M and 6.88 +/- 0.91 l/eq at 0.01M). The results are discussed in the light of possible intrinsic problems of the two experimental methods.

Europium complexation by an aquatic fulvic acid - effects of competing ions.

Effects of competing ions, Fe (2+)Fe (3+) and Al(3+), on Eu(3+) complexation with an aquatic fulvic acid (FA), have been investigated using an ion exchange technique. The influence of different concentrations (10(-6), 10(-4) M) of the competing ions on the distribution coefficient for Eu was measured, and the overall complex formation function, beta(ov), was resolved for the Eu systems with Fe and Al. All systems showed pH-dependent beta(ov)-functions. The presence of 10(-4) M concentration of competing ion reduced the resolved complex formation function (logbeta(ov)) for Eu complexation with fulvic acid by 0.6 and 0.4 log units at pH 5 for Fe and Al, respectively. this indicates that Fe has a more perturbing effect on Eu-FA complexation than Al. In similar competition studies Sr and Eu were found not to perturb each others complexation with fulvic acid, suggesting therefore that the two metals probably bind to different sites on the fulvic acid molecule.

Determination of low molecular weight organic acids in soil solution by HPLC.

An HPLC method employing an ion exclusion column was developed for the determination of low molecular weight organic acids in soil solution. The method includes extensive sample pretreatment using ultrafiltration and cation exchange. The method showed linear calibration graphs (r>0.99) and the limits of detection in the range 0.1-26 muM. The recovery of eleven added acids ranged from 89 to 102%. Soil solutions of five horizons of a podzolised soil were analysed. The results showed that these compounds made up 1-3% of the dissolved organic carbon and 0-14% of the acidity. Identification of the major acids was also carried out by capillary zone electrophoresis.