bluuebunny/crossref_metadata_2025 huggingface dataset:
PLATELET ALPHA2-ADRENERGIC RECEPTOR ABNORMALITIES IN PATIENTS WITH IDIOPATHK: SCOLIOSIS
Authors: Wachtfogel Yanina T , Floman Yizhar , Liebergall Meir , Colman Robert W , Eldor Amiram
Published: August 2018

Idiopathic scoliosis is a genetic multisystem disease involving skeletal, biochemical, central nervous svstem, muscle and blood platelet abnormalities. Platelets of patients with idiopathic scoliosis have been shown to have decreased adenosine diphosphate and epinephrine-induced aggregation. Similarities between the contractile protein system of platelets and muscle have made the platelet a popular model for certain aspects of muscle physiology. This study confirmed that 64% of the patient platelets tested exhibited a significantly decreased sensitivity to aggregation bv epinephrine. In seven of the eleven patients studied, epinephrine induced aggregation was markedly decreased, i.e., the threshold of agonist was markedly elevated ≥11 uM). The geometric mean concentration of epinephrine required to produce complete second-wave aggregation in idiopathic scoliosis patients was 8μM. as compared to a control concentration of luM. We therefore examined the platelet alpha2-adrenergic receptors of 17 patients with idiopathic scoliosis bv measuring ligand binding using the selective antagonist, methyl yohimbine. Platelets from healthv individuals had 185 ± 16 sites per platelet with a Kd of 1.90 ± 0.32 nM, while patients with idiopathic scoliosis had 54 ± 22 sites per platelet with a of 1.02 ± 0.03 nM. The number of binding sites per platelet in idiopathic scoliosis patients were significantly decreased (p < 0.05) as compared to controls , while the was not significantly different (p > 0.05) between the two groups. Seven of these patients exhibited a significant decrease (p < 0.05) in the number of alpha2-adrenergic receptors on their platelets while the binding in 7 additional patients was undetectable.Three patients exhibited normal receptor number and affinity as compared to normal individuals. This study indicates a profound alteration in the number and function of the alpha2-adrenergic receptors in platelets of patients with idiopathic scoliosis and indicates the functional heterogeneity of the receptor disorder. Further investigation of platelet abnormalities may give insight into the putative muscle defects.
CONTAMINATING LEUKOCYTES INFLUENCE THE STORAGE CONDITIONS OF PLATELET CONCENTRATES
Authors: Pietersz R N I , de Korte D , Roos D , Reesink H W
Published: August 2018

Leukocyte poor platelet concentrates (PC), containing less than 10 leukocytes, prepared from buffycoats can be stored in normal PVC bags for 7 days at 22°C without deterioration of the pH. We assumed that a low number of leukocytes present in the PC, is a critical factor to maintain the pH. To test this hypothesis increasing amounts of leukocytes were added to four groups of three PC with comparable plasma volumes (mean 58.6 ± 0.8 (SD) ml) and platelet concentrations (1.01 ± 0.04×109 /ml). Group I had a leukocyte concentration of 0.14±0.048×106 /ml, group II 1.96±0.09×106 /ml, group III 5.53±0.98×106 /ml, and group IV 13.0±0.93×106 /ml. The PC were stored in normal PVC bags for 7 days at 22°C. Measurements in vitro were performed at day 0, 2, 5 and 7.

The initial mean pH value was 7.12±0.02 (SD) for all PC and dropped to 6.89, 6.85, 6.77 and 6.61 for group I to IV respectively, at day 7. A significant correlation (Spearman rank test) between low pH values and high leukocytes was found. The same significant positive correlation was observed between high leukocyte concentrations and high glucose consumption and high lactate production and LDH release during storage.

These results show that the amount of leukocytes in PC has a significant contribution to the detrimental effect on pH during platelet storage. It is therefore important to prepare PC with a leukocyte count lower than 10 . Moreover the risk of alloimmunisation against HLA antigens will be diminished.
ACTIVATION OF PROTEIN KINASE C INHIBITS THROMBIN AND FLUORIDE STIMULATED EICOSANOID PRODUCTION IN HUMAN PLATELETS
Authors: Poll C T , Kyrle P A , Westwick J
Published: August 2018

Touqui et al (1986) have suggested that phosphorylation by protein kinase C of a 1ipomodulin-1 ike polypeptide extracted from platelets renders it inactive as an inhibitor of phospholipase A2. We have examined this suggestion by measuring thromboxane (Tx) B2 generation and cytosolic free calcium concentration ([Ca++]i) in stimulated, washed human platelets loaded with or without quin-2. Addition of thrombin (0.077, 0.23, 0.77, 2.3 and 7.7 nM) to control platelets produces a dose-related elevation of [Ca++]i (10±5, 50±7, 260±30, 550±25 and 1500±100 nM respectively) and generation of TxB2 (0, 9±4, 45±6, 194±10 and 375±30 pmoles/108 platelets respectively). Preincubation of platelets for 1 min with 1-oleoyl-2-acetyl-rac-glycerol (OAG, 22-198 μM), phorbol myristate acetate (PMA, 1.616 nM) or EGTA (2 mM) produces a marked inhibition of high and low dose thrombin (7.7 nM and 0.77 nM) or NaF (18 mM) induced elevation of [Ca++]i and TxB2 generation. Pretreatment of platelets with the protein kinase C inhibitor, H-7 (60 uM), prevented the inhibition of TxB2 formation induced by PMA (4.816 nM) or OAG (66-198 μM) in either thrombin (0.77 nM) or NaF (18 mM) stimulated platelets. When arachidonic acid (AA, 10 μM) is used as the stimulus, the Δ[Ca++]i is 190±15 nM and TxB2 generation is 35.9±2 pmoles/108 platelets. While pretreatment with 4.8 nM PMA obliterates the AA-induced Δ[Ca++]i and partially reduces (p< 0.05) the TxB2 generation to 27.8+3 pmoles/108 platelets. PMA and OAG pretreatment also inhibits TxB2 generation in thrombin-stimulated, non-quin-2-1oaded platelets. Thus, at least with intact, agonist- and NaF-stimulated platelets, activation of protein kinase C inhibits eicosanoid production.

We thank the British Heart Foundation and Ciba-Geigy USA for financial support.
HUMAN MEIZOTHROMBIN 1, ITS ISOLATION AND PROPERTIES
Authors: Latallo Zbigniew S , Jackson Craig M
Published: August 2018

Meizothrombin (MT) and meizothrombin des Fragment 1 (MT1) are intermediates in the conversion of prothrombin to α-thrombin (αTH). Due to their transient character, properties of these enzymes are difficult to establish. Isolation of MT1 was achieved by affinity chromatography on D-Phe-Pro-Arginal (FPRal)immobilized on Affi-Gel 10 as originally employed for thrombin purification (Patel et al. Biochim.Biophys. Acta 748,321 (1983)). Human prethrombin 1 was activated with the purified activator from Echis carinatus venom in the presence of Ca++;, benzamidine and FPRal gel at pH 7.8. After exhaustive washing the MT1 was eluted with 0.1 M hydroxylamine in 0.15 M Na acetate buffer, pH 5.5. Under these conditions the MT1 is stable and can bestored at -70°C. Upon changing the pH of the preparation to 8.0, complete conversion into aTH occurred atroom temperature within 48 hours. Homogeneity of both preparations wasdemonstrated by PAGE. The Km and ke, values for MT1 measured on Tos-Gly-Pro-Arg pNA(0.1 M NaCl, 0.01 M TRIS, 0.01 M HEPES, 0.1% PEG, pH 7.8, 25°C) were 15.7 /iM and 126 s-1. The kinetic con stants for the aTH resulting from autocatalytic degradation of MT1 were indistinguishable from those previously established forαTH obtained by Xa activation i.e. 4.77 /μM and 126 s-1. Clotting activity of MT1 was found to be only one fifth as high as that of the resulting μTH(746 u/mg vs. 3900 u/mg as tested using the NIH standard) .Inhibitionof MTl by antithrombin III was alsomuch less rapid than αTH andmost importantly, it was not affected by high affinity heparin( Mr20,300). Under conditions of the experiment (0.3 M NaCl, 0.0rl M TRIS, 0.01 M HEPES, 2.5 mM EDTA, 0.1% PEG, pH 7.8, 25°C; [ATIII] 100 nM, [E] 10 nM), the pseudo first order rate constants in the absence of heparin were 4.04 × 10-3V1 (MTl) and 1.13 × 10-3V1 (αTH), giving apparent second order rate constants of 4.04 × 103 and 1.13 × 10-4M-1s-1. In the presence of 4.5 nM of heparin the observed first order rate constant for MTl remained unchanged whereas it increased to 6.241 × 10-3s-1 (5.5 fold) for αTH. This apparent lack of an effect of heparin may be of significance in vivo.

Supported by a Matching Grant from the American National Red Cross and by the Southeastern Michigan Blood Service.
AN IMPORTANT ROLE OF CARBOHYDRATE MOIETIES ON CANCER CELL MEMBRANE GLYCOPROTEINS IN CANCER CELL-INDUCED PLATELET AGGREGATION
Authors: Kitagawa H , Yamamoto N , Kosaki G , Yamazaki H
Published: August 2018

Platelet aggregation induced by cancer cells may be an essential process in the development of hematogenous metastasis of cancers. A mechanism in HMV-I (human vaginal melanoma cell line)-induced platelet aggregation was studied by using monoclonal antibodies against membrane proteins of cancer cells or platelets. HMV-I cells or their membrana ractions induced platelet aggregation of human heparinized PRP, to which hirudin had no inhibitory effect. The platelet aggregation by HMV-I was completely lost after the pretreatment of the cells with 0.3U/ml neuraminidase for 60 min at 37°C. Preincubation of platelets with monoclonal antibodies against platelet GP lb or GP Ilb/lIIa inhibited HMV-I induced aggregation. A monoclonal antibody MB3 (igM) against another human melanoma (HMMB) which had been transplanted in nude mice was produced by hybridoma technique. Screening studies by cell binding ELISA revealed that MB3 antibody reacted with not only HMMB cells but also many other cells including HMV-I, M7609 (colon carcinoma cell line) and normal fibroblasts. Western-blot analyses showedthat MB3 antibody reacted with multiple, more than ten, proteins with molecular weights ranging from UO to 200 kDa in unreduced SDS-PAGE of HMV-I, HMMB or M7609. In contrast, when .these cells pretreated with neuraminidase were used in Western-blot, MB3 reactivity were all lost. MB3 reacted with at least three glycoproteins of human red cell membrane in Western-blot, but it did not react with human platelets. Immune adherent asgay with trypsin-treated HMV-I or HMMB cells as target cells showed negative reactivity. MB3 antibody inhibited HMV-I-induced aggregation of platelets, but did not inhibit M7609-induced aggregation which depended on thrombin generation.

These results suggest that MB3 antibody may be against sialic acid-containing carbohydrate moieties of membrane glycoproteins on these cancercells and that the carbohydrate(s) may play a critical role in' cancer cell-platelet interaction.
THROMBASTHENIA WITH AN ABNORMAL PLATELET MEMBRANE GPIIb OF DIFFERENT MOLECULAR WEIGHT
Authors: Moroi M , Jung S M , Yoshida N , Aoki N , Tanoue K
Published: August 2018

We describe several individuals with abnormal platelet glycoprotein lib (GPIIb) of different molecular weight (MW), a novel defect in that previously reported thrombasthenics have not shown GPIIb molecules of abnormal MW. Patient 1 shows 2 bands of GPIIb (one with normal MW and one with abnormal MW) in SDS-PAGE (lectin and antibody staining). This patient has a mild bleeding tendency, and her platelets did not aggregate in response to ADP (2-10 μM) and had severely depressed collagen induced aggregation ,but responded normally to ristocetin. The MW of the abnormal GPIIb band was calculated to be 122 KDa (compared to the 129 kDa of normal GPIIb) in non-reduced SDS-PAGE; the MW was 128 kDa (compared to the normal 118 kDa) in reduced SDS-PAGE. The amount of each GPIIb band, calculated from densitometry, was approximately 35% for the GPIIb of abnormal MW and 20% for the normal MW GPIIb, relative to the amounts of GPIIb found in normal individuals. Assays of fibrinogen binding to the patient`s platelets indicate that they contain 25% of the fibrinogen receptor as compared to normal platelets. Crossed immunoelectrophoresis showed the formation of the GPIIb/IIIa complex, which was found to consist mostly of normal MW GPIIb and GPIIIa. The patient's father showed decreased aggregability in response to ADP, and his platelets also contained abnormal and normal GPIIb. The father's platelets, however, contained about 50% normal GPIIb as compared to normal platelets, and his platelets have about 50% the number of fibrinogen receptors compared to normal platelets. From these results, the patient was suggested to have heterozygous GPIIb molecules, and the observed defects in aggregability would be attributable to the decrease of normal GPIIb to 20-30% of the normal level. Quite recently, we found another thrombasthenic individual who has homozygous abnormal GPIIb molecules. Electrophoretic mobilities of his abnormal GPIIb on SDS-PAGE indicated that the abnormal GPIIb's were very similar between the 2 cases, and two-dimensional, unreduced-reduced SDS-PAGE suggested that the abnormal GPIIb consists of a single chain.
ABNORMAL CALCIUM TRANSPORT INTO MICROSOMES OF GRAY PLATELET SYNDROME
Authors: Levy-Toledano S , Enouf J , Lebret M , Bredoux R , Caen J P
Published: August 2018

Gray platelets initially described as lacking α granules also show thrombin-induced aggregation and release lower than normal. One of the possible explanation is a modified intracellular Ca2+ concentration which is involved in platelet activation. We then decided to investigate the relationship between the morphological abnormality and a possible regulation of platelet Ca2+ concentration.

We isolated a platelet membrane fraction (100,000 g) enriched in intracellular membranes which actively sequesters Ca2+. This Ca2+ uptake was mediated by a characterized (Ca2+ + Mg2+) ATPase.

The isolated membrane vesicles from two patients show an increase in the calcium uptake. The stimulation reaches a factor 2 to 3 agd the Ca2+ uptake appears greatly increased whatever the Ca concentration used. This led us to investigate the Ca2+ + Mg2+ ATPase activity. The enzymatic activity appears increased in the first 10 minutes which correlates with the increased rate in calcium uptake. The specific activity of the enzyme is increased by a factor 2.4 to 2.7 which again agrees with the calcium uptake results. Therefore we suggest that the severe impairment in secretion found in the Gray platelets is probably related to the low cytoplasmic mobilization as it is found by Hardisty et al, 1985 ; this would be the consequence of an increased Ca2+ uptake rather than a decrease in the Ca liberation.

The absence of α granules in Gray platelets together with the described abnormality in internal membranes and the recently described modification of external membrane fluidity (Rendu et al 1985) would suggest that these platelets have a general membrane disorder.
DETECTION OF AUTOANTIBODIES AND ALLOANTIBODIES AGAINST PLATELET-ASSOCIATED ANIGENS
Authors: McMillan R , Tani P , Berchtold P , Millard F
Published: August 2018

Although autoantibodies against the platelet glycoproteins (GP) and a 1loantibodies toward class I HLA antigens have been demonstrated using various methods, practical techniques for their detection have not been available.

We studied 59 patients with chronic immune thrombocytopenic purpura (ITP) where platelet-associated and plasma autoantibodies against the GP Ilb/IIIa complex and GP lb were measured using a newly developed imraunobead assay and a previously described microtiter well assay. The specificity of both assays depends on the monoclonal antibody employed (e.g., GPIIb/IIIa, lb or HLA). Platelet-associated autoantibody was detected using the immunobead assay in 21 of 28 patients (13 with anti-GPIIb/IIIa and 8 with anti-GPIb). Plasma autoantibodies were noted in 34 of 59 patients (21 with anti-GPIIb/IIIa, 11 with anti-GPIb and 2 with both). Positive results were noted in 30 of 59 ITP patients using the immunobead assay and in only 14 of 59 using the microtiter well assay, suggesting that solubilization prior to antibody addition, as in the microtiter well assay, alters epitope stability. However, the microtiter well assay appears to define a poor prognostic group. Of 11 patients with positive well assays who underwent splenectomy, only one achieved a complete remission, 3 have died and all require continuous high-dose steroids or immunosuppressants. Of the 31 thrombocytopenic controls studied, all gave negative results using both assays.

The immunobead assay was adapted to specifically measure anti-HLA antibodies and was used to evaluate 51 single donor platelet transfusions given to 7 patients refractory to random platelets. Twenty-nine of 33 (88%) transfusions associated with a negative assay had successful outcomes (1 hr increment >7500) while only 2 of 18 (11.1%) episodes associated with a positive test had successful outcomes. Only 1 unsuccessful transfusion episode was associated with a negative immunobead and a positive antiglobulin test suggesting that transfusion-related alloantibodies, other than to class I HLA antigens, are an uncommon cause of refractoriness.

We conclude that these two clinically adaptable assays are capable of measuring both autoantibodies and anti-HLA alloantibodies with a high degree of sensitivity.
IMMUNOHISTOCHEMICAL LOCALISATION OF SEROTONIN IN RABBIT PLATELETS
Authors: Kanzaki M , Kimura H , Ochi J
Published: August 2018

Although it has been accepted that the dense bodymay be the most predominant storage site of serotonin (5HT), some literatures suggested that 5KT was localized more abundantly in the alpha-granules or theplasma membrane than in the dense body. The discrepancy may be due to different methods used.For example, the former dense body theory is mostly based on biochemical measurements of 5HT which may easily diffusible among subcellular fractions, and the latter hypothesis is proposed by autoradiographic demonstration of exogenously applied 5HT. In the present study, endogenous 5HT has been visualized by immunoelectron microscopy using monoclonal antibody against 5HT.Platelet rich plasma (PRP) of rabbits was suspended for 30 min in a fixative containing 0.5% glutaraldehyde, 4% paraformaldehyde and 0.5% picric acid in 0.1M phosphate buffer (PB; pH 7.4), and resuspended overnight in the glutaraldehyde-free fixative. After wash the PRP was incubated for 3 days with PB containing saline and 0.03% Triton X-100 (PBST), and reacted for 3 days with monoclonal 5HT antibody ( 1μg/ml). The immunoreactive sites were rendered visible byABC immunohistochemistry (ABC from Vector Co. USA) with DAB precipitation. The colorized PRP was osmificated (1%) for 30 min, dehydrated with alcohol, embedded in Spurr and cut into ultrathin sections for electron microscopic observation. For immunohistochemical controls monoclonal 5HT antibody preabsorbed with O.lmM 5HT or non-immune normal mouse serum was used as the primary antibody, and no specific reaction was observed. Very fine 5HT-positive immunoreaction products were clearly localized in some granules with different staining intensity. These positive granules were mostly round or ovoid in shape with variousdiameters. The present immunohistochemical results appears to support previous results suggesting that 5HT is located in such granules as alpha-granules anddense bodies.
DETECTION OF SOLUBLE FIBRIN MONOMER COMPLEXES - COMPARISON OF A HAEMAGGLUTINATION ASSAY WITH THE ETHANOL GELATION TEST
Authors: Oehler G , Klaus H , Spanuth E , Stötzer K E
Published: August 2018

Hypercoagulability and disseminated intravascularcoagulation (DIC) are characterized by the presenceof circulating fibrin monomer complexes in plasma.In342 patients with possible DIC fibrin monomers, fibrinogen, reptilase time, antithrombin III and othercoagulation parameters were determined at frequent intervals.Testing of soluble fibrin monomer complexeswas performed using a sensitive and reliable haemagglut- ination assay, with red cells sensitized by fibrin monomers (FM-Test) and the ethanol gelation test(EGT). Method comparison regarding the influence offibrinogen levels and fibrin degradation products shows that high fibrinogen levels lead to false positive results with EGT. The same effect is observed forfibrin degradation products and EGT whereas no influence of fibrinogen level and fibrin degradation products on the FM-Test occurs.

It could be shown that with normal fibrinogen concentrations (200-400 mg/dl) the positive test results by FMT and EGT are comparable, whereas with fibrinogen concentrations below 200 mg/dl the number of positive results obtained with the EGT amounted to half the number given by FMT. In the case of fibrinogen concentrations above 400 mg/dl, positive results obtained with EGT were 3.3 times higher than FMT. Nearlyidentical results were obtained by comparing the influence of degradation products. In case of high degradation product concentrations, EGT gives 4.5 timesmore positive results than FMT.

Further we compared the number of positive test results obtained by the FMT with the level of AT III because it is wellknown that the AT IIIHevel decreases caused by proteolytic activity generated in DIC.In this study it could be shown that fibrin monomer increases in parallel with the decrease of AT III. Thiseffect does not occur with fibrin degradation products.
VISUALISATION OF THE MULTIMERIC STRUCTURE OF VON WILLEBRAND FACTOR USING PEROXIDASE-CONJUGATED MONOCLONAL ANTIBODIES
Authors: Ruan X Xi and C
Published: August 2018

Two new murine monoclonal antibodies to human vonWitlebrand factor (vWF), designated as SZ - 29 (IgG2a) and SZ-34 (IgG1), were utilized for observing the multimeric structure of vWF. These two monoclonal antibodies reacted specifically with vWF whilethey had no effects on fibringen, fibronectin and thrombospondin. In S DS-agarose electrophoresis and autoradiography experiments SZ _ 29 and SZ-34 were found binding to all multimers of vWF. 5mg of purified monoclonal antibodies were coupled to 4mg of horseradish peroxidase (HRP).Four to ten microlitres of citrated normal plasma or cryoprecipitate were applied to SDS-agarose gel plate (get concentration was 1.7%), and the electrophoresis was performed in the discontinuous buffer system. When the marker reached the anodic terminal, the plate was assembled with a nitrocellulose film, then the electroblot was carried out.The film was washed and followed by incubationfor 2 hours with HRP-con- jugated monoclonal antibodies which were diluted in 10% bovine serum albumin. After being thoroughly washed, the film was developed in substrate solution(4~chloro-1-naphthoI,0.5mg/mI) in the dark for fifteen minutes. In some experiments, the film was then incubated with HRP-conjugatedrabbit-anti mouse IgG F(ab´ )2 secondary antibodiesfor another 2 hours and followed by the same development procedure so as to increase the staining intensity.The whole procedure took about thirty-six hours.With the aid of this technique, we have obtained thedistinct patterns of multimeric structure of normalvWF.Plasma from a patient with 11A variant of von Willebrand's disease(vWD) gave a typical multimeric composition pattern as that observed by using autoradiography. These results suggested that the use of peroxidase-conjugated monoclonal antibodies was more convenient and timesaving, despite its relatively lower sensitivity which could be improved by mixing some monoclonal antibodies to recognize different epitope of vWF in the same system. We have used both SZ_ 29 and SZ-34 simul-taneously in one experiment andfound the sensitivity markedly increased. Thus, thismethod might be useful for analysis of the multimeric structure of vWF and differentiation of vWD.
Exchange of Sodium between Bovine Blood Platelets and Their Suspension Media
Authors: Honorato C. R , Vásquez T. R , Brunet C. A , Chayet H. C
Published: August 2018

No sodium at least no important part is fixed on the platelets, even with an excess of sodium in the suspension media. Aldosterone and potassium did not modify these results. The platelets used for these experiments were functionally normal as shown by their retraction ability.
Artificial Intelligence in Public Health and Epidemiology
Authors: Thiébaut Rodolphe , Thiessard Frantz ,   Section Editors for the IMIA Yearbook Section on Public Health and Epidemiology Informatics
Published: August 2018

Objectives: To introduce and summarize current research in the field of Public Health and Epidemiology Informatics.

Methods: The 2017 literature concerning public health and epidemiology informatics was searched in PubMed and Web of Science, and the returned references were reviewed by the two section editors to select 14 candidate best papers. These papers were then peer-reviewed by external reviewers to provide the editorial team with an enlightened vision to select the best papers.

Results: Among the 843 references retrieved from PubMed and Web of Science, two were finally selected as best papers. The first one analyzes the relationship between the disease, social/mass media, and public emotions to understand public overreaction (leading to a noticeable reduction of social and economic activities) in the context of a nation-wide outbreak of Middle East Respiratory Syndrome (MERS) in Korea in 2015. The second paper concerns a new methodology to de-identify patient notes in electronic health records based on artificial neural networks that outperformed existing methods.

Conclusions: Surveillance is still a productive topic in public health informatics but other very important topics in Public Health are appearing. For example, the use of artificial intelligence approaches is increasing.
Cancer Informatics in 2017: A New Beginning and a Bright Future
Authors: Warner Jeremy , Patt Debra ,   Section Editors for the IMIA Yearbook Section on Cancer Informatics
Published: August 2018

Objective: To summarize significant research contributions on cancer informatics published in 2017.

Methods: An extensive search using PubMed/Medline, Google Scholar, and manual review was conducted to identify the scientific contributions published in 2017 that address topics in cancer informatics. The selection process comprised three steps: (i) 15 candidate best papers were first selected by the two section editors, (ii) external reviewers from internationally renowned research teams reviewed each candidate best paper, and (iii) the final selection of three best papers was conducted by the editorial board of the Yearbook.

Results: Results: The three selected best papers present studies addressing many facets of cancer informatics, with immediate applicability in the research and clinical domains.

Conclusion: Cancer informatics is a broad and vigorous subfield of biomedical informatics. Strides in knowledge management, crowdsourcing, and visualization are especially notable in 2017.
Depression bei Erwachsenen mit Autismus-Spektrum-Störung
Authors: Albantakis L. , Parpart H. , Thaler H. , Krankenhagen M. , Böhm J. , Zillekens I. , Schilbach L.
Published: August 2018

Gegenstand und Ziel: Depressionen zählen zu den häufigsten Komorbiditäten von Autismus im Erwachsenenalter und gehen insbesondere bei Erwachsenen mit hochfunktionalem Autismus (HFA) mit einer hohen Suizidrate einher. Welche Risikofaktoren hierbei relevant sind, ist unklar. Material und Methoden: In einer Stichprobe von 186 autistischen Erwachsenen aus der Ambulanz bzw. Tagklinik für Störungen der sozialen Interaktion des Max-Planck-Instituts für Psychiatrie wurden epidemiologische, psychometrische und psychosoziale Daten mit Einverständnis der Patienten wissenschaftlich ausgewertet. Ergebnisse: 50% der Patienten litten neben einer ASS an einer depressiven Episode. Als Risikofaktoren für eine depressive Erkrankung wurden das Alter der Patienten sowie Arbeitslosigkeit identifiziert. Schlussfolgerungen und klinische Relevanz: Aufgrund der hohen Rate von Depressionen und Suiziden bei Erwachsenen mit ASS ist eine sorgfältige Exploration dahingehend mit Abklärung von Suizidalität zu empfehlen. Weiterhin besteht ein großer Bedarf bei der Weiterentwicklung von störungsspezifischen Behandlungsmaßnahmen sowie Unterstützungsmöglichkeiten bei der beruflichen Integration. Hier liegen für spätdiagnostizierte Personen mit HFA erste psychotherapeutische und teilstationäre Behandlungskonzepte vor.
Local dimension and recurrent circulation patterns in long-term climate simulations
Authors: Buschow Sebastian , Friederichs Petra
Published: August 2018

With the recent advent of a sound mathematical theory for extreme events in dynamical systems, new ways of analyzing a system’s inherent properties have become available: Studying only the probabilities of extremely close Poincaré recurrences, we can infer the underlying attractor’s local dimensionality—a quantity which is closely linked to the predictability of individual configurations, as well as the information gained from observing them. This study examines possible ways of estimating local and global attractor dimensions, identifies potential pitfalls, and discusses conceivable applications. The Portable University Model of the Atmosphere serves as a test subject of intermediate complexity between simple mathematical toys and truly realistic atmospheric data-sets. It is demonstrated that the introduction of a simple, analytical estimator can streamline the procedure and allows for additional tests of the agreement between theoretical expectation and observed data. We, furthermore, show how the newly gained knowledge about local dimensions can complement classical techniques like principal component analysis and may assist in separating meaningful patterns from mathematical artifacts.
Forming-free resistive switching in solution-processed silicon nanocrystal thin film
Authors: Kawauchi Takeshi , Kano Shinya , Fujii Minoru
Published: August 2018

We report a forming-free resistive switching using a solution-processed silicon nanocrystal (Si NC) thin film. A Si NC thin film is formed on an ITO/glass substrate by spin-coating a colloidal Si NC solution in air. The Si NC thin film shows bipolar resistive switching without a forming process. Electrical characteristics at low temperatures and in various gas environments suggest that a non-stoichiometric SiOx shell on Si NCs contributes to the resistive switching. We propose that the origin of the resistive switching is a conductive filament of oxygen vacancies on the SiOx shell by an electric field.
The pressure in interfaces having cylindrical geometry
Authors: Addington Cody K. , Long Yun , Gubbins Keith E.
Published: August 2018

While much work has been reported on the statistical mechanics and molecular simulation of interfaces of planar and spherical geometries, very little has been published on the interfaces of cylindrical geometry. The cylindrical geometry is important for the study of cylindrical micelles and particularly for nano-phases confined within cylindrical pores since the most well-defined porous materials (e.g., carbon and silicon nanotubes, SBA-15 and KIT-6 silicas) that are presently available are of this geometry. In this work, we derive the statistical mechanical equations for the pressure tensor for an interfacial region of cylindrical geometry via the virial route and for the condition of mechanical (hydrostatic) equilibrium. We also report the equation for the surface tension via the mechanical route. Monte Carlo and molecular dynamics simulation results are obtained for two example systems involving a fluid nano-phase of Lennard-Jones argon: a gas-liquid interface of cylindrical geometry and a confined nano-phase within a cylindrical carbon pore. All three diagonal elements of the pressure tensor are reported in each case, the component normal to the interface, PN = Pρρ, and the two tangential components PTϕ = Pϕϕ and PTz = Pzz, where (ρ, z, ϕ) are the usual cylindrical polar coordinates. For the cylindrical pore, the tangential pressures, Pϕϕ and Pzz, show strong compression in the adsorbed layers, as has been found in slit-shaped and spherical pores.
Temporal evolution of jet induced scour depth in cohesionless granular beds and the phenomenological theory of turbulence
Authors: Bombardelli Fabián A. , Palermo Michele , Pagliara Stefano
Published: August 2018

In this work, we investigate the temporal evolution of the jet-driven scour depth in a pothole lying on a cohesionless granular bed by using diverse approaches. First, we present new experiments which encompass cases with jet angles ranging from 45° to 90° from the horizontal, several initial water depths, and different particle sizes, supplementing experiments developed recently by the last two authors. In particular, we address relatively large angles, mostly absent in previous analyses. Our results initially confirm the existence of two very different stages in the scour process, essentially overlooked in datasets used to obtain the traditional formulas—developing and developed phases; they then provide unprecedented evidence of the very distinct behavior at 90°, characterized by a step-wise behavior. Second, after revisiting the rationale of a theory for the equilibrium condition developed elsewhere by the first author and a collaborator, we employ the existing and new datasets to determine the multiplicative constants embedded in the equilibrium scour formulas. Third, we present a novel theory for the temporal evolution of the scour depth during the developed phase (but with good prediction capabilities in the developing phase as well). By invoking the conservation of mass of sediment in the pothole, in addition to the energy conservation within the pothole and the phenomenological theory of turbulence, we obtain ordinary differential equations which we solve by numerical means. We validate the theory using our new and other datasets. Finally, we provide interesting interpretations of the scour process by using the results of the theory.
The influence of polarization and charge gradient forces on the dust sheath formation
Authors: He Kerong , Chen Hui , Liu Sanqiu
Published: August 2018

The influence of the polarization and charge gradient forces on the dust sheath formation using a fluid model is investigated. The corresponding new Bohm criterion for the dust sheath formation is obtained. By analyzing the Sagdeev potential numerically, it is found that the polarization and charge gradient forces have opposite effects on the Sagdeev potential and the critical Mach number, i.e., the polarization effect enlarges the width and depth of the Sagdeev potential, while the charge gradient effect narrows the width and depth of the Sagdeev potential. Furthermore, the critical Mach number decreases with the increase in polarization parameter RP and increases with the increase in charge gradient parameter RCG. Finally, regardless of whether the polarization effect or the charge gradient effect is considered, the depth and width of the potential well increase with the increase in the Mach number, while the critical Mach number decreases with the increase in the ratio of ion and electron density ρ.
Effects of surface roughness on surface charge accumulation characteristics and surface flashover performance of alumina-filled epoxy resin spacers
Authors: Xue Jianyi , Wang Han , Chen Junhong , Li Kefeng , Liu Yanqin , Song Baipeng , Deng Junbo , Zhang Guanjun
Published: August 2018

The accumulated charges on the insulator surface become a key factor to incur surface flashover. The charge accumulation process is closely related to the surface condition. This research investigates the effects of surface roughness on surface charge accumulation behavior and surface flashover performance of alumina-filled epoxy resin spacers in SF6/N2 mixtures under DC voltage. The insulator is prepared with only half surface subjected to rough treatment. The accumulated charges are distributed in two regions. Considerable homo-charges are located near the high voltage (HV) electrode and few hetero-charges are near the grounded (GND) electrode (region I). These charges are injected by electrodes. The bipolar charges between HV and GND electrodes (region II) originate from gas ionization. Surface rough treatment can suppress surface charge accumulation and improve surface insulation strength. When increasing surface roughness, surface charge declines first slowly (stage I) and then rapidly (stage II), which coincides with the two stages of surface flashover voltage increment. Surface charge declination at stage I is mainly due to the increase in surface conductivity, while at stage II, the introduced deep traps also play a role. Surface flashover voltage increment at stage I is mainly due to the extended creepage distance, while at stage II, the declination of surface charge also plays a role. Besides, the block of electron avalanche development by the roughed surface is also responsible for the increase in surface flashover voltage at these two stages.
Interfacial conduction in organic ferroelectric memory diodes
Authors: Sharifi Dehsari Hamed , Kumar Manasvi , Ghittorelli Matteo , Glasser Gunnar , Lenz Thomas , de Leeuw Dago M. , Torricelli Fabrizio , Asadi Kamal
Published: August 2018

Solution-processed memory diodes based on phase separated blends of ferroelectric and semiconducting polymers in the low resistance on-state operate similar to a vertical field-effect transistor at the pinch-off. Numerical simulations have shown that the performance of the diode is dominated by the conduction of charge carriers at the interface between the semiconductor and ferroelectric phases. Here, we present an unambiguous experimental demonstration of the charge injection process in the diodes. We employ a modified diode structure, wherein the electrode in contact with the semiconductor phase has been intentionally removed. Even in the absence of an electrical contact with the semiconductor phase, the diode still shows resistance switching. We provide numerical simulations that reproduce the experimentally measured I-V characteristics and therefore confirm interfacial conduction in the diodes. Furthermore, we discuss the implications of the proposed memory structure particularly in the performance of light-emitting diodes with built-in memory functionality, i.e., MEMOLEDs.
Complex momentum behavior of electronic excitations in β-CuPc
Authors: Naumann Marco , Knupfer Martin
Published: August 2018

The electronic excitation spectrum of β-CuPc has been investigated using electron energy-loss spectroscopy in transmission. Our results demonstrate a rather strong momentum dependence of the lowest exciton features. Both main components show a negative dispersion, and the momentum dependence indicates that this negative dispersion is parallel to the molecular stacks in β-CuPc. In addition, the spectral shape also varies upon increasing momentum transfer indicating a particular momentum dependence of the inter-molecular interactions.
Evolution Analysis of Silver Nanoparticles Synthesised by Lactam Reduction: A Case Study of ϵ-Caprolactam
Authors: Zhang Na , Duan Jianping , Zhao Dajiang , Yang Guisheng
Published: August 2018

Without using protecting agent and solvent, silver nanoparticles (Ag NPs) were synthesised by using lactams as reducing agents. Being the most commercially available lactam, ϵ-caprolactam (CL) was taken as a model to illustrate the evolution of Ag NPs in the medium of lactams. The results showed that there were two different stages involved in the Ag NP evolution process. In the first stage, particles were stabilised against further coalescence at a smaller size (< 5 nm) because of face-bound CL. In the second stage, the Ostwald ripening mechanism cooperated with continuous reduction of residual silver ions, which resulted in the resultant particles being distributed with different size distribution. The participation of CL in the reducing and protecting procedures raised a complex evolution of Ag NPs.
High-resolution repertoire analysis reveals a major bystander activation of Tfh and Tfr cells
Authors: Ritvo Paul-Gydeon , Saadawi Ahmed , Barennes Pierre , Quiniou Valentin , Chaara Wahiba , El Soufi Karim , Bonnet Benjamin , Six Adrien , Shugay Mikhail , Mariotti-Ferrandiz Encarnita , Klatzmann David
Published: August 2018

T follicular helper (Tfh) and regulatory (Tfr) cells are terminally differentiated cells found in germinal centers (GCs), specialized secondary lymphoid organ structures dedicated to antibody production. As such, follicular T (Tfol) cells are supposed to be specific for immunizing antigens, which has been reported for Tfh cells but is debated for Tfr cells. Here, we used high-throughput T cell receptor (TCR) sequencing to analyze the repertoires of Tfh and Tfr cells, at homeostasis and after immunization with self- or foreign antigens. We observed that, whatever the conditions, Tfh and Tfr cell repertoires are less diverse than those of effector T cells and Treg cells of the same tissues; surprisingly, these repertoires still represent thousands of different sequences, even after immunization with a single antigen that induces a 10-fold increase in Tfol cell numbers. Thorough analysis of the sharing and network of TCR sequences revealed that a specific response to the immunizing antigen can only, but hardly, be detected in Tfh cells immunized with a foreign antigen and Tfr cells immunized with a self-antigen. These antigen-specific responses are obscured by a global stimulation of Tfh and Tfr cells that appears to be antigen-independent. Altogether, our results suggest a major bystander Tfol cell activation during the immune response in the GCs.
14-3-3εa directs the pulsatile transport of basal factors toward the apical domain for lumen growth in tubulogenesis
Authors: Mizotani Yuji , Suzuki Mayu , Hotta Kohji , Watanabe Hidenori , Shiba Kogiku , Inaba Kazuo , Tashiro Etsu , Oka Kotaro , Imoto Masaya
Published: August 2018

The
Ciona
notochord has emerged as a simple and tractable in vivo model for tubulogenesis. Here, using a chemical genetics approach, we identified UTKO1 as a selective small molecule inhibitor of notochord tubulogenesis. We identified 14-3-3εa protein as a direct binding partner of UTKO1 and showed that 14-3-3εa knockdown leads to failure of notochord tubulogenesis. We found that UTKO1 prevents 14-3-3εa from interacting with ezrin/radixin/moesin (ERM), which is required for notochord tubulogenesis, suggesting that interactions between 14-3-3εa and ERM play a key role in regulating the early steps of tubulogenesis. Using live imaging, we found that, as lumens begin to open between neighboring cells, 14-3-3εa and ERM are highly colocalized at the basal cortex where they undergo cycles of accumulation and disappearance. Interestingly, the disappearance of 14-3-3εa and ERM during each cycle is tightly correlated with a transient flow of 14-3-3εa, ERM, myosin II, and other cytoplasmic elements from the basal surface toward the lumen-facing apical domain, which is often accompanied by visible changes in lumen architecture. Both pulsatile flow and lumen formation are abolished in larvae treated with UTKO1, in larvae depleted of either 14-3-3εa or ERM, or in larvae expressing a truncated form of 14-3-3εa that lacks the ability to interact with ERM. These results suggest that 14-3-3εa and ERM interact at the basal cortex to direct pulsatile basal accumulation and basal–apical transport of factors that are essential for lumen formation. We propose that similar mechanisms may underlie or may contribute to lumen formation in tubulogenesis in other systems.
Human iPSC-derived trigeminal neurons lack constitutive TLR3-dependent immunity that protects cortical neurons from HSV-1 infection
Authors: Zimmer Bastian , Ewaleifoh Osefame , Harschnitz Oliver , Lee Yoon-Seung , Peneau Camille , McAlpine Jessica L. , Liu Becky , Tchieu Jason , Steinbeck Julius A. , Lafaille Fabien , Volpi Stefano , Notarangelo Luigi D. , Casanova Jean-Laurent , Zhang Shen-Ying , Smith Gregory A. , Studer Lorenz
Published: August 2018

Significance

We previously demonstrated that induced pluripotent stem cell (iPSC)-derived cortical neurons from HSV-1 encephalitis patients with Toll-like receptor 3 (TLR3) pathway deficiencies are highly susceptible to HSV-1, due to impairment of cell autonomous TLR3-IFN immunity. In this study we present a protocol for efficient derivation/purification of trigeminal ganglion (TG) neurons from human iPSCs. The resulting TG neurons are of sensory identity and exhibit robust biological function. We also show that TG neurons and cortical neurons play distinct roles in host defense against HSV-1 in the central nervous system: unlike cortical neurons, TG neurons are vulnerable to HSV-1 because they require preemptive induction of TLR3-, IFN-α/β–mediated immunity. This is an important step to further our understanding of the HSV-1 encephalitis disease mechanism.
Cell circuits between B cell progenitors and IL-7+ mesenchymal progenitor cells control B cell development
Authors: Fistonich Chris , Zehentmeier Sandra , Bednarski Jeffrey J. , Miao Runfeng , Schjerven Hilde , Sleckman Barry P. , Pereira João P.
Published: August 2018

B cell progenitors require paracrine signals such as interleukin-7 (IL-7) provided by bone marrow stromal cells for proliferation and survival. Yet, how B cells regulate access to these signals in vivo remains unclear. Here we show that proB and IL-7+ cells form a cell circuit wired by IL-7R signaling, which controls CXCR4 and focal adhesion kinase (FAK) expression and restricts proB cell movement due to increased adhesion to IL-7+CXCL12Hi cells. PreBCR signaling breaks this circuit by switching the preB cell behavior into a fast-moving and lower-adhesion state via increased CXCR4 and reduced FAK/α4β1 expression. This behavioral change reduces preB cell exposure to IL-7, thereby attenuating IL-7R signaling in vivo. Remarkably, IL-7 production is downregulated by signals provided by preB cells with unrepaired double-stranded DNA breaks and by preB acute lymphoblastic leukemic cells. Combined, these studies revealed that distinct cell circuits control the quality and homeostasis of B cell progenitors.
Syntaxin clusters at secretory granules in a munc18-bound conformation
Authors: Yin Peng , Gandasi Nikhil R. , Arora Swati , Omar-Hmeadi Muhmmad , Saras Jan , Barg Sebastian
Published: August 2018

Syntaxin (stx)-1 is an integral plasma membrane protein that is crucial for two distinct steps of regulated exocytosis, docking of secretory granules at the plasma membrane and membrane fusion. During docking, stx1 clusters at the granule docking site, together with the S/M protein munc18. Here we determined features of stx1 that contribute to its clustering at granules. In live insulin-secreting cells, stx1 and stx3 (but not stx4 or stx11) accumulated at docked granules, and stx1 (but not stx4) rescued docking in cells expressing botulinum neurotoxin-C. Using a series of stx1 deletion mutants and stx1/4 chimeras, we found that all four helical domains (Ha, Hb, Hc, SNARE) and the short N-terminal peptide contribute to recruitment to granules. However, only the Hc domain confers specificity, and it must be derived from stx1 for recruitment to occur. Point mutations in the Hc or the N-terminal peptide designed to interfere with binding to munc18-1 prevent stx1 from clustering at granules, and a mutant munc18 deficient in binding to stx1 does not cluster at granules. We conclude that stx1 is recruited to the docking site in a munc18-1–bound conformation, providing a rationale for the requirement for both proteins for granule docking.