bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Analysis of the Amino- and Carboxyl-Termini of Streptokinase
Authors: Fay William P. , Bokka Lakshmi V.
Published: May 2019

Streptokinase (SK) is a 414 amino acid bacterial protein that activates human plasminogen. Streptokinase fragments derived from the central portion of the protein bind plasminogen, but are inactive, indicating that the amino- and/or carboxyl-termini are required for normal plasminogen activator activity. To better define the function of the N- and C-termini of SK we generated and characterized 21 N-terminal and 20 C-terminal deletion mutants. All mutants lacking ≥18 N-terminal or ≥51 C-terminal amino acids exhibited markedly reduced plasminogen activator activity, while mutants lacking ≤12 N-terminal or ≤40 C-terminal residues were fully active. The decrease in SK activity with N-terminal deletion appeared to result not from loss of plasminogen binding capacity, but rather from increased susceptibility of deletion mutants to degradation by plasmin. Point mutations at positions 13 (SK V13D) or 20 (SK V20D) produced functional abnormalities similar to those observed in N-terminal deletion mutants, with SK V13D exhibiting delayed amidolytic activity and SK V20D exhibiting only 1% plasminogen activator activity and marked sensitivity to degradation by plasmin. C-terminal deletion mutants lacking ≥51 amino acids also bound plasminogen, but did not induce significant amidolytic activity in plasminogen or activator activity in plasmin. Prevention of cleavage at position 59 of SK had no effect on plasminogen activator activity, suggesting that the rapid hydrolysis of this bond that occurs after SK-plasminogen complex formation is not required for normal function of the N-terminus. These results suggest that residues within or near positions 13-20 of SK are important determinants of its capacity to generate amidolytic activity and are a critical determinant of the stability of SK, while residues within or near position 364-374 are required for generating amidolytic activity and for conferring plasminogen activator activity to plasmin(ogen). These results also suggest that SK fragments significantly smaller than SK 13-374 are unlikely to be effective thrombolytic agents.
Preparation of a Novel Streptokinase Mutant with Improved Stability
Authors: Shi Guey-Yueh , Chang Bi-Ing , Su Su-Wen , Young Kung-Chia , Wu Dung-Ho , Chang Li-Ching , Tsai Yau-Sheng , Wu Hua-Lin
Published: May 2019

The novel mutant streptokinase, SK-K59E, can activate human plasminogen as efficiently as the purified commercially available streptokinase. Several peptide bonds including Lys59-Ser60 in native streptokinase were hydrolyzed in reaction with plasmin and peptides of small molecular masses were generated. The plasminogen activator activity of native streptokinase in reaction with human plasmin declined to 25% of the original activity in a 120-min incubation. On the other hand, the NH2-terminal peptide of SK-K59E remained intact in reaction with plasmin and the activator activity of streptokinase decreased to 75% of the original activity in 120 min. The major degraded peptide fragments of native streptokinase in reaction with plasmin had molecular masses of 36 and 30 kDa. However, two major peptide fragments of 42 and 34 kDa were observed in the reaction of SK-K59E with human plasmin. The 42 kDa peptide fragment, which contained NH2-terminal of streptokinase, could activate human plasminogen as efficiently as the native streptokinase. SK-K59E can induce greater degree of caseinolysis and fibrinolysis than the native streptokinase. In conclusion, the results demonstrate that the prevention of cleavage at Lys59 of streptokinase prolongs the half-life of streptokinase in complex with plasmin and that the NH2-terminal of streptokinase (Ile1-Lys59) plays an important role in maintaining its stability.
Maturation of Megakaryoblastic Cells Is Accompanied by Upregulation of GSα-L Subtype and Increased cAMP Accumulation
Authors: Vuurst Hans van der , Hendriks Maaike , Lapetina Eduardo G. , Willigen Gijsbert van , Akkerman Jan-Willem N.
Published: May 2019

In platelets and megakaryoblasts Gs, the trimeric G-protein that stimulates adenylyl cyclase, is present in a short, 45 kDa, and a long, 52 kDa isoform termed Gsα-S and Gsα-L, respectively. To assess the relative contribution of these isoforms in the cellular synthesis of cAMP, the ratio Gsα-S/Gsα-L was changed in the megakaryoblastic cell line DAMI by inducing cell maturation with recombinant human thrombopoietin (TPO) or the phorbol ester PMA. Flow cytometric analysis confirmed that this treatment induced a moderate (TPO) and extensive (PMA) increase in nuclear ploidy and expression of the glycoproteins-IIIa and -Ib. Northern blot analysis revealed down-regulation of total GS-mRNA after treatment of DAMI-cells with TPO and PMA. Western blot analysis showed significant (P <0.05) upregulation of Gs-L with respective amounts of 27 ± 4% of total G s in untreated cells, 35 ± 1% in TPO- and 41 ± 3% in PMA-treated DAMI cells (n = 3-4). DAMI cells contained 6 ± 1 pmol cAMP/106 cells, which was not changed by treatment with TPO or PMA. In untreated cells this level increased to 70 ± 9 pmol cAMP/106 cells after 10 min stimulation with 1 μmol/l of the stable prostacyclin analog iloprost. The same stimulation with iloprost resulted in 165 ± 32 pmol cAMP/106 in TPO-treated cells and in 588 ± 100 pmol cAMP/106 in cells treated with PMA. Thus, a shift from Gsα-S to Gsα-L during megakaryoblast maturation strongly potentiates the production of cAMP. A similar shift may occur during normal megakaryocyte maturation and may explain the extreme sensitivity to prostacyclin of platelets, which contain Gsα-S and Gsα-L in approximately equal amounts.
Human Platelet CD36 (GPIIIb, GPIV) Binds to Cholesteryl-Hemisuccinate and Can Be Purified by a Simple Two-Step Method Making Use of this Property
Authors: Kronenberg A. , Grahl H. , Kehrel B.
Published: May 2019

CD36, also known as GPIIIb or GPIV, is a main protein of the platelet membrane. Accumulating evidence implicates CD36 in the pathogenesis of atherosclerosis. CD36 binds to cholesteryl-hemisuccinate coupled to agarose. This binding may be of physiologic relevance since CD36 has a long extracellular hydrophobic region at its N-terminus and belongs to a family of proteins involved in lipid metabolism. This newly discovered binding property of CD36 was used to develop a rapid, efficient and gentle two-step purification method for CD36 from human platelets.
CD40 Engagement on Endothelial Cells Promotes Tissue Factor-dependent Procoagulant Activity
Authors: Zhou Ling , Stordeur Patrick , Lavareille Aurore de , Thielemans Kris , Capel Paul , Goldman Michel , Pradier Olivier
Published: May 2019

The CD40 molecule expressed on endothelial cells has been shown to transduce activation signals resulting in upregulation of adhesion molecules. Herein, we studied the impact of CD40 engagement on the induction of tissue factor (TF)-dependent procoagulant activity (PCA) at the surface of human umbilical vein endothelial cells (HUVECs). First, we found that co-incubation of HUVECs with 3T6 fibroblasts transfected with the CD40L gene (3T6-CD40L) resulted in a clear induction of PCA which was not observed with control untransfected fibroblasts. The specificity of this finding was established by inhibition experiments using monoclonal antibodies (mAbs) blocking CD40 or CD40L. PCA induced by CD40 ligation was TF-related as it was not observed in factor VII-deficient plasma and was associated with the accumulation of TF mRNA. To investigate the role of CD40/CD40L interactions in the induction of endothelial cell PCA by lymphocytes, interferon (IFN)-γ-stimulated EC were incubated with T cells in the absence or presence of anti-CD40 or anti-CD40L mAb. The 60-70% inhibition of PCA induced by these mAbs but not their isotype-matched control indicated that the CD40 pathway is involved in the induction of PCA resulting from interactions between activated HUVECs and T cells. We conclude that activation signals elicited by CD40 engagement on endothelial cells result in the induction of TF-dependent PCA. The CD40/CD40L pathway might therefore be involved in the development of prothrombic states during diseases associated with endothelial cell and T cell activation.
The Effects of Sex Steroids on Plasma Levels of Marker Proteins of Endothelial Cell Functioning
Authors: van Kesteren P. J. M. , Kooistra T. , Lansink M. , van Kamp G. J. , Asscheman H. , Gooren L. J. G. , Emeis J. J. , Vischer U. M. , Stehouwer C. D. A.
Published: May 2019

We studied thirteen male-to-female (M→F) and ten female-to-male (F→M) transsexuals who, for four months, received cross-sex treatment with, respectively, ethinylestradiol and cyproterone acetate, and with testosterone esters. We assessed the effects of treatment on plasma levels of tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), vWF-propeptide (vWF:AgII) and bigendothelin-1 (big-ET-1), four proteins that are markers of endothelial cell functioning. We also measured urokinase-type PA (uPA) and plasminogen activator inhibitor-type 1 (PAI-1), which may not be endothelium-derived but share major clearance pathways with tPA.

In M→F transsexuals, mean plasma levels of tPA (minus 4.4 ng/ml), big-ET-1 (minus 0.8 pg/ml), uPA (minus 0.5 ng/ml) and PAI-1 (minus 26 ng/ml) decreased (all Ps ≤0.02). The level of vWF increased (plus 24%; P = 0.005), while vWF:AgII did not change (P = 0.49).

In F→M transsexuals, levels of big-ET-1 increased (plus 0.4 pg/ml; P = 0.02), while tPA, uPA and PAI-1 did not change (all Ps >0.25). In this group vWF decreased (minus 14%; P = 0.06), but vWF:AgII did not change (P = 0.38).

Estrogens and androgens have clear effects on plasma levels of endothelial marker proteins. The mechanisms behind these effects are complex and appear to involve both altered secretion (big-ET-1) and processing and/or clearance (vWF and possibly tPA). Therefore, effects of hormones on the levels of endothelial marker proteins do not necessarily reflect changes in endothelial cell functioning, at least with regard to changes in vWF level associated with the oral administration of high doses of ethinylestradiol and cyproterone acetate to healthy men and the parenteral administration of testosterone to healthy women.
Coagulation Signalling and Metabolic Disorders: Lessons Learned from Animal Models
Authors: Madhusudhan Thati , Ruf Wolfram
Published: May 2019

Nutrient excess in obesity drives metabolic reprogramming in multiple tissues involving extensive interorgan and intercellular crosstalk. Experimental and clinical studies show that prolonged nutrient excess often compromises metabolic adaptation propagating proobesogenic and proinflammatory responses. Chronic inflammation further promotes insulin resistance and associated comorbidities. Obesity and type 2 diabetes are characterized by a hypercoagulable state and clinical studies show a strong correlation of markers of coagulation activation in metabolic disorders. Coagulation protease-dependent signalling via protease-activated receptors is intimately associated with inflammation. The experimental evidence supports roles of tissue factor and G protein coupled protease-activated receptor-2 signalling in the regulation of insulin resistance and metabolic inflammation in diet-induced obesity. Likewise, increases in plasminogen activator inhibitor-1 levels and fibrin-driven inflammation promote insulin resistance in obesity. Additionally, impaired thrombomodulin-dependent protein C activation is mechanistically linked to diabetic kidney disease. Given the increased usage of direct oral anticoagulants, understanding the role of specific coagulation proteases in regulation of metabolic inflammation is highly relevant and might provide insights into the design of novel treatment regimens for patients suffering from thromboinflammatory and cardiometabolic disorders.
Splinting after Distal Radius Fracture Fixation: A Prospective Cohort Analysis of Postoperative Plaster Splint versus Soft Dressing
Authors: Poiset Spencer , Abboudi Jack , Gallant Gregory , Jones Christopher , Kirkpatrick William , Kwok Moody , Liss Frederic , Rivlin Michael , Takei T. Robert , Wang Mark , Ilyas Asif M.
Published: May 2019

Background The effect of postoperative dressing and splinting after distal radius fracture (DRF) open reduction internal fixation (ORIF) is not well understood. A prospective cohort analysis was performed to assess differences in functional and radiographic outcomes with the use of plaster splinting or soft dressing following DRF ORIF.

Methods All patients undergoing DRF ORIF with locking volar plates were consecutively enrolled. Preoperative demographic and postoperative radiographic and functional outcome data were collected at 2 weeks and 3 months postoperatively. Functional data included range of motion (ROM), pain on visual analog scale (VAS), Patient-Rated Wrist Evaluation (PRWE), and quick Disabilities of the Arm, Shoulder and Hand (DASH) scores. Radiographic data included loss of fracture reduction.

Results A total of 139 patients were enrolled (79 plaster splinting, 60 soft dressing). By the first postoperative visit (POV), there was one case of loss of reduction with plaster splinting and one case with soft dressing with no hardware failure or revision surgery in either group, and no difference in DASH, PRWE, or VAS pain scores. By the final POV, the soft dressing group showed greater ROM in extension by 9.6, flexion by 10.9, and supination by 4.8 degrees over plaster splinting. Additionally, the soft dressing group demonstrated statistically significant improvement in PRWE and DASH scores, as well as VAS pain scores as compared with plaster splinting.

Conclusions Applying only soft dressing following DRF ORIF demonstrated improvements in ROM, VAS, and functional outcomes by final follow-up, with no significant differences in radiographic outcomes. No benefit of applying a plaster splint was identified.
Long-Term Outcomes of All-Arthroscopic Pre-Tied Suture Device Triangular Fibrocartilage Complex Repair
Authors: Sarkissian Eric J. , Burn Matthew B. , Yao Jeffrey
Published: May 2019

Background A pre-tied suture device has been utilized for all-arthroscopic peripheral triangular fibrocartilage complex (TFCC) repairs with promising early clinical results.

Purpose The purpose of this study was to evaluate long-term functional outcomes of these repairs.

Patients and Methods A retrospective review of patients undergoing arthroscopic TFCC repair was performed. Inclusion criteria were the Palmer type 1B TFCC tears diagnosed on arthroscopy and repaired using the all-arthroscopic pre-tied suture device. Patients with any evidence of concomitant wrist injury at the time of surgery, history of prior wrist surgery, or nonrepairable and nonperipheral TFCC tears were excluded. Postoperative complications, range of motion, grip strength, and outcome assessments were recorded for each patient.

Results Eleven patients (mean age, 36 years; range, 20–64 years) satisfied our inclusion criteria and comprised the study cohort. The mean follow-up period was 7.0 years (range, 4.3–10.9 years). Mean range of motion of the wrist revealed flexion of 76 ± 11 degrees and extension of 73 ± 12 degrees. Mean grip strength was 98 ± 15% of the nonsurgical extremity. QuickDASH, modified Mayo, and patient-rated wrist evaluation (PRWE) average scores were 9 ± 8, 80 ± 6, and 12 ± 12, respectively. No surgical complications were observed and no patient required any further surgical intervention.

Conclusions Our cohort of patients following all-arthroscopic pre-tied suture device repair of isolated Palmer type 1B TFCC tears demonstrated excellent clinical function at a mean follow-up of 7 years. These findings indicate that the pre-tied suture device is a reliable, safe, effective, and most importantly, durable treatment option for repair of peripheral TFCC tears.

Level of Evidence This is a Level IV, therapeutic study.
Phylogeny of the Echinoderes coulli-group (Kinorhyncha : Cyclorhagida : Echinoderidae) – a cosmopolitan species group trapped in the intertidal
Authors: Randsø Phillip Vorting , Yamasaki Hiroshi , Bownes Sarah Jane , Herranz Maria , Di Domenico Maikon , Qii Gan Bin , Sørensen Martin Vinther
Published: May 2019

Kinorhyncha is a phylum of microscopic, benthic marine invertebrates found throughout the world, from the Arctic to Antarctica and from the intertidal zone to the deep sea. Within the most species-rich genus, Echinoderes, we find a putatively monophyletic species group, the so-called Echinoderes coulli-group. The remarkable morphological similarities of the E. coulli-group species and the fact that the group has a global distribution even though most of the species are restricted to intertidal habitats, has led to the hypothesis that dispersal and speciation within the group has been driven by the process of continental drift. However, this has never been confirmed empirically. With morphology and two molecular loci, COI and 18S, we calculated phylogenetic trees by analysing datasets separately and in combination using Maximum Parsimony, Maximum Likelihood and Bayesian Inference. Using different models of evolution in combination with different statistical approaches, we show that two major clade divergences were consistent with historic drifting of continents, suggesting that vicariance has played an important role for the speciation within the E. coulli-group. Furthermore, we found that reconstructions of past tectonic drifting since the Devonian (416–359 million years ago) were able to explain present species distributions, and suggest that the group originated in a supposedly vast shallow marine environment in north-eastern Gondwana by the mid-late Silurian, 426–416 million years ago.
Experimentalism and cognition
Authors: Farsi Roghayeh
Published: May 2019

This study approaches experimental literary texts from a cognitive perspective. It investigates if a constructivist modeling of cognition can be applied to such texts, and contends that there is a two-way relation between memory and literary experimentations. It suggests a fresh look at literary experimentalism – from the perspective of the cognitive processes involved in challenging (text, language, and world) schemata to varying degrees. There exists a vast body of knowledge on experimental texts, but the study of cognitive processing of such texts has until now been a less studied area of cognitive research.

This study defines two main types of experimental texts based on their closeness to or divergence from the schematic parameters of world, text, and language: proximal and distal. The study shows how distal experimentations are conventionalized over the course of time and call for re-innovation.
Weaknesses of wickedness: a critical perspective on wickedness theory
Authors: Noordegraaf Mirko , Douglas Scott , Geuijen Karin , Van Der Steen Martijn
Published: May 2019

It is attractive to frame societal challenges such as climate change, terrorism and migration as ‘wicked issues’. Wickedness theory in its various guises has become popular as it connects the uncertain and political nature of issues with hopeful strategies for strengthening networks, trust and learning. In this paper we take a critical approach towards wickedness, advancing three criticisms: (1) the daily experiences of people and their practices are missing from the grand narratives about wickedness, (2) the potential of collaborations and learning to address these problems is romanticized, (3) the implications for managerial and professional perspectives are unclear. We argue that the wickedness literature can be strengthened by further emphasizing situated relations, routines and rituals, adopting the perspective of situated wickedness. This would link insight into grand wickedness to insights into daily ambiguity. We illustrate this argument with two specific cases, (counter)terrorism and forced migration/refugees.
Does religiosity affect the dividend payouts of Italian-listed companies?
Authors: Rossi Fabrizio , R. Barth James , Sun Yanfei
Published: May 2019

This study investigates the relationship between local culture, as measured by religiosity, and dividend payouts based on a sample of 155 Italian firms over the period 2000–2016, yielding 2,382 firm-year observations. We find a significantly positive relationship between religiosity
and dividend payouts, with firms headquartered in higher religiosity areas paying more dividends than firms located in lower religiosity areas. We also find no relationship between religiosity and stock returns. An additional test also suggests that religiosity of Italian firms could mitigate
agency costs. Our results are consistent with the “bird-in-the-hand theory” and generally consistent with the empirical literature on the relationship between social values (local culture) and corporate decisions. Since religiosity is a determinant of dividend payouts, it also
is an appropriate explanatory variable when examining the behavior of a firm’s dividend policies.
Use of the anaerobic speed reserve to normalize the prescription of high‐intensity interval exercise intensity
Authors: Julio Ursula F. , Panissa Valéria L. G. , Paludo Ana C. , Alves Elaine D. , Campos Fábio A. D. , Franchini Emerson
Published: May 2019

The aim of this study was to compare the perceptual and physiological responses and time‐to‐exhaustion in high intensity interval exercise (HIIE) protocols that are prescribed based on the relative anaerobic speed reserve (ASR) or maximal aerobic speed (MAS) in athletes with different ASR values, as well as the coefficient of variation (CV) of the abovementioned variables. Eleven long‐distance runners and ten rugby players were submitted to five experimental sessions on different days; the first and second session were intended for the determination of the anthropometry, MAS and maximal sprint (MSS). In the subsequent sessions, three HIIE15:15s protocols were performed until exhaustion (110%MAS, Δ25%ASR, and Δ50%ASR) in random order. The anthropometric characteristics and variables obtained from the MAS and MSS tests in the different groups were compared by Student's unpaired t‐test. The analysis of mixed models for repeated measures (groups and protocols) was used to compare the speed, delta blood lactate, rating of perceived exertion, and time‐to‐exhaustion. Rugby players presented higher ASR (13.6 ± 0.9 km h−1) compared to long‐distance runners (12.6 ± 0.9 km h−1) (P = .049). For the HIIE15:15s protocols, there were no protocol and group interaction effects. However, lower CV values were observed for time‐to‐exhaustion (a mean reduction of 52%) and delta blood lactate (a mean reduction of 48%) in Δ25%ASR and Δ50%ASR when compared to 110%MAS. Furthermore, the rating of perceived exertion CV was similar in all HIIE15:15s protocols. The prescription of intensity of HIIE based on the ASR was able to reduce the inter‐subject variability of lactate and time‐to‐exhaustion in rugby players and long‐distance runners.
Effectiveness of sensor monitoring in a rehabilitation programme for older patients after hip fracture: a three-arm stepped wedge randomised trial
Authors: Pol Margriet C , ter Riet Gerben , van Hartingsveldt Margo , Kröse Ben , Buurman Bianca M
Published: May 2019

Objectives

to test the effects of an intervention involving sensor monitoring-informed occupational therapy on top of a cognitive behavioural treatment (CBT)-based coaching therapy on daily functioning in older patients after hip fracture.

Design, setting and patients

three-armed randomised stepped wedge trial in six skilled nursing facilities, with assessments at baseline (during admission) and after 1, 4 and 6 months (at home). Eligible participants were hip fracture patients ≥ 65 years old.

Interventions

patients received care as usual, CBT-based occupational therapy or CBT-based occupational therapy with sensor monitoring. Interventions comprised a weekly session during institutionalisation, followed by four home visits and four telephone consultations over three months.

Main outcomes and measures

the primary outcome was patient-reported daily functioning at 6 months, assessed with the Canadian Occupational Performance Measure.

Results

a total of 240 patients (mean[SD] age, 83.8[6.9] years were enrolled. At baseline, the mean Canadian Occupational Performance Measure scores (range 1–10) were 2.92 (SE 0.20) and 3.09 (SE 0.21) for the care as usual and CBT-based occupational therapy with sensor monitoring groups, respectively. At six months, these values were 6.42 (SE 0.47) and 7.59 (SE 0.50). The mean patient-reported daily functioning in the CBT-based occupational therapy with sensor monitoring group was larger than that in the care as usual group (difference 1.17 [95% CI (0.47-1.87) P = 0.001]. We found no significant differences in daily functioning between CBT-based occupational therapy and care as usual.

Conclusions and relevance

among older patients recovering from hip fracture, a rehabilitation programme of sensor monitoring-informed occupational therapy was more effective in improving patient-reported daily functioning at six months than to care as usual.

Trial registration

Dutch National Trial Register, NTR 5716.
Germ cell-less hybrid fish: ideal recipient for spermatogonial transplantation for the rapid production of donor-derived sperm†
Authors: Xu Dongdong , Yoshino Tasuku , Konishi Junpei , Yoshikawa Hiroyuki , Ino Yasuko , Yazawa Ryosuke , dos Santos Nassif Lacerda Samyra Maria , de França Luiz Renato , Takeuchi Yutaka
Published: May 2019

An interspecific hybrid marine fish that developed a testis-like gonad without any germ cells, i.e., a germ cell-less gonad, was produced by hybridizing a female blue drum Nibea mitsukurii with a male white croaker Pennahia argentata. In this study, we evaluated the suitability of the germ cell-less fish as a recipient by transplanting donor testicular cells directly into the gonads through the urogenital papilla. The donor testicular cells were collected from hemizygous transgenic, green fluorescent protein (gfp) (+/−) blue drum, and transplanted into the germ cell-less gonads of the 6-month-old adult hybrid croakers. Fluorescent and histological observations showed the colonization, proliferation, and differentiation of transplanted spermatogonial cells in the gonads of hybrid croakers. The earliest production of spermatozoa in a hybrid recipient was observed at 7 weeks post-transplantation (pt), and 10% of the transplanted recipients produced donor-derived gfp-positive spermatozoa by 25 weeks pt. Sperm from the hybrid recipients were used to fertilize eggs from wild-type blue drums, and approximately 50% of the resulting offspring were gfp-positive, suggesting that all offspring originated from donor-derived sperm that were produced in the transplanted gfp (+/−) germ cells. To the best of our knowledge, this is the first report of successful spermatogonial transplantation using a germ cell-less adult fish as a recipient. This transplantation system has considerable advantages, such as the use of comparatively simple equipment and procedures, and rapid generation of donor-derived spermatogenesis and offspring, and presents numerous applications in commercial aquaculture.
PRRDB 2.0: a comprehensive database of pattern-recognition receptors and their ligands
Authors: Kaur Dilraj , Patiyal Sumeet , Sharma Neelam , Usmani Salman Sadullah , Raghava Gajendra P S
Published: May 2019

PRRDB 2.0 is an updated version of PRRDB that maintains comprehensive information about pattern-recognition receptors (PRRs) and their ligands. The current version of the database has ~2700 entries, which are nearly five times of the previous version. It contains extensive information about 467 unique PRRs and 827 pathogens-associated molecular patterns (PAMPs), manually extracted from ~600 research articles. It possesses information about PRRs and PAMPs that has been extracted manually from research articles and public databases. Each entry provides comprehensive details about PRRs and PAMPs that includes their name, sequence, origin, source, type, etc. We have provided internal and external links to various databases/resources (like Swiss-Prot, PubChem) to obtain further information about PRRs and their ligands. This database also provides links to ~4500 experimentally determined structures in the protein data bank of various PRRs and their complexes. In addition, 110 PRRs with unknown structures have also been predicted, which are important in order to understand the structure–function relationship between receptors and their ligands. Numerous web-based tools have been integrated into PRRDB 2.0 to facilitate users to perform different tasks like (i) extensive searching of the database; (ii) browsing or categorization of data based on receptors, ligands, source, etc. and (iii) similarity search using BLAST and Smith–Waterman algorithm.
Phenotypic Variation in Paediatric Inflammatory Bowel Disease by Age: A Multicentre Prospective Inception Cohort Study of the Canadian Children IBD Network
Authors: Dhaliwal J , Walters T D , Mack D R , Huynh H Q , Jacobson K , Otley A R , Debruyn J , El-Matary W , Deslandres C , Sherlock M E , Critch J N , Bax K , Seidman E , Jantchou P , Ricciuto A , Rashid M , Muise A M , Wine E , Carroll M , Lawrence S , Van Limbergen J , Benchimol E I , Church P , Griffiths A M
Published: May 2019

Background and Aims

Incidence of paediatric inflammatory bowel disease [IBD] in Canada is among the highest worldwide, and age of onset may be decreasing. In a multicentre nationwide inception cohort study, we examined variation in phenotype of IBD throughout the paediatric age spectrum.

Methods

Children aged ≥2 years [y] and <17y [A1 age at diagnosis], with new onset IBD, were systematically evaluated at sites of the Canadian Children IBD Network. Prospectively recorded phenotypic data were compared between age groups.

Results

Among 1092 children (70% Caucasian; 64% Crohn’s disease [CD], 36% ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U]; median age 13 y, interquartile range [IQR] 11–15 y), 210 [19%] were diagnosed before the age of age 10 y [Paris A1a] and 43 [4%] before age 6 y (very-early-onset [VEO-IBD]). CD was less common in younger children [42%, 56%, 66%, respectively, of VEO-IBD, A1a; A1b]. Colon-only IBD [UC/IBDU or CD-colon] was present in 81% of VEO-IBD and 65% of A1a; ileal disease increased progressively, reaching plateau at age 10 y. CD location was ileocolonic [L3] in 53% overall. Ileitis [L1] increased with age [6% of VEO-IBD; 13% of A1a; 21% of A1b], as did stricturing/penetrating CD [4% of A1a; 11% of A1b]. At all ages UC was extensive [E3/E4] in >85%, and disease activity moderate to severe according to Physician’s Global Assessment [PGA] and weighted Paediatric Crohn’s Disease Activity Index/Paediatric Ulcerative Colitis Activity Index [wPCDAI/PUCAI] in >70%. Heights were modestly reduced in CD [mean height z score -0.30 ± 1.23], but normal in UC/IBD-U.

Conclusions

Paris classification of age at diagnosis is supported by age-related increases in ileal disease until age 10 years. Other phenotypic features, including severity, are similar across all ages. Linear growth is less impaired in CD than in historical cohorts, reflecting earlier diagnosis.
Aortic haemorrhage during late pectus bar removal
Authors: Dahlbacka Sebastian J M , Ilonen Ilkka K , Kauppi Juha T , Räsänen Jari V
Published: May 2019

Nuss bars are increasingly used for minimally invasive correction of pectus excavatum and are usually removed within 3 years of insertion. Previously, several complications related to pectus bar removal have been reported with only 1 case report of aortic haemorrhage. Herein, we report a case with life-threatening aortic haemorrhage during late removal of displaced double Nuss bars.
The evolution of self-esteem before, during and after orthodontic treatment in adolescents with dental malocclusion, a prospective cohort study
Authors: Avontroodt Stephanie , Lemiere Jurgen , Cadenas de Llano-Pérula Maria , Verdonck Anna , Laenen Annoushka , Willems Guy
Published: May 2019

Objectives

This study aimed (1) to investigate the evolution of self-esteem through orthodontic treatment, and (2) to study how key demographic factors would affect these evolutions and to assess relationships between self-esteem and orthodontic treatment need.

Methods

This longitudinal prospective cohort study comprised of 326 adolescents (172 girls and 154 boys) aged 11–16 years; data were obtained from 325 adolescents at T0 and 123 at T2. Three hundred twenty-one adolescents filled in questionnaires at T0, whereas 118 at T2. They were selected in the University Hospitals Leuven, Belgium, where they all received orthodontic treatment. Self-esteem was assessed with the Dutch adaptation of the Harter’s test and treatment need was defined by the Index of Orthodontic Treatment Need (IOTN). Data were analysed with multivariate linear models and Spearman correlations.

Results

There was no evidence of a change in global self-esteem during orthodontic treatment. A significant gender by time interaction for scholastic competence (P < 0.05), a decrease in self-esteem for females, and an increase for males between T0 and T1 was observed. A significant age (at T0) by time interaction for physical appearance and global self-worth (P < 0.05) and a negative correlation between self-esteem and self-assessed IOTN aesthetic component for the subdomain of close friendship (P < 0.05) were found.

Conclusions

Global self-esteem acts as a stable construct during orthodontic treatment. The subdomains of self-esteem could be influenced by age and gender. Self-esteem and the subjective need for orthodontic treatment were found to be negatively correlated.
Explaining Differences in Welfare Chauvinism Between and Within Individuals Over Time: The Role of Subjective and Objective Economic Risk, Economic Egalitarianism, and Ethnic Threat
Authors: Kros Mathijs , Coenders Marcel
Published: May 2019

A considerable portion of European citizens are in favour of limited or conditional access for migrants to welfare provisions. Previous studies found that this welfare chauvinism is stronger among citizens with less favourable economic positions. This study seeks to explain the relationship between economic risk, both objective and subjective, and welfare chauvinism by looking at two distinct mechanisms: the traditional economic explanation of economic egalitarianism and the cultural explanation of ethnic threat. Given the lack of longitudinal studies, we also examine whether changes in economic risk, economic egalitarianism and threat can explain changes in welfare chauvinism over time. Using a four-wave panel-study (2013–2015) collected in Great Britain and the Netherlands, these relationships were studied both cross-sectionally and longitudinally. The longitudinal mediation model was tested by making use of parallel process latent growth curve modelling. In both Great Britain and the Netherlands, economic egalitarianism and ethnic threat explained the link between economic risk and welfare chauvinism. Furthermore, in both countries, an increase over time in perceptions of ethnic threat was found to be the driving force behind an increase in welfare chauvinism, irrespective of changes in economic egalitarianism.
Overexpression of the Cdk5 inhibitory peptide in motor neurons rescue of amyotrophic lateral sclerosis phenotype in a mouse model
Authors: BK Binukumar , Skuntz Susan , Prochazkova Michaela , Kesavapany Sashi , Amin Niranjana D , Shukla Varsha , Grant Philip , Kulkarni Ashok B , Pant Harish C
Published: May 2019

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor nerve cells in the brain and the spinal cord. Etiological mechanisms underlying the disease remain poorly understood; recent studies suggest that deregulation of p25/Cyclin-dependent kinase 5 (Cdk5) activity leads to the hyperphosphorylation of Tau and neurofilament (NF) proteins in ALS transgenic mouse model (SOD1G37R). A Cdk5 involvement in motor neuron degeneration is supported by analysis of three SOD1G37R mouse lines exhibiting perikaryal inclusions of NF proteins and hyperphosphorylation of Tau. Here, we tested the hypothesis that inhibition of Cdk5/p25 hyperactivation in vivo is a neuroprotective factor during ALS pathogenesis by crossing the new transgenic mouse line that overexpresses Cdk5 inhibitory peptide (CIP) in motor neurons with the SOD1G37R, ALS mouse model (TriTg mouse line). The overexpression of CIP in the motor neurons significantly improves motor deficits, extends survival and delays pathology in brain and spinal cord of TriTg mice. In addition, overexpression of CIP in motor neurons significantly delays neuroinflammatory responses in TriTg mouse. Taken together, these data suggest that CIP may serve as a novel therapeutic agent for the treatment of neurodegenerative diseases.
The leukotriene receptors as therapeutic targets of inflammatory diseases
Authors: Sasaki Fumiyuki , Yokomizo Takehiko
Published: May 2019

Leukotrienes (LTs) are inflammatory mediators derived from arachidonic acid. LTs include the di-hydroxy acid LT (LTB4) and the cysteinyl LTs (CysLTs; LTC4, LTD4 and LTE4), all of which are involved in both acute and chronic inflammation. We and other groups identified a high-affinity LTB4 receptor, BLT1; the LTC4 and LTD4 receptors, CysLT1 and CysLT2; and the LTE4 receptor, GPR99. Pharmacological studies have shown that BLT1 signaling stimulates degranulation, chemotaxis and phagocytosis of neutrophils, whereas CysLT1 and CysLT2 signaling induces airway inflammation by increasing vascular permeability and the contraction of bronchial smooth muscle. Recently, we and other groups suggested that the LTB4–BLT1 axis and the cysteinyl LTs–CysLT1/2 axis are involved in chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, atherosclerosis, arthritis, obesity, cancer and age-related macular degeneration using animal models for disease and gene knockout mice. This review describes the classical and novel functions of LTs and their receptors in several inflammatory diseases and discusses the potential clinical applications of antagonists for LT receptors and inhibitors of LT biosynthesis.
How Do Professions Globalize? Lessons from the Global South in US Medical Education
Authors: Hanrieder Tine
Published: May 2019

This article explores the professional construction of the space of Global Health. I argue that the growth of Global Health as a field of practice does not merely indicate an intensification of North-South intervention. It is also a professional project of reimporting lessons from the South to countries in the North. I focus on the emerging didactic regime for Global Health in US medical education and the deterritorialized “global” lessons that students are taught in poor countries. By rescaling these lessons to precarious settings at home, the space of Global Health is reterritorialized as a Global Medical South stretching into the United States, reinforcing the perception that health is not a right but a privilege. The analysis is based on a content analysis of university websites and didactic handbooks and a sample of sixty-four articles evaluating the education effects of study abroad experiences. It reveals an emerging canon of Global Health virtues and the construction of domestic scales for Global Health practices, which are based on ethnic and socioeconomic categories. This analysis of professional projects as spatial projects sheds new light on the geography of Global Health and of professional globalization more generally.
Successful treatment with daptomycin and ceftaroline of MDR Staphylococcus aureus native valve endocarditis: a case report
Authors: Duss François-Régis , Garcia de la Mària Cristina , Croxatto Antony , Giulieri Stefano , Lamoth Frédéric , Manuel Oriol , Miró José M
Published: May 2019

Objectives

The best therapeutic approach for treating MRSA endocarditis remains unknown, particularly in cases of high vancomycin MICs. We report here a case of daptomycin-non-susceptible, ceftaroline-resistant and fosfomycin-resistant MRSA native left valve endocarditis that was successfully treated with valve repair and a combination of high-dose daptomycin and ceftaroline.

Methods

Antimicrobial testing of the clinical strain was performed using Etest and microdilution broth methods. Time–kill and chequerboard methodologies were used to test the activity of antibiotic combinations.

Results

By Etest, the MIC of vancomycin was 2 mg/L, the MIC of daptomycin was 2 mg/L, the MIC of fosfomycin was 1024 mg/L and the MIC of ceftaroline was 1.5 mg/L. At the standard inoculum (105 cfu/mL), the three combinations of daptomycin plus ceftaroline, cloxacillin or fosfomycin were synergistic and bactericidal. However, when these combinations were tested using a higher inoculum (108 cfu/mL), all combinations were synergistic, but only daptomycin plus ceftaroline had bactericidal activity.

Conclusions

These results confirmed a synergistic effect between daptomycin plus ceftaroline and increased bactericidal activity against MRSA, suggesting that this combination may be effective for the treatment of invasive MRSA infection. Our experience highlights the potential clinical use of synergy testing to guide difficult treatment decisions in patients with MDR MRSA infection.
‘Too High’, ‘Too Low’, or ‘Just Fair Enough’?
Authors: Nicholson Joanna
Published: May 2019

That an accused receives a fair trial is essential to the legitimacy of international criminal courts and tribunals. However, how best to interpret the right to a fair trial in order to maximize the legitimacy of international criminal courts and tribunals’ decision-making? Some argue that international criminal courts and tribunals should aspire to the highest standards of fairness and should aim to set an example for domestic courts in this regard. Others argue that the unique context within which international criminal courts and tribunals operate allows them, at times, to interpret the right to a fair trial in a way which falls below minimum international human rights standards. This article examines both of these positions and finds both to be problematic. Rather, the article argues that international criminal courts and tribunals should aim for a middle path, the ‘fair enough’ standard, when interpreting the right to a fair trial. In situations where a different standard than that found within international human rights law is applied, international criminal courts and tribunals should expend greater effort in being open and clear as to why this is so, and should take care in communicating this to their audience, including victims and the accused. By doing so, the legitimacy of their decision-making will be enhanced.
Increased Tau Phosphorylation in Motor Neurons From Clinically Pure Sporadic Amyotrophic Lateral Sclerosis Patients
Authors: Stevens Claire H , Guthrie Natalie J , van Roijen Marloes , Halliday Glenda M , Ooi Lezanne
Published: May 2019

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons. There is a pathological and genetic link between ALS and frontotemporal lobar degeneration (FTLD). Although FTLD is characterized by abnormal phosphorylated tau deposition, it is unknown whether tau is phosphorylated in ALS motor neurons. Therefore, this study assessed tau epitopes that are commonly phosphorylated in FTLD, including serine 396 (pS396), 214 (pS214), and 404 (pS404) in motor neurons from clinically pure sporadic ALS cases compared with controls. In ALS lower motor neurons, tau pS396 was observed in the nucleus or the nucleus and cytoplasm. In ALS upper motor neurons, tau pS396 was observed in the nucleus, cytoplasm, or both the nucleus and cytoplasm. Tau pS214 and pS404 was observed only in the cytoplasm of upper and lower motor neurons in ALS. The number of motor neurons (per mm2) positive for tau pS396 and pS214, but not pS404, was significantly increased in ALS. Furthermore, there was a significant loss of phosphorylated tau-negative motor neurons in ALS compared with controls. Together, our data identified a complex relationship between motor neurons positive for tau phosphorylated at specific residues and disease duration, suggesting that tau phosphorylation plays a role in ALS.
Suppression in interpreting adjective noun combinations and the nature of the lexicon
Authors: Hogeweg Lotte
Published: May 2019

A common assumption about our internal lexicon is that the meaning of words is underspecified and this underspecified representation is filled in based on the context in which the word occurs. In this paper I would like to explore a different hypothesis, that words are stored with overspecified representations which are ‘trimmed down’ by the context. This view seems to be in line with a well-known mechanism from psycholinguistics: suppression. Many studies have shown that conceptual properties of a word are initially activated but subsequently suppressed when these properties are in conflict with the context the word occurs in. This mechanism has not been tested, however, in a context where compositional application takes place as between an adjective and a noun. In this study I will discuss two lexical decision experiments testing the interpretation of two types of adjective noun combinations. For both types of combinations it is expected that the representation of the noun undergoes a change due to the conflicting information provided by the adjective. It is hypothesized that the properties of the noun that are in conflict with the adjective are initially activated, but subsequently suppressed to form a coherent representation of the adjective noun combination. While the results provide evidence for the initial activation of the conceptual properties, no evidence for the subsequent suppression was found. The initial activation shows that also in the case of adjective noun combinations, conceptual features do not ‘wait for’ an initial well-formed semantic structure. The lack of evidence for suppression primarily suggests the need for further research. If future experiments confirm that suppression does not take place within the time frame tested in the experiments, we must conclude, based on experimental findings by Schumacher (2013), that conceptual specification takes place after the shift in reference of the noun.