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Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13-mutant trachea phenotypes. These results provide insight into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.
Background: Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD), which is sometimes associated with severe central nervous system disease in children. There is currently no specific medication for EV71 infection. Quercetin, one of the most widely distributed flavonoids in plants, has been demonstrated to inhibit various viral infections. However, investigation of the anti-EV71 mechanism has not been reported to date.
Methods: The anti-EV71 activity of quercetin was evaluated by phenotype screening, determining the cytopathic effect (CPE) and EV71-induced cells apoptosis. The effects on EV71 replication were evaluated further by determining virus yield, viral RNA synthesis and protein expression, respectively. The mechanism of action against EV71 was determined from the effective stage and time-of-addition assays. The possible inhibitory functions of quercetin via viral 2Apro, 3Cpro or 3Dpol were tested. The interaction between EV71 3Cpro and quercetin was predicted and calculated by molecular docking.
Results: Quercetin inhibited EV71-mediated cytopathogenic effects, reduced EV71 progeny yields, and prevented EV71-induced apoptosis with low cytotoxicity. Investigation of the underlying mechanism of action revealed that quercetin exhibited a preventive effect against EV71 infection and inhibited viral adsorption. Moreover, quercetin mediated its powerful therapeutic effects primarily by blocking the early post-attachment stage of viral infection. Further experiments demonstrated that quercetin potently inhibited the activity of the EV71 protease, 3Cpro, blocking viral replication, but not the activity of the protease, 2Apro, or the RNA polymerase, 3Dpol. Modeling of the molecular binding of the 3Cpro-quercetin complex revealed that quercetin was predicted to insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and thereby inhibiting EV71 3Cpro activity.
Conclusions: Quercetin can effectively prevent EV71-induced cell injury with low toxicity to host cells. Quercetin may act in more than one way to deter viral infection, exhibiting some preventive and a powerful therapeutic effect against EV71. Further, quercetin potently inhibits EV71 3Cpro activity, thereby blocking EV71 replication.
A small single molecule with multiple photoswitchable subunits, selectively and independently controllable by light of different wavelengths, is highly attractive for applications in multi-responsive materials and biological sciences. Herein, triple photoswitches are presented consisting of three independent azobenzene (AB) subunits that share a common central phenyl ring: the meta-trisazobenzenes (MTA). It is the unique meta-connectivity pattern leading to decoupling of all azo-subunits although they do overlap spatially. Based on this pattern, we design a triple MTA photoswitch, as proof-of-principle, with three different, electronically independent AB branches on the computer, which can be individually photo-excited to trigger ultra-fast E → Z isomerization at the selected AB branch.
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.
Background: Transient elastography (TE) has been validated as an effective noninvasive tool for the assessment of liver fibrosis. The XL probe is a new probe that was initially designed for use in patients with obesity. A meta-analysis was performed to assess the feasibility and efficacy of TE using the XL probe.
Methods: In September 2016, we systematically searched the PubMed and Science Direct search engines. The feasibility of TE was evaluated based on the failure rate and the results of the unreliable liver stiffness measurement (LSM). The efficacy of TE was measured using sensitivity, specificity, and summary receiver-operating characteristic as measures/indices assessed in different stages of fibrosis. Heterogeneity was measured using the chi-squared test and the Q-statistic. We used the 95% confidence interval (95% CI) as an effect measure.
Results: We included 8 studies in the meta-analysis. When the XL was compared to the M probe, the former showed a lower risk of failure rate [relative risk (RR) 0.24, 95% CI 0.14–0.38]. In patients with a body mass index ≥30 kg/m2, the XL probe showed a statistically significantly lower risk of failure rate (RR 0.16, 95% CI 0.08–0.32) but no significant improvement (RR 0.76, 95% CI 0.50–1.16) in the unreliable LSM result. In patients showing liver fibrosis stage ≥F2, the XL probe showed a sensitivity of 0.56 (95% CI 0.39–0.72), specificity of 0.71 (95% CI 0.61–0.79), and an area under the curve (AUC) of 0.71. The results observed in patients with liver fibrosis stage F4 were more promising with a sensitivity of 0.84 (95% CI 0.76–0.90), specificity of 0.78 (95% CI 0.70–0.84), and an AUC of 0.88.
Conclusion: TE using the XL probe demonstrates significant diagnostic utility in patients with liver fibrosis and is likely to be more reliable than the M probe in patients with obesity. Large prospective multicenter studies are, however, necessary to establish the new cut-off values to be used for the XL probe in patients with obesity.
The Dodd Frank Act of 2010 (DFA) was the legislative response by the US Government to the Global Financial Crisis of 2007. DFA’s rescission of Rule 436 (g) of the Securities Act of 1933 - the exemption from liability clause - was the response to the post-crisis perception that credit rating agencies were insufficiently constrained by reputational risk considerations and consistently failed to provide high quality and accurate credit ratings as a consequence of the immunity they enjoyed and the regulatory reliance placed on ratings, as well as the conflicts of interest that they faced. This paper investigates whether the market failure event that occurred in the Asset Backed Securities market immediately after DFA was signed into law on July 21, 2010 was due to real economic concerns held by rating agencies about operating under a liability regime or whether it was merely an act of brinkmanship on the part of the rating agencies. The paper also predominantly examines US case law to identify the dilution of the freedom of speech defence in state courts, the conflict of interest issues and the legal challenges faced by plaintiffs when bringing a lawsuit against credit rating agencies, and proposes a novel co-pay and capped liability model to address the concerns of both credit rating agencies and investors.
Hemispherical and cylindrical antenna arrays are widely used in radar-based and tomography-based microwave breast imaging systems. Based on the dielectric contrast between healthy and malignant tissue, a three-dimensional image could be formed to locate the tumor. However, conventional X-ray mammography as the golden standard in breast cancer screening produces two-dimensional breast images so that a comparison between the 3D microwave image and the 2D mammogram could be difficult. In this paper, we present the design and realisation of a UWB breast imaging prototype for the frequency band from 1 to 9 GHz. We present a refined system design in light of the clinical usage by means of a planar scanning and compare microwave images with those obtained by X-ray mammography. Microwave transmission measurements were processed to create a two-dimensional image of the breast that can be compared directly with a two-dimensional mammogram. Preliminary results from a patient study are presented and discussed showing the ability of the proposed system to locate the tumor.
Background: Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, growth retardation, immunodeficiency, chronic pulmonary disease and chromosomal instability. Cutaneous granulomas are a known phenomenon in A-T but extra-dermal manifestation of granulomas at bone and synovia has not been reported so far. The clinical presentation, immunological findings, the long-term course and treatment options of eight patients with severe granulomas will be reported.
Methods: From our cohort of 44 classical A-T patients, eight patients aged 2–11 years (18.2%) presented with granulomas. Immunological features of patients with and without granulomas were compared. Five patients suffered from cutaneous manifestation, in two patients we detected a bone and in one a joint involvement. Patients with significant extra-dermal involvement as well as one patient with massive skin manifestation were treated with TNF inhibitors. The patient with granulomas at his finger joint and elbow was treated with hematopoietic stem cell transplantation (HSCT).
Results: Interestingly, seven of eight patients with granulomas were total IgA deficient, but there were no differences in IgG and IgM levels. All lymphocytes subsets were equally distributed except patients with granuloma had significantly lower naïve CD8 cells. In patients without treatment, four of eight showed a slow but significant enlargement of the granuloma. Treatment success with TNF inhibitors was variable. In one patient, treatment with TNF inhibitors led to a total remission for 3 years up to now. In two patients, treatment with TNF inhibitors led to a partial regression of granulomas. Treatment interruptions caused deterioration again.
Conclusions: Granulomas in A-T progress slowly over years and can lead to significant morbidity.Treatment with TNF inhibitors was safe and in part successful in our patients. Interestingly HSCT leads to complete remission, and indicates that aberrant immune function is responsible for granulomas in A-T patients.
At a glance commentary:
Scientific knowledge on the subject: Little is known about the clinical presentation, course and treatment of granulomas in ataxia telangiectasia (A-T). In addition, this is the first report of extra-dermal manifestation of granulomas at bone and synovia in patients with A-T.
What This Study Adds to the Field: Granulomas in A-T progress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients.
In primary early breast cancer, the aim of treatment planning is to obtain an increasingly better understanding of the disease. The identification of patients with an excellent prognosis could help this group avoid unnecessary treatments. Furthermore, the planning of treatment is becoming increasingly patient-focussed. There is a growing understanding of those patients who benefit particularly from chemotherapy, as well as of those who could benefit from immunotherapy. Studies conducted on immunotherapies will be published shortly. Smaller individual studies offer an initial insight into the efficacy of checkpoint inhibitors (anti-PD1/PDL1 therapies). Not least, one of the largest breast cancer studies of all times has recently come to an end. The use of a multigene test has shown that it is sufficient to identify patients with such a good prognosis that chemotherapy is unnecessary. This review article is intended to summarise the current studies and give an outlook on current developments.
Purpose: The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer.
Methods: The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure.
Recommendations: Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.
DIGITIZATION CHALLENGES COMPANIES TO ACCELERATE THEIR INNOVATION CYCLES TO STAY COMPETITIVE. THIS RESEARCH INVESTIGATES HOW IT KNOWLEDGE ESTABLISHED ON DIFFERENT HIERARCHICAL LEVELS LEADS TO ORGANIZATIONAL INNOVATIVENESS. DIFFERENTIATING BETWEEN STRATEGICALLY MORE AND LESS DIGITIZED ORGANIZATIONS, THE RESULTS REVEAL: ORGANIZATIONAL INNOVATIVENESS IS SIGNIFICANTLY HIGHER INFLUENCED BY THE IT KNOWLEDGE OF BUSINESS EMPLOYEES IN ORGANIZATIONS GIVING THE DIGITAL BUSINESS STRATEGY HIGH IMPORTANCE, WHEREAS THE MANAGEMENT’S ROLE DECREASES. WE FURTHER DEDUCE THE CIO’S POSITIVE ROLE FOR IT-ENABLED BUSINESS INNOVATION IN KNOWLEDGE-INTENSIVE INDUSTRIES, SUCH AS THE FINANCIAL SERVICES SECTOR.
EXTANT STRATEGY CONCEPTS ARE CHALLENGED DUE TO THE ONGOING DIGITIZATION, WHICH FUNDAMENTALLY CHANGES CONDITIONS FOR ALL MARKET PARTICIPANTS. THIS RESEARCH COMPARES THE CONCEPT OF IT ALIGNMENT WITH THE RECENTLY INTRODUCED “DIGITAL BUSINESS STRATEGY” (DBS), WHICH DESCRIBES A CROSS-FUNCTIONAL AND AGILE FUSION OF BUSINESS AND IT STRATEGY. THE RESULTS REVEAL A TOTAL ABSENCE OF A DIRECT INFLUENCE OF IT LEADERS (CIOS) ON DBS, WHEREAS A HIGH IMPACT ON IT ALIGNMENT IS STILL GIVEN. BUSINESS LEADERS IN TURN IMPACT MORE ON DBS.
Background: The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX® Quattro Plus 1.0 ml Birch 100%) is an effective, well‐tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose.
Methods: The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012‐004336‐28 PQBirch203 and 2015‐000984‐15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3‐4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED50), a measure of potency.
Results: Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED50 2723 SU, just over half the current dose. Prevalence of treatment‐emergent adverse events was similar for active doses, most being short‐lived and mild. Compliance was over 85% in all groups.
Conclusion: Increasing the cumulative dose of PQBirch 5.5‐fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.
The multi-valence nature of vanadium means that its geochemical behaviour will be ƒO2-dependent, so that its concentration or V/Sc (or V/Ga), can serve as proxies for oxidation state in mantle peridotites. Compared to Fe3+/Fe2+-based equilibria, such trace elements may be less sensitive to metasomatic processes. To investigate these systematics, we have measured V, Sc, Ga and Fe3+ contents in clinopyroxene from well-characterised spinel peridotite xenoliths from the Massif Central, France. These samples were metasomatised by a variety of agents with different oxidation states.V contents can be modified by metasomatic interactions, and other geochemically similar elements including Sc and Ga can also be added, removed or remain constant. A link between V/Sc and Fe3+-Fe2+ equilibria is apparent. Partial removal of V is caused by different metasomatic agents; the common factor is that all agents were significantly more oxidised than the initial ambient mantle peridotite. This extraction can be understood by a decreasing partition coefficient for V for ΔlogƒO2 > ~FMQ-2. Considering that mineral/melt partitioning of V decreases similarly for all peridotite minerals, the bulk-rock V/Sc will also change during relatively oxidising metasomatic interactions and mirror the results obtained for clinopyroxene.
Background: Subdural hematoma (SDH) is a common disease associated with high morbidity, which is becoming more prominent due to the increasing incidence. Decision for a surgical evacuation is made depending on the clinical appearance and the volume of SDH, wherefore it is important to have a simple ‘bedside’ method to measure and compare the volume of SDH.
Objective: The aim of the study was to verify the accuracy of the simplified ABC/2 volumetric formula to determine a valuable tool for the clinical practice.
Methods: Preoperative CT-scans of 83 patients with SDHs were used for the computer-assisted volumetric measurement via BrainLab® as well as the ABC/2 volumetric measurement. A = largest length (anterior to posterior) of the SDH; B = maximum width (lateral to midline) 90° to A; C = maximum height (coronal plane or multiplication of slices) of the hematoma. These measurements were performed by two independent clinicians in a blinded fashion. Both volumes were compared by linear regression analysis of Pearson and Bland-Altman regression analysis.
Results: Among 100 SDHs, 53% were under an 47% were over 100cm3 showing a well distribution of the hematoma sizes. There was an excellent correlation between computer-assisted volumetric measurement and ABC/2 (R2 = 0.947, p<0.0001) and no undesirable deviation and trend were detected (p = 0.101; p = 0.777). A 95% tolerance region of the ratios of both methods was [0.805–1.201].
Conclusion: The ABC/2 method is a simple and fast bedside formula for the measurement of SDH volume in a timely manner without limited access through simple adaption, which may replace the computer-assisted volumetric measurement in the clinical and research area. Reason for the good accuracy seems to be the spherical form of SDH, which has a similarity to a half ellipsoid.
The paper illustrates based on an example the importance of consistency between the empirical measurement and the concept of variables in estimated macroeconomic models. Since standard New Keynesian models do not account for demographic trends and sectoral shifts, the authors proposes adjusting hours worked per capita used to estimate such models accordingly to enhance the consistency between the data and the model. Without this adjustment, low frequency shifts in hours lead to unreasonable trends in the output gap, caused by the close link between hours and the output gap in such models.
The retirement wave of baby boomers, for example, lowers U.S. aggregate hours per capita, which leads to erroneous permanently negative output gap estimates following the Great Recession. After correcting hours for changes in the age composition, the estimated output gap closes gradually instead following the years after the Great Recession.
The pyrrolobenzodiazepine tilivalline (1) was originally identified in the human gut pathobiont Klebsiella oxytoca, the causative agent of antibiotic-associated hemorrhagic colitis. Here we show the identification of tilivalline and analogs thereof in the entomopathogenic bacterium Xenorhabdus eapokensis as well as the identification of its biosynthesis gene cluster encoding a bimodular non-ribosomal peptide synthetase. Heterologous expression of both genes in E. coli resulted in the production of 1 and from mutasynthesis and precursor directed biosynthesis 11 new tilivalline analogs were identified in X. eapokensis. These results allowed the prediction of the tilivalline biosynthesis being similar to that in K. oxytoca.
In April 2018 the European Commission announced its holistic approach to Artificial Intelligence (AI) based on the following three pillars: first, to boost financial support and encourage uptake by the public and private sectors in order to reach investments in AI-related research and innovation by at least 20 billion Euros by the end of 2020. The second pillar aims at preparing for socio-economic changes in terms of the upcoming transformation of the labour market. Finally, the European Commission will ensure an appropriate ethical and legal framework by developing AI ethics guidelines and providing guidance on the interpretation of the Product Liability directive. ...
Aim: To evaluate the occurrence and severity of enterostomy complications in newborns suffering from different intestinal disorders.
Methods: A 10-year retrospective cohort study (2008-2017) investigated newborns that underwent enterostomy formation and reversal for different intestinal disorders. Only infants less than 28 d old at the time of enterostomy creation were included in the study (corrected age was applied in the cases of preterm neonates). The patients were divided into two groups according to their underlying diseases. Group 1 included infants suffering from necrotizing enterocolitis (NEC), whereas Group 2 included newborns diagnosed with intestinal disorders other than NEC, such as meconium obstruction, anorectal malformation, focal intestinal perforation, ileus, intestinal atresia and volvulus. The primary outcome measure was enterostomy-related morbidity. The data were analyzed statistically using Pearson’s χ2 test or Fisher’s exact test for categorical variables and the Wilcoxon-Mann-Whitney U-Test for continuous variables.
Results: In total, 76 infants met the inclusion criteria and were evaluated for enterostomy-related complications. Neither group showed significant differences regarding gender, gestational age, weight at birth or weight at enterostomy formation. Infants suffering from NEC (Group 1) were significantly older at enterostomy formation than the neonates of Group 2 [median (range), 11 (2-75) d vs 4 (1-101) d, P = 0.004)]. Significantly more ileostomies were created in Group 1 [47 (92.2%) vs 16 (64.0%), P = 0.007], whereas colostomies were performed significantly more often in Group 2 [2 (3.9%) vs 8 (32.0%), P = 0.002]. The initiation of enteral nutrition after enterostomy was significantly later in Group 1 infants than in Group 2 infants [median (range), 5 (3-13) vs 3 (1-9), P < 0.001]. The overall rate of one or more complications in patients of both groups after enterostomy formation was 80.3%, with rates of 86.3% in Group 1 and 68.0% in Group 2 (P = 0.073). Most patients suffered from two complications (23.7%). Four or more complications occurred in 21.6% of the infants in Group 1 and in 12.0% of the infants in Group 2 (P = 0.365). Following enterostomy closure, at least one complication was observed in 26.0% of the patients (30.6% in Group 1 and 16.7% in Group 2, P = 0.321). The occurrence of complications was not significantly different between neonates with NEC and infants with other intestinal disorders. 48 (65.8%) patients required no treatment or only pharmacological treatment for the complications that occurred [Clavien-Dindo-Classification (CDC) < III], while 25 (34.2%) required surgery to address the complications (CDC ≥ III). Early reversal of the enterostomy was performed significantly more often (P = 0.003) and the time to full enteral nutrition after closure was significantly longer [median (range), 7 (3-87) d vs 12 (5-93) d, P = 0.006] in infants with a CDC grading ≥ III than in infants with a CDC grading < III.
Conclusion: Complications occur in almost all infants with enterostomies. The majority of these complications are minor and do not require surgical treatment. There is a clear trend that neonates with NEC have a higher risk for developing complications than those without NEC.