Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting TAO Kinases Using a New Inhibitor Compound Delays Mitosis and Induces Mitotic Cell Death in Centrosome Amplified Breast Cancer Cells

Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death, and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes, and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome-amplified cancer cells preferentially, while sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells, and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur. Mol Cancer Ther; 16(11); 2410–21. ©2017 AACR.
Geographic variation in the spotted-wing drosophila, Drosophila suzukii (Diptera: Drosophilidae), based on mitochondrial DNA sequences

Abstract The spotted-wing drosophila (SWD), Drosophila suzukii (Diptera: Drosophilidae), is an economically damaging pest that feeds on most thin-skinned fruits. It was originally native to a few Asian countries, including Korea, but is now found in North America and Europe. In this study, we sequenced portions of the mitochondrial (mt) COI and ND4 genes from a total of 195 individuals collected mainly from Korea. We then combined GenBank-registered COI sequences from all ancestral-range and introduced-range populations with our own COI data to assess the worldwide diversity, divergence, and relatedness of SWD haplotypes. A total of 139 haplotypes were obtained from the concatenated COI and ND4 sequences. Most haplotypes were confined to single localities, but 12 of them were found in more than two localities, and one haplotype (SWDCN61) was found from Korea to Canada. A dataset combining GenBank sequences with our own data identified a total of 94 worldwide COI haplotypes with a maximum sequence divergence (MSD) of 5.433% (32 bp). Although most haplotypes were found in only a single country, a few haplotypes were found commonly in China, Korea, and Japan; these occurred at a higher frequency and were often involved in introductions. A rough estimate of genetic diversity in each country showed higher diversity in ancestral distributional ranges, but the invasion over Asian countries seems to have been substantial because haplotype diversity was only 2.35 to 3.97-fold lower in the U.S.A, Canada, and Italy than that in the populations’ ancestral ranges.
Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.

OBJECTIVE NIDDM occurs commonly among women with polycystic ovary syndrome (PCOS). The prevalence and natural history of its precursor, impaired glucose tolerance (IGT), is less well known. The objective of this study was to characterize the prevalence and incidence of glucose intolerance in a large cohort of women with well-characterized PCOS. RESEARCH DESIGN AND METHODS A total of 122 women with clinical and hormonal evidence of PCOS were recruited from the Medicine, Endocrinology, Gynecology, and Pediatrics Clinics at the University of Chicago. All women had a standard oral glucose tolerance test (OGTT) with measurement of glucose and insulin levels. A subset of 25 women were subsequently restudied with the aim of characterizing the natural history of glucose tolerance in PCOS. RESULTS Glucose tolerance was abnormal in 55 (45%) of the 122 women: 43 (35%) had IGT and 12 (10%) had NIDDM at the time of initial study. The women with NIDDM differed from those with normal glucose tolerance in that they had a 2.6-fold higher prevalence of first-degree relatives with NIDDM (83 vs. 31%, P < 0.01 by chi 2) and were significantly more obese (BMI 41.0 +/- 2.4 vs. 33.4 +/- 1.1 kg/m2, P < 0.01). For the entire cohort of 122 women, there was a significant correlation between fasting and 2-h glucose concentrations (r = 0.76, P < 0.0001); among the subset with IGT, the fasting glucose concentration was poorly predictive of the 2-h level (r = 0.25, NS). After a mean follow-up of 2.4 +/- 0.3 years (range 0.5-6.3), 25 women had a second OGTT. The glucose concentration at 2 h during the second glucose tolerance test was significantly higher than the 2-h concentration during the first study (161 +/- 9 vs. 139 +/- 6 mg/dl, P < 0.02). CONCLUSIONS The prevalence of IGT and NIDDM in women with PCOS is substantially higher than expected when compared with age- and weight-matched populations of women without PCOS. The conversion from IGT to NIDDM is accelerated in PCOS. The fasting glucose concentration does not reliably predict the glucose concentration at 2 h after an oral glucose challenge, particularly among those with IGT, the subgroup at highest risk for subsequent development of NIDDM. We conclude that women with PCOS should periodically have an OGTT and must be closely monitored for deterioration in glucose tolerance.
Focal Adhesion Kinase (FAK) tyrosine 397E mutation restores the vascular leakage defect in endothelium‐specific FAK‐kinase dead mice

Focal adhesion kinase (FAK) inhibitors have been developed as potential anticancer agents and are undergoing clinical trials. In vitro activation of the FAK kinase domain triggers autophosphorylation of Y397, Src activation, and subsequent phosphorylation of other FAK tyrosine residues. However, how FAK Y397 mutations affect FAK kinase‐dead (KD) phenotypes in tumour angiogenesis in vivo is unknown. We developed three Pdgfb‐iCreert‐driven endothelial cell (EC)‐specific, tamoxifen‐inducible homozygous mutant mouse lines: FAK wild‐type (WT), FAK KD, and FAK double mutant (DM), i.e. KD with a putatively phosphomimetic Y397E mutation. These ECCre+;FAKWT/WT, ECCre+;FAKKD/KD and ECCre+;FAKDM/DM mice were injected subcutaneously with syngeneic B16F0 melanoma cells. Tumour growth and tumour blood vessel functions were unchanged between ECCre+;FAKWT/WT and ECCre−;FAKWT/WT control mice. In contrast, tumour growth and vessel density were decreased in ECCre+;FAKKD/KD and ECCre+;FAKDM/DM mice, as compared with Cre − littermates. Despite no change in the percentage of perfused vessels or pericyte coverage in either genotype, tumour hypoxia was elevated in ECCre+;FAKKD/KD and ECCre+;FAKDM/DM mice. Furthermore, although ECCre+;FAKKD/KD mice showed reduced blood vessel leakage, ECCre+;FAKDM/DM and ECCre−;FAKDM/DM mice showed no difference in leakage. Mechanistically, fibronectin‐stimulated Y397 autophosphorylation was reduced in Cre+;FAKKD/KD ECs as compared with Cre+;FAKWT/WT cells, with no change in phosphorylation of the known Src targets FAK‐Y577, FAK‐Y861, FAK‐Y925, paxillin‐Y118, p130Cas‐Y410. Cre+;FAKDM/DM ECs showed decreased Src target phosphorylation levels, suggesting that the Y397E substitution actually disrupted Src activation. Reduced VE‐cadherin‐pY658 levels in Cre+;FAKKD/KD ECs were rescued in Cre+FAKDM/DM ECs, corresponding with the rescue in vessel leakage in the ECCre+;FAKDM/DM mice. We show that EC‐specific FAK kinase activity is required for tumour growth, angiogenesis, and vascular permeability. The ECCre+;FAKDM/DM mice restored the KD‐dependent tumour vascular leakage observed in ECCre+;FAKKD/KD mice in vivo. This study opens new fields in in vivo FAK signalling. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Immunoglobulin E antibody reactivity to bacterial antigens in atopic dermatitis patients

Cite this as: K. Reginald, K. Westritschnig, T. Werfel, A. Heratizadeh, N. Novak, M. Focke‐Tejkl, A. M. Hirschl, D. Y. M. Leung, O. Elisyutina, E. Fedenko and R. Valenta, Clinical & Experimental Allergy, 2011 (41) 357–369.
Activity of Thalidomide and Capecitabine in Patients With Advanced Hepatocellular Carcinoma

BackgroundThalidomide has shown modest activity in advanced hepatocellular carcinomas (HCCs). Single-agent capecitabine has also been used in patients with HCC, with objective responses being reported. In our study, we review the use of thalidomide and capecitabine combination in advanced HCC. MethodsFrom November 2003 and September 2008, 42 patients with advanced HCC who were not eligible for clinical trial or conventional chemotherapy were treated with oral capecitabine (2000 mg/m2/d) for 14 days every 3 weeks and oral thalidomide at the doses of 50 to 200 mg/d. ResultsAlmost 50% of patients had Child-Pugh B or C liver cirrhosis and a history of regional or systemic therapy. Three patients achieved complete responses lasting more than 52 weeks, including 1 patient who achieved pathological complete response and underwent curative resection. There were 3 patients with partial responses and 13 with stable disease. Median overall survival of all 42 patients was 9.9 months. The median progression-free survival was 5.1 months. The presence of ascites, portal vein thrombosis, and poorer Child-Pugh liver cirrhosis status also resulted in significantly poorer survival outcome. Treatment was well tolerated. Fatigue was the most common side effect occurring in 16 (38%) patients, but only 1 patient had grade 3 toxicity and had to stop treatment. Two other patients developed grade 3 palmar-plantar erythrodysesthesia from capecitabine. ConclusionsThe combination of thalidomide and capecitabine has activity in advanced HCC and can result in complete pathological response. Treatment is well tolerated even in less-fit patients who have been pretreated and deserve further study.
A new triple stain for Helicobacter pylori suitable for the autostainer: carbol fuchsin/Alcian blue/hematoxylin-eosin.

OBJECTIVE To develop an inexpensive stain to simultaneously visualize gastric morphology and Helicobacter pylori. METHODS Gastric biopsies were stained with Genta stain using manual methods, and with carbol fuchsin/Alcian blue/hematoxylin-eosin using an automatic slide stainer (Sakura DRS-601). Slides were then coded and interpreted by 2 pathologists. Helicobacter pylori was scored using a visual scale (0 [none] to 5 [maximum]). RESULTS One hundred slides were scored; H pylori was present in 64%. Carbol fuchsin/Alcian blue/hematoxylin-eosin stain gave excellent demonstration of gastric morphology. All positive cases (score > or =2) were correctly interpreted. Thirty-six slides had a score of 1 (< or =2 bacteria per entire slide). Of these, 10 were scored negative by Genta stain and 12 were scored negative by the carbol fuchsin/Alcian blue/hematoxylin-eosin stain (P = not significant). Hematoxylin-eosin was significantly less accurate than either of the other 2 stains (P < .02). CONCLUSION The carbol fuchsin/Alcian blue/hematoxylin-eosin (El-Zimaity) stain is an economical stain suitable for simultaneous visualization of H pylori infection and gastric morphology.
Transient Analysis of IEEE 802.15.4 Sensor Networks

We study the delay performance of a sensor network, whose nodes access the medium by using the unslotted MAC protocol specified by the IEEE 802.15. 4 standard. Unlike previous works, which focus on the average throughput and delay analysis, we develop a detailed model that allows us to obtain the delivery delay distribution of messages sent by concurrently contending sensors toward a central controller. We carry out a transient analysis that is of particular interest when sensor networks are deployed to provide k-coverage for real-time applications, and we study both single- and multi-hop network topologies. We validate our analytical results against simulation results obtained through ns2.
The introduction of simple cardiorespiratory fitness testing in overweight/obese type 2 diabetics: a pilot study

Background Low level of cardiorespiratory fitness has been recognized as an important independent and modifiable risk factor of increased morbidity and mortality. However, in standard outpatient settings, patients are not routinely screened for fitness and advantages of such testing for the management of type 2 diabetes have not been defined. Aim To describe the toleration of a fast, simple and practicable fitness test (2-min step-in-place test) by overweight/obese type 2 diabetics and their performance indicated by 2-min step-in-place test score (STS). To study short-term anthropometric, functional and metabolic changes following the implementation of the test in the selected population. Methods A total of 33 overweight/obese type 2 diabetics underwent, besides routine examination at the outpatient clinic, the fitness test (group A). Patients were asked to increase their regular physical activity with focus on walking without change in diet and chronic medication. Three to four months later, the subjects were tested again. An identical number of age- and sex-matched obese diabetics followed in our outpatient clinic (without fitness testing), was randomly selected from the Hospital Information System (control group B). Findings All patients subjected to fitness testing completed the protocol successfully. STS score was found to have a considerable range with differences between males and females at the borderline of statistical significance. The data are compliant with lower aerobic endurance of obese diabetics compared with healthy population. Within study period, the tested group presented with improvements in STS (referring especially to the males) as well as in several laboratory parameters of glucose and lipid homeostasis, glomerular function and subclinical inflammation with no reflection in anthropometry. Group B demonstrated no significant change. In conclusion, 2-min step-in-place test is fast, undemanding and well-tolerated by patients and personnel. Following its validation based on cardiopulmonary exercise testing, the test may prove recommendable for screening or self-monitoring purposes.
Climate change, transgenic corn adoption and field-evolved resistance in corn earworm

Increased temperature anomaly during the twenty-first century coincides with the proliferation of transgenic crops containing the bacterium Bacillus thuringiensis (Berliner) (Bt) to express insecticidal Cry proteins. Increasing temperatures profoundly affect insect life histories and agricultural pest management. However, the implications of climate change on Bt crop–pest interactions and insect resistance to Bt crops remains unexamined. We analysed the relationship of temperature anomaly and Bt adoption with field-evolved resistance to Cry1Ab Bt sweet corn in a major pest, Helicoverpa zea (Boddie). Increased Bt adoption during 1996–2016 suppressed H. zea populations, but increased temperature anomaly buffers population reduction. Temperature anomaly and its interaction with elevated selection pressure from high Bt acreage probably accelerated the Bt-resistance development. Helicoverpa zea damage to corn ears, kernel area consumed, mean instars and proportion of late instars in Bt varieties increased with Bt adoption and temperature anomaly, through additive or interactive effects. Risk of Bt-resistant H. zea spreading is high given extensive Bt adoption, and the expected increase in overwintering and migration. Our study highlights the challenges posed by climate change for Bt biotechnology-based agricultural pest management, and the need to incorporate evolutionary processes affected by climate change into Bt-resistance management programmes.
Design and Operation of a Hybrid Modular Multilevel Converter

This paper presents a hybrid modular multilevel converter (MMC), which combines full-bridge submodules (FBSM) and half-bridge submodules (HBSM). Compared with the FBSM-based MMC, the proposed topology has the same dc fault blocking capability but uses fewer power devices hence has lower power losses. To increase power transmission capability of the proposed hybrid MMC, negative voltage states of the FBSMs are adopted to extend the output voltage range. The optimal ratio of FBSMs and HBSMs, and the number of FBSMs generating a negative voltage state are calculated to ensure successful dc fault blocking and capacitor voltage balancing. Equivalent circuits of each arm consisting of two individual voltage sources are proposed and two-stage selecting and sorting algorithms for ensuring capacitor voltage balancing are developed. Comparative studies for different circuit configurations show excellent performance balance for the proposed hybrid MMC, when considering dc fault blocking capability, power losses, and device utilization. Experimental results during normal operation and dc fault conditions demonstrate feasibility and validity the proposed hybrid MMC.
…But Watch Out for the Weather: FACTORS AFFECTING ADHERENCE TO PROGRESSIVE RESISTANCE EXERCISE FOR PERSONS WITH COPD

PURPOSE: Exercise is an important treatment modality for persons with chronic obstructive pulmonary disease (COPD), but factors influencing adherence have been examined infrequently. The purpose of this investigation was to explore adherence factors to a progressive resistance exercise program for persons with COPD. METHODS: Persons with COPD enrolled in a 12-week trial of progressive resistance exercise were invited to participate in 2 semistructured qualitative interviews exploring program adherence. Interviews were audio-taped, transcribed, and then coded independently by 2 researchers. Themes relating to short-term and long-term adherence were then developed and described. RESULTS: Twenty-two participants were interviewed at the conclusion of the intervention (12 weeks), and 19 completed a second interview at 24 weeks. Short-term exercise adherence was facilitated by expected outcomes, self-motivation, supervision, and group support, whereas health and weather factors were the major barriers to adherence. The barriers to exercise remained unchanged at 24 weeks despite a large decline in exercise adherence. Removal of environmental support at 12 weeks may have contributed to poor long-term exercise maintenance, with participants identifying group support and regular monitoring by a therapist as the most important strategies for maintaining exercise. CONCLUSIONS: The provision of external support in training program design appears important for persons with COPD. Longer-term adherence declined when group support and regular monitoring by a therapist was removed, despite the major perceived exercise barriers remaining unchanged. Therefore, further investigation is required to determine effective strategies for maximizing longer-term exercise adherence in this population.
Nurses' Perspectives on Compassionate Care for Patients with Exacerbated Chronic Obstructive Pulmonary Disease

The aim of the study was to gain insight into intensive care nurses’ perspectives on compassionate care for patients with exacerbated chronic obstructive pulmonary disease. Patients who experience acute exacerbation are vulnerable because they experience a life-threatening situation and are wholly dependent on health-care interventions to relieve breathlessness. A hermeneutic phenomenological approach was used. Three focus group interviews with intensive-care nurses were conducted at two hospitals in western Norway in the autumn of 2009. One group had five participants, and two groups had six participants each (N=17). A collaborative practice was regarded as essential to provide compassionate care in these situations. Three main themes emerged from the data: (a) preparing to care for breathlessness; (b) establishing a trusting relationship; (c) to approach each patient as a person with unique needs. These were experienced as important in rendering compassionate care for patients with exacerbation of chronic obstructive pulmonary disease. The study showed that compassionate care involves interventions at different levels with particular attention to simple comforting care and technical adjustments. The study also showed a need for enhanced multidisciplinary cooperation in planning the subsequent clinical pathway.
Deletion of dop in Mycobacterium smegmatis abolishes pupylation of protein substrates in vivo

Proteasome‐bearing bacteria make use of a ubiquitin‐like modification pathway to target proteins for proteasomal turnover. In a process termed pupylation, proteasomal substrates are covalently modified with the small protein Pup that serves as a degradation signal. Pup is attached to substrate proteins by action of PafA. Prior to its attachment, Pup needs to undergo deamidation at its C‐terminal residue, converting glutamine to glutamate. This step is catalysed in vitro by Dop. In order to characterize Dop activity in vivo, we generated a dop deletion mutant in Mycobacterium smegmatis. In the Δdop strain, pupylation is severely impaired and the steady‐state levels of two known proteasomal substrates are drastically increased. Pupylation can be re‐established by complementing the mutant with either DopWt or a Pup variant carrying a glutamate at its ultimate C‐terminal position (PupGGE). Our data show that Pup is deamidated by Dop in vivo and that likely Dop alone is responsible for this activity. Furthermore, we demonstrate that a putative N‐terminal ATP‐binding motif is crucial for catalysis, as a single point mutation (E10A) in this motif abolishes Dop activity both in vivo and in vitro.
A discordant-sibship test for disequilibrium and linkage: no need for parental data.

The sibship disequilibrium test (SDT) is designed to detect both linkage in the presence of association and association in the presence of linkage (linkage disequilibrium). The test does not require parental data but requires discordant sibships with at least one affected and one unaffected sibling. The SDT has many desirable properties: it uses all the siblings in the sibship; it remains valid if there are misclassifications of the affectation status; it does not detect spurious associations due to population stratification; asymptotically it has a chi2 distribution under the null hypothesis; and exact P values can be easily computed for a biallelic marker. We show how to extend the SDT to markers with multiple alleles and how to combine families with parents and data from discordant sibships. We discuss the power of the test by presenting sample-size calculations involving a complex disease model, and we present formulas for the asymptotic relative efficiency (which is approximately the ratio of sample sizes) between SDT and the transmission/disequilibrium test (TDT) for special family structures. For sib pairs, we compare the SDT to a test proposed both by Curtis and, independently, by Spielman and Ewens. We show that, for discordant sib pairs, the SDT has good power for testing linkage disequilibrium relative both to Curtis's tests and to the TDT using trios comprising an affected sib and its parents. With additional sibs, we show that the SDT can be more powerful than the TDT for testing linkage disequilibrium, especially for disease prevalence >. 3.