Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of Xanthine Oxidoreductase Enhances the Potential of Tyrosine Kinase Inhibitors against Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is characterized by the expression of the oncogenic kinase BCR-ABL. Although tyrosine kinase inhibitors (TKIs) against BCR-ABL represent the standard therapeutic option for CML, resistances to TKIs can be a serious problem. Thus, the search for novel therapeutic approaches is still needed. CML cells show an increased ROS production, which is required for maintaining the BCR-ABL signaling cascade active. In line with that, reducing ROS levels could be an interesting therapeutic strategy for the clinical management of resistant CML. To analyze the therapeutic potential of xanthine oxidoreductase (XOR) in CML, we tested the effect of XOR inhibitor allopurinol. Here, we show for the first time the therapeutic potential of allopurinol against BCR-ABL-positive CML cells. Allopurinol reduces the proliferation and clonogenic ability of the CML model cell lines K562 and KCL22. More importantly, the combination of allopurinol with imatinib or nilotinib reduced cell proliferation in a synergistic manner. Moreover, the co-treatment arms hampered cell clonogenic capacity and induced cell death more strongly than each single-agent arm. The reduction of intracellular ROS levels and the attenuation of the BCR-ABL signaling cascade may explain these effects. Finally, the self-renewal potential of primary bone marrow cells from CML patients was also severely reduced especially by the combination of allopurinol with TKIs. In summary, here we show that XOR inhibition is an interesting therapeutic option for CML, which can enhance the effectiveness of the TKIs currently used in clinics.
Host permissiveness to baculovirus influences time‐dependent immune responses and fitness costs

Insects possess specific immune responses to protect themselves from different types of pathogens. Activation of immune cascades can inflict significant developmental costs on the surviving host. To characterize infection kinetics in a surviving host that experiences baculovirus inoculation, it is crucial to determine the timing of immune responses. Here, we investigated time‐dependent immune responses and developmental costs elicited by inoculations from each of two wild‐type baculoviruses, Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and Helicoverpa zea single nucleopolyhedrovirus (HzSNPV), in their common host H. zea. As H. zea is a semi‐permissive host of AcMNPV and fully permissive to HzSNPV, we hypothesized there are differential immune responses and fitness costs associated with resisting infection by each virus species. Newly molted 4th‐instar larvae that were inoculated with a low dose (LD15) of either virus showed significantly higher hemolymph FAD‐glucose dehydrogenase (GLD) activities compared to the corresponding control larvae. Hemolymph phenoloxidase (PO) activity, protein concentration and total hemocyte numbers were not increased, but instead were lower than in control larvae at some time points post‐inoculation. Larvae that survived either virus inoculation exhibited reduced pupal weight; survivors inoculated with AcMNPV grew slower than the control larvae, while survivors of HzSNPV pupated earlier than control larvae. Our results highlight the complexity of immune responses and fitness costs associated with combating different baculoviruses.
Prevalence of Cervical Cellular Abnormalities by Liquid Based Cytology in Taif Province : A Hospital Based Study

Aim of the work: The aim of this study was to determine the prevalence of the cervical cellular Abnormalities using liquid based thin-layer preparations as screening test for women who attended the gynaecology outpatient clinic at King Abdul Aziz Specialist Hospital, Taif, Saudi Arabia. Material and method: In this retrospective chart review study, we reviewed the records and data of all women for whom liquid base cytological studies were performed as screening test to detect the cervical cellular abnormalities at King Abdul Aziz Specialist Hospital, Taif, Saudi Arabia from June 2010 to June 2012. Results:The total number of women for whom liquid base, thin-layer cytological studies were performedwas 2168 patients 79.9% of them were symptomatic. The mean age was 38.6 years. Liquid based thin-layer preparations were used for all patients. Cervical abnormality was seen in 25.6% of the patients, of which 6.5% were malignant or premalignant and 19.1% were of benign nature. Conclusion: Liquid-based, thin-layer cytology reduces sampling and preparation errors of the conventional smear; however, screening should include human papilloma virus (HPV), DNA testing to increase the sensitivity and specificity of primary screening.
Proactive interference in working memory is related to adult age and cognitive factors: cross-sectional and longitudinal evidence from the Betula study

ABSTRACT In working memory (WM), successful maintenance of information is affected by interference. Older adults may be especially susceptible to the effects of interference, which may cause age-related cognitive impairments. A relative score of IC was derived from cross-sectional (n = 869) and longitudinal (n = 443) data to investigate (1) if IC is reduced in normal aging, (2) if individual differences in IC related to individual performance in other cognitive domains, and (3) if 5-year change in IC is related to change in general cognition. Older age was associated with reduced IC, but no decline in IC occurred over 5 years. Also, the ability to control interference in WM was related to performance in episodic memory, verbal fluency, and block design. We also found that IC mediates the relationship between age and cognition, suggesting that age-related cognitive decline is linked to IC. Finally, we demonstrate that change in IC was related to decline in episodic memory.
Effects of Orange Extracts on Longevity, Healthspan, and Stress Resistance in Caenorhabditis elegans

Orange, with various bioactive phytochemicals, exerts various beneficial health effects, including anti-cancer, antioxidant, and anti-inflammatory properties. However, its anti-aging effects remain unclear. In this study, the Caenorhabditis elegans (C. elegans) model was used to evaluate the effects of orange extracts on lifespan and stress resistance. The results indicated that orange extracts dose-dependently increased the mean lifespan of C. elegans by 10.5%, 18.0%, and 26.2% at the concentrations of 100, 200, and 400 mg/mL, respectively. Meanwhile, orange extracts promoted the healthspan by improving motility, and decreasing the accumulation of age pigment and intracellular reactive oxygen species (ROS) levels without damaging fertility. The survival rates of orange extract-fed worms were obviously higher than those of untreated worms against thermal and ultraviolet-B (UV-B) stress. Moreover, the activities of superoxide dismutase (SOD) and catalase (CAT) were significantly enhanced while malondialdehyde (MDA) contents were diminished. Further investigation revealed that worms supplemented with orange extracts resulted in upregulated levels of genes, including daf-16, sod-3, gst-4, sek-1, and skn-1, and the downregulation of age-1 expression. These findings revealed that orange extracts have potential anti-aging effects through extending the lifespan, enhancing stress resistance, and promoting the healthspan.
Intraflagellar transport protein RABL5/IFT22 recruits the BBSome to the basal body through the GTPase ARL6/BBS3

Significance Bardet-Biedl syndrome (BBS) is a rare human ciliopathy associated with blindness, obesity, and kidney anomalies. It is caused by defects in the assembly or transport of the BBSome, a conserved octamer of BBS proteins, which assists intraflagellar transport (IFT) with the removal of signaling proteins from cilia. Here, we show that the GTPase component of IFT-B1, IFT22, autonomous of IFT-B1 association, binds and stabilizes BBS3 in the cell body. When both are in their GTP-bound state, IFT22 and BBS3 recruit the BBSome to the basal body for loading onto the IFT machinery for ciliary entry. IFT22 recruits the BBSome to the basal body through BBS3 in a nucleotide-dependent manner providing a regulatory mechanism for BBSome entry into the cilium. Bardet-Biedl syndrome (BBS) is a ciliopathy caused by defects in the assembly or distribution of the BBSome, a conserved protein complex. The BBSome cycles via intraflagellar transport (IFT) through cilia to transport signaling proteins. How the BBSome is recruited to the basal body for binding to IFT trains for ciliary entry remains unknown. Here, we show that the Rab-like 5 GTPase IFT22 regulates basal body targeting of the BBSome in Chlamydomonas reinhardtii. Our functional, biochemical and single particle in vivo imaging assays show that IFT22 is an active GTPase with low intrinsic GTPase activity. IFT22 is part of the IFT-B1 subcomplex but is not required for ciliary assembly. Independent of its association to IFT-B1, IFT22 binds and stabilizes the Arf-like 6 GTPase BBS3, a BBS protein that is not part of the BBSome. IFT22/BBS3 associates with the BBSome through an interaction between BBS3 and the BBSome. When both IFT22 and BBS3 are in their guanosine triphosphate (GTP)-bound states they recruit the BBSome to the basal body for coupling with the IFT-B1 subcomplex. The GTP-bound BBS3 likely remains to be associated with the BBSome upon ciliary entry. In contrast, IFT22 is not required for the transport of BBSomes in cilia, indicating that the BBSome is transferred from IFT22 to the IFT trains at the ciliary base. In summary, our data propose that nucleotide-dependent recruitment of the BBSome to the basal body by IFT22 regulates BBSome entry into cilia.
The effect of socioeconomic deprivation on 12 month Traumatic Brain Injury (TBI) outcome

ABSTRACT Objectives: To assess the impact of social deprivation on Traumatic Brain Injury (TBI) global outcome. Design: The study was a prospective observational study conducted using consecutive admissions with TBI. Subjects: 1322 consecutive adult patients with TBI were recruited into the study between 2010 and 2015. Methods: All patients were assessed by the TBI rehabilitation team at both six weeks and 12 months following TBI. Details of the injury and demographic data was collated at six weeks. This included age, gender and ZIP Code. Social deprivation was measured by the Indices of Multiple Deprivation (IMD) Score. The outcome measure used was the Extended Glasgow Outcome Score (GOSE) at 12 months. Univariate analysis was followed by a Multi-Ordinal Regression to evaluate predictor variables. Results: With regard to the representation of IMD deciles, the study population approximated to the general Sheffield population (p = .139). Within the univariate analysis, statistically significant relationships were noted between IMD and GOSE (p = <.001). The Ordinal Regression revealed a significant relationship between worse GOSE and IMD (p = .002), age (p = .001), GCS (p < .001), alcohol intoxication (p < .001) and Medical Comorbidity (p = .041). Conclusion: Increasing social deprivation is associated with poorer global TBI outcomes at 12 months.
Ciguatera Fish Poisoning: The Risk from an Aotearoa/New Zealand Perspective

Gambierdiscus and Fukuyoa species have been identified in Aotearoa/New Zealand’s coastal waters and G. polynesiensis, a known producer of ciguatoxins, has been isolated from Rangitāhua/Kermadec Islands (a New Zealand territory). The warming of the Tasman Sea and the waters around New Zealand’s northern subtropical coastline heighten the risk of Gambierdiscus proliferating in New Zealand. If this occurs, the risk of ciguatera fish poisoning due to consumption of locally caught fish will increase. Research, including the development and testing of sampling methods, molecular assays, and chemical and toxicity tests, will continue. Reliable monitoring strategies are important to manage and mitigate the risk posed by this emerging threat. The research approaches that have been made, many of which will continue, are summarised in this review.
Short-term dehydration influences baseline but not stress-induced corticosterone levels in the house sparrow (Passer domesticus)

ABSTRACT Future environmental variations linked to climate change are expected to influence precipitation regimes and thus drinking water availability. Dehydration can be a particularly challenging physiological state for most organisms, yet no study has examined the effect of dehydration on the functioning of the hypothalamic–pituitary–adrenal axis in wild endothermic animals, despite its central role in maintaining homeostasis. In this study, we experimentally imposed a temporary water shortage (∼20 h) on captive house sparrows in order to investigate the consequences of short-term dehydration on baseline and stress-induced corticosterone levels. As expected, water-deprived birds displayed higher plasma osmolality and haematocrit. Additionally, water-deprived birds had lower defecation rates, suggesting that the mechanisms allowing caecal water absorption may be triggered very rapidly during water deprivation. Baseline but not stress-induced corticosterone levels were higher in water-deprived birds. Taken together, these results suggest that water restriction may have critical consequences on several corticosterone-related traits such as energy budget (protein catabolism and possibly feeding reduction), enhanced mobility (to promote water acquisition) and potential responses to predators (thirst threshold overriding the acute stress response). Owing to the possible fitness consequences of such components of the day-to-day life of birds, further studies should aim at investigating the influence of future changes in precipitation regimes and drinking water availability on bird populations. Summary: Elevated baseline corticosterone levels induced by water restriction may have critical consequences on several major life-history traits such as energy budget, mobility and potential responses to predators.
Electron Beam Structuring of Ti6Al4V: New Insights on the Metal Surface Properties Influencing the Bacterial Adhesion

Soft tissue adhesion and infection prevention are currently challenging for dental transmucosal or percutaneous orthopedic implants. It has previously been shown that aligned micro-grooves obtained by Electron Beam (EB) can drive fibroblast alignment for improved soft tissue adhesion. In this work, evidence is presented that the same technique can also be effective for a reduction of the infection risk. Grooves 10–30 µm wide and around 0.2 µm deep were obtained on Ti6Al4V by EB. EB treatment changes the crystalline structure and microstructure in a surface layer that is thicker than the groove depth. Unexpectedly, a significant bacterial reduction was observed. The surfaces were characterized by field emission scanning electron microscopy, X-ray diffraction, confocal microscopy, contact profilometry, wettability and bacterial adhesion tests. The influence of surface topography, microstructure and crystallography on bacterial adhesion was systematically investigated: it was evidenced that the bacterial reduction after EB surface treatment is not correlated with the grooves, but with the microstructure induced by the EB treatment, with a significant bacterial reduction when the surface microstructure has a high density of grain boundaries. This correlation between microstructure and bacterial adhesion was reported for the first time for Ti alloys.
Heat-Killed Bifidobacterium breve B-3 Enhances Muscle Functions: Possible Involvement of Increases in Muscle Mass and Mitochondrial Biogenesis

A previous clinical study on pre-obesity subjects revealed that Bifidobacterium breve B-3 shows anti-obesity effects and possibly increases muscle mass. Here, we investigated the effects of B-3 on muscle function, such as muscle strength and metabolism, and some signaling pathways in skeletal muscle. Male rodents were orally administered live B-3 (B-3L) or heat-killed B-3 (B-3HK) for 4 weeks. We found that administration of B-3 to rats tended to increase muscle mass and affect muscle metabolism, with stronger effects in the B-3HK group than in the B-3L group. B-3HK significantly increased muscle mass and activated Akt in the rat soleus. With regard to muscle metabolism, B-3HK significantly increased phosphorylated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and cytochrome c oxidase (CCO) gene expression in the rat soleus, suggesting an effect on the AMPK-PGC1α-mitochondrial biogenesis pathway. Furthermore, B-3HK promoted oxidative muscle fiber composition in the gastrocnemius. We also observed a significantly higher level of murine grip strength in the B-3HK group than in the control group. These findings suggest the potential of heat-killed B-3 in promoting muscle hypertrophy and modifying metabolic functions, possibly through the Akt and AMPK pathways, respectively.
Dietary supplement of essential oil from oregano affects growth performance, nutrient utilization, intestinal morphology and antioxidant ability in Pekin ducks.

A study was conducted to investigate the effects of oregano essential oil (EO) on growth performance, nutrients utilization, intestinal morphology, intestinal barrier-related gene expression and antioxidant capability in meat ducks. A total of 360 1-day-old ducks were divided into three groups (12 replicates pens per diet of 10 ducks in each pen): negative control (no essential oil or antibiotic), positive control (antibiotic: 500 mg/kg aureomycin of diet) and oregano EO (100 mg/kg of diet). The experiment was carried out for 35 days. Ducks were given feed and water ad libitum. Ducks fed EO supplement showed similar body weight and feed to gain ratio to antibiotic fed ducks. EO supplementation significantly increased (p < .05) feed intake (day 1-35), jejunal villus height (VH) to crypt depth (CD) ratio, serum superoxide dismutase activities (SOD) and jejunal total antioxidant capacity (T-AOC) of ducks compared to controls. Ducks fed diets supplemented with oregano EO also had decreased (p < .05) jejunal CD, serum and hepatic malondialdehyde (MDA) concentration, and the mRNA expression of jejunal zonula occludens-3 (ZO-3) and secretory immunoglobulin A (sIgA) genes in comparison to the control group. Compared to the antibiotic supplementation group, the mRNA expression of claudin1 (CLND1) and CLND2 significantly increased (p < .05), but the mRNA expression of ZO-3 and mucin 2 markedly decreased (p < .05) in the jejunum of ducks in oregano EO supplementation group. These results suggest that oregano EO improves the antioxidant capacity and intestinal defence and structural measures and may aide in helping to maintain enteric health in production without growth-promoting antibiotics.
Open Data for Differential Network Analysis in Glioma

The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes. By using selected exemplary tools and open-access resources for cancer research and differential network analysis, we highlight disturbed signaling components in brain cancer subtypes of glioma.
Comparative gonadotoxicity of the chemotherapy drugs cisplatin and carboplatin on prepubertal mouse gonads

Abstract The treatment of childhood cancer with chemotherapy drugs can result in infertility in adulthood. Newer generations of drugs are developed to replace parent drugs, with the potential benefits of less toxic side effects. For platinum alkylating-like drugs, in contrast to the parent compound cisplatin, the newer-generation drug carboplatin is reported to have reduced toxicity in some respects, despite being administered at 5–15 times higher than the cisplatin dose. Whether carboplatin is also less toxic than cisplatin to the reproductive system is unknown. Here we compare the gonadotoxic impact of cisplatin and carboplatin on female and male mouse prepubertal gonads. In vitro cultured CD1 mouse ovaries or testis fragments were exposed to either cisplatin or carboplatin for 24 h on Day 2 of culture and analysed by Day 6. A dose response for each drug was determined for the ovary (0.5, 1 & 5 μg/ml cisplatin and 1, 5 & 10 μg/ml carboplatin) and the testis (0.01, 0.05 & 0.1 μg/ml cisplatin and 0.1, 0.5 & 1 μg/ml carboplatin). For the ovary, unhealthy follicles were evident from 1 μg/ml cisplatin (73% unhealthy, P = 0.001) and 5 μg/ml carboplatin (84% unhealthy, P = 0.001), with a concomitant reduction in follicle number (P = 0.001). For the testis, the proliferating germ cell population was significantly reduced from 0.05 μg/ml cisplatin (73% reduction, P = 0.001) and 0.5 μg/ml carboplatin (75% reduction, P = 0.001), with no significant impact on the Sertoli cell population. Overall, results from this in vitro animal model study indicate that, at patient equivalent concentrations, carboplatin is no less gonadotoxic than cisplatin.