Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluating the Potential Therapeutic Role of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers for Alzheimer's Disease using a Drosophila Model

Presenilins (PS) play a role in familial Alzheimer’s disease (AD) and Notch signalling. In a genetic screen looking for modifiers of APP but not Notch, we identified Drosophila orthologs of Angiotensin Converting Enzyme (ACE). Interestingly, ACE polymorphisms are associated with AD and Apo-E, the best characterized risk factor for late-onset AD. Moreover, ACE inhibitors (ACE-I) delayed the onset of cognitive impairment and neurodegeneration in mice and humans. However, it remains unclear why ACE-I are beneficial in AD. Here, we explore the link between PS and ACE in a Drosophila model using genetics and pharmacology. We found that ACE disruption does not affect Notch related phenotypes. Moreover, we found that ACE-I and Angiotensin Receptor Blockers are beneficial in an AD Drosophila model. Since inhibition of ACE has no detrimental effects on Notch and modulates AD related phenotypes, it could provide an important therapeutic target for AD.
Daily Step Count and Postprandial Fat Metabolism

ABSTRACT Introduction Two benefits of acute exercise are the next day’s lowering of the postprandial plasma triglyceride response to a high-fat meal and increased fat oxidation. However, if activity levels (daily steps) are very low, these acute adaptations to exercise do not occur. This phenomenon has been termed “exercise resistance. ” This study sought to systematically reduce daily step number and identify the range of step counts that elicit “exercise resistance. ” Methods Ten participants completed three, 5-d trials in a randomized, crossover design with differing levels of step reduction. After 2 d of controlled activity, participants completed 2 d of LOW, LIMITED, or NORMAL steps (2675 ± 314, 4759 ± 276, and 8481 ± 581 steps per day, respectively). Participants completed a 1-h bout of running on the evening of the second day. High-fat tolerance tests were performed on the next morning, and postprandial responses were compared. Results After LOW and LIMITED, postprandial incremental area under the curve (AUC) of plasma triglyceride was elevated 22%–23% compared with NORMAL (P < 0.05). Whole body fat oxidation was also significantly lower (16%–19%, P < 0.05, respectively) in LOW and LIMITED compared with NORMAL. No significant differences were found between LOW and LIMITED. Conclusion Two days of step reduction to approximately 2500–5000 steps per day in young healthy individuals impairs the ability of an acute bout of exercise to increase fat oxidation and attenuate postprandial increases in plasma triglycerides. This suggests that “exercise resistance” occurs in individuals taking approximately 5000 or fewer steps per day, whereas 8500 steps per day protects against exercise resistance in fat metabolism. It seems that fat metabolism is influenced more by the inhibitory effects of inactivity than by the stimulating effects derived from 1 h of moderate-intensity running.
Climate, landscape diversity, and food sovereignty in arid Australia: The firestick farming hypothesis

Climate change has long been recognized as a significant driver of dietary diversity and dietary quality. An often overlooked aspect of climate change are shifts in fire regimes, which have the potential to drastically affect landscape diversity, species distributions, and ultimately, human diets. Here, we investigate whether the fire regimes shaped by Indigenous Australians change landscape diversity in ways that improve dietary quality, considering both the diversity and the quantity of traditional foods in the diet.
Contributions of PARP‐1 rs1136410 C>T polymorphism to the development of cancer

Poly(ADP‐ribose) polymerase‐1 (PARP‐1) is a nuclear chromatin‐associated enzyme involved in the DNA damage response. SNP rs1136410 C>T, the most studied polymorphism in PARP‐1 gene, is highly implicated in the susceptibility of cancer. However, the roles of PARP‐1 rs1136410 C>T on cancer risk vary from different studies. We comprehensively screened all qualified publications from several databases, including PubMed, EMBASE, MEDLINE, CNKI and Wanfang. The searching was updated to April 2020. Our meta‐analysis included 60 articles with 65 studies, comprised of a total of 23 996 cases with cancer and 33 015 controls. Overall, pooled data showed that the PARP‐1 rs1136410 C>T polymorphism was significantly but a border‐line associated with an increased risk of overall cancer (CC vs. TT/TC: OR = 1.11, 95% CI = 1.00‐1.24; C vs T: OR = 1.07, 95% CI = 1.01‐1.14). Subgroup analysis indicated that rs1136410 C allele contributed to high risk among gastric, thyroid, and cervical cancer, but lower risk among brain cancer. Furthermore, increased cancer risk was detected in the subgroups of Asian, controls from population‐based design studies, and HWE ≤ 0.05 studies. Sensitivity analysis and Egger's test showed that results of the meta‐analysis were fairly stable. The current study indicated that PARP1 rs1136410 C>T polymorphism may have an impact on certain types of cancer susceptibility.
Color Stability of Dental Reinforced CAD/CAM Hybrid Composite Blocks Compared to Regular Blocks

This study compares the color stability of dental reinforced computer-aided design/computer-aided manufacturing (CAD/CAM) hybrid composite blocks to that of regular blocks. One hundred fifty disc-type specimens (n = 15) were prepared from five sets of hybrid composite blocks (Cerasmart-200/Cerasmart-300, KZR-CAD HR/KZR-CAD HR3, Estelite Block/ Estelite-P Block, Avencia Block/Avencia-P Block, Mazic Duro/Duro Ace). The specimen color and translucency parameter (TP) were assessed using a spectrophotometer before and after immersion in staining solutions (water, 10% ethanol, simulated red wine). Changes in color (ΔE) and translucency (ΔTP) of specimens were calculated. The data were analyzed using the analysis of variance (ANOVA) and Tukey’s post hoc test (p < 0.05). Microstructural features of the hybrid composite blocks were also examined using FE-SEM. Immersion in deionized water or 10% ethanol made no significant color or translucency changes (except for Avencia-P Block); however, the simulated red wine caused significant changes to the color and translucency of almost all specimens, especially after 4 weeks of immersion. The reinforced hybrid blocks (except for Estelite-P Block and Duro Ace) showed lower color stability than corresponding regular blocks. Avencia-P Block showed significantly reduced color stability compared to Avencia Block. Even in deionized water and 10% ethanol, Avencia-P Block showed perceptible ΔE and decreased translucency. Estelite Block/ Estelite-P Block and Mazic Duro/Duro Ace showed better color stability than the other materials tested.
Associations between pornography exposure, body image and sexual body image: A systematic review

There is evidence for associations between pornography exposure and sexual behaviors of adults and adolescents. Here, we review associations between pornography exposure and body image/sexual body image. Using a systematic search, we found 26 studies meeting inclusion criteria. Compelling evidence shows that frequency of pornography exposure is associated with negatively perceived body image and sexual body image; both heterosexual men and women appear to be affected. Due to scarcity of studies in adolescents and non-heterosexual samples, findings cannot be generalized to adolescents or individuals who identify as sexual minorities. Implications and future directions are discussed.
Treatment and resistance mechanisms in castration-resistant prostate cancer: new implications for clinical decision making?

ABSTRACT Introduction: The armamentarium of treatment options in metastatic and non-metastatic CRPC is rapidly evolving. However, the question of how individual treatment decisions should be balanced by available predictive clinical parameters, pharmacogenetic and drug interaction profiles, or compound-associated molecular biomarkers is a major challenge for clinical practice. Areas covered: We discuss treatment and resistance mechanisms in PC with regard to their association to drug efficacy and tolerability. Current efforts of combination treatment and putative predictive biomarkers of available and upcoming compounds are highlighted with regard to their implication on clinical decision-making. Expert opinion: Several treatment approaches are delineated, where identification of resistance mechanisms in CRPC may guide treatment selection. To date, most of these candidate biomarkers will however be found only in a small subset of patients. While current approaches of combination treatment in CRPC are proving synergistic effects on cancer biology, higher complexity with regard to biomarker analysis and interaction profiles of the respective compounds may be expected. Among other aspects of personalized treatment, consideration of drug–drug interaction and pharmacogenetics is an underrepresented issue. However, the non-metastatic castration resistant prostate cancer situation may be an example for treatment selection based on drug interaction profiles in the future.
Fluorescent Dye Labeling Changes the Biodistribution of Tumor-Targeted Nanoparticles

Fluorescent dye labeling is a common strategy to analyze the fate of administered nanoparticles in living organisms. However, to which extent the labeling processes can alter the original nanoparticle biodistribution has been so far neglected. In this work, two widely used fluorescent dye molecules, namely, ATTO488 (ATTO) and Sulfo-Cy5 (S-Cy5), have been covalently attached to a well-characterized CXCR4-targeted self-assembling protein nanoparticle (known as T22-GFP-H6). The biodistribution of labeled T22-GFP-H6-ATTO and T22-GFP-H6-S-Cy5 nanoparticles has been then compared to that of the non-labeled nanoparticle in different CXCR4+ tumor mouse models. We observed that while parental T22-GFP-H6 nanoparticles accumulated mostly and specifically in CXCR4+ tumor cells, labeled T22-GFP-H6-ATTO and T22-GFP-H6-S-Cy5 nanoparticles showed a dramatic change in the biodistribution pattern, accumulating in non-target organs such as liver or kidney while reducing tumor targeting capacity. Therefore, the use of such labeling molecules should be avoided in target and non-target tissue uptake studies during the design and development of targeted nanoscale drug delivery systems, since their effect over the fate of the nanomaterial can lead to considerable miss-interpretations of the actual nanoparticle biodistribution.
Glaucoma and Antioxidants: Review and Update

Glaucoma is a neurodegenerative disease characterised by the progressive degeneration of retinal ganglion cells. Oxidative stress has been related to the cell death in this disease. Theoretically, this deleterious consequence can be reduced by antioxidants substances. The aim of this review is to assemble the studies published in relation to antioxidant supplementation and its effects on glaucoma and to offer the reader an update on this field. With this purpose, we have included studies in animal models of glaucoma and clinical trials. Although there are variable results, supplementation with antioxidants in glaucoma may be a promising therapy in glaucoma.
Vitamin D Binding Protein (VDBP) and Its Gene Polymorphisms—The Risk of Malignant Tumors and Other Diseases

Vitamin D is an important component of the endocrine system that controls calcium homeostasis and bone mineralization. Because of the very short half-life of free serum vitamin D it is stabilized and transported to target tissues by being bound to the vitamin D binding protein (VDBP). The most common polymorphisms: rs4588 and rs7041 in the vitamin D binding protein gene may correlate with differences in vitamin D status in the serum. This review presents data that relate to the presence of genetic variants in the VDBP gene in correlation with certain diseases, mostly concerning cancers (breast, prostate, pancreatic, lung, colorectal, basal cell carcinoma cancer and cutaneous melanoma) or other related diseases (thyroid autoimmunity disorders, obesity, diabetes mellitus, bone metabolism, rheumatoid arthritis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, tuberculosis and coronary artery diseases).
Physiological and Behavioural Responses of Largemouth Bass Yearlings (Micropterus salmoides) to Hypoxia at Summer and Winter Temperatures

ii ACKNOWLEDGEMENTS . iv TABLE OF CONTENTS. v LIST OF TABLES. vii LIST OF FIGURES . viii LIST OF APPENDICES . ix LIST OF ABBREVIATIONS . x CHAPTER 1: LITERATURE REVIEW 1.1 Overview. 1 1.2 Environmental Influences . 1 1.3 Oxygen. 2 1.4 Hypoxia. 2 1.5 Responses to Hypoxia. 4 1.5. 1 Behavioural Responses to Hypoxia. 4 1.5. 2 Physiological Responses to Hypoxia. 6 1.6 Temperature . 12 1.6. 2 Temperature and Oxygen . 15 1.7 Study Species . 16 1.8 Summary of Thesis Objectives. 18 CHAPTER 2: MATERIALS AND METHODS 2.1 Source and Maintenance of Fish . 19 2.2 Hypoxia Apparatus . 19 2.3 Hypoxia at Identical Oxygen Saturation Levels. 21 2.3. 1 Experimental Design . 21 2.4 Hypoxia at Identical Dissolved Oxygen Levels . 22 2.4. 1 Experimental Design . 22 2.5 Tissue and Blood Sampling . 23 2.6 Calculations. 24 2.7 Laboratory Analyses . 24 2.7. 1 Metabolite Assay Analysis . 24 2.7. 2 Tissue Glycogen . 24 2.7. 3 Tissue Metabolite Extraction . 25
Spatiotemporal transmission dynamics of co-circulating dengue, Zika, and chikungunya viruses in Fortaleza, Brazil: 2011–2017

The mosquito-borne viruses dengue (DENV), Zika (ZIKV), and chikungunya (CHIKV), now co-endemic in the Americas, pose growing threats to health worldwide. However, it remains unclear whether there exist interactions between these viruses that could shape their epidemiology. This study advances knowledge by assessing the transmission dynamics of co-circulating DENV, ZIKV, and CHIKV in the city of Fortaleza, Brazil. Spatiotemporal transmission dynamics of DENV, ZIKV, and CHIKV were analyzed using georeferenced data on over 210,000 reported cases from 2011 to 2017 in Fortaleza, Brazil. Local spatial clustering tests and space-time scan statistics were used to compare transmission dynamics across all years. The transmission of co-circulating viruses in 2016 and 2017 was evaluated at fine spatial and temporal scales using a measure of spatiotemporal dependence, the τ-statistic. Results revealed differences in the diffusion of CHIKV compared to previous DENV epidemics and spatially distinct transmission of DENV/ZIKV and CHIKV during the period of their co-circulation. Significant spatial clustering of viruses of the same type was observed within 14-day time intervals at distances of up to 6.8 km (p<0.05). These results suggest that arbovirus risk is not uniformly distributed within cities during co-circulation. Findings may guide outbreak preparedness and response efforts by highlighting the clustered nature of transmission of co-circulating arboviruses at the neighborhood level. The potential for competitive interactions between the arboviruses should be further investigated.
An allosteric peptide inhibitor of HIF-1α regulates hypoxia-induced retinal neovascularization

Significance Retinal ischemia causes hypoxia-induced neovascularization that stimulates production of proangiogenic cytokines such as VEGF by the hypoxia-inducible transcription factors HIF-1 and HIF-2. Current therapies for ischemic retinal diseases target circulating VEGF but do not modulate the activity of the transcription factors that control its production. We demonstrate that inhibiting HIF-mediated transcription with a peptide derived from the intrinsically disordered protein CITED2, a negative feedback regulator of HIF-1α, reduces pathological angiogenesis in a mouse model of ischemic retinopathy. Combining the CITED2 peptide with the VEGF-Trap aflibercept causes potent suppression of neovascularization and promotes revascularization of the ischemic retina, an outcome not observed for anti-VEGF agents alone, suggesting that dual targeting of the HIF transcription factors and VEGF may be advantageous. Retinal neovascularization (NV), a leading cause of vision loss, results from localized hypoxia that stabilizes the hypoxia-inducible transcription factors HIF-1α and HIF-2α, enabling the expression of angiogenic factors and genes required to maintain homeostasis under conditions of oxygen stress. HIF transcriptional activity depends on the interaction between its intrinsically disordered C-terminal domain and the transcriptional coactivators CBP/p300. Much effort is currently directed at disrupting protein–protein interactions between disease-associated transcription factors like HIF and their cellular partners. The intrinsically disordered protein CITED2, a direct product of HIF-mediated transcription, functions as a hypersensitive negative regulator that attenuates the hypoxic response by competing allosterically with HIF-1α for binding to CBP/p300. Here, we show that a peptide fragment of CITED2 is taken up by retinal cells and efficiently regulates pathological angiogenesis in murine models of ischemic retinopathy. Both vaso-obliteration (VO) and NV were significantly inhibited in an oxygen-induced retinopathy (OIR) model following intravitreal injection of the CITED2 peptide. The CITED2 peptide localized to retinal neurons and glia, resulting in decreased expression of HIF target genes. Aflibercept, a commonly used anti-VEGF therapy for retinal neovascular diseases, rescued NV but not VO in OIR. However, a combination of the CITED2 peptide and a reduced dose of aflibercept significantly decreased both NV and VO. In contrast to anti-VEGF agents, the CITED2 peptide can rescue hypoxia-induced retinal NV by modulating the hypoxic response through direct competition with HIF for CBP/p300, suggesting a dual targeting strategy for treatment of ischemic retinal diseases and other neovascular disorders.
FLeAC: A Human-Centered Associative Classifier Using the Validity Concept

Fuzzy associative classifiers (FACs) have recently received considerable attention in the data mining community due to their ability to address the imprecision and graduality of truth. Similar to their more traditional statistical peers, these classifiers, however, have remained largely data driven, not leveraging human knowledge to their advantage. This is while human expert opinion and intuition should be a unique vantage point for such systems. We introduce here, for the first time, a human-centered framework (FLeAC) for FACs based on extended fuzzy logic and <inline-formula> <tex-math notation="LaTeX">${f}$ </tex-math></inline-formula>-transformation that uses experts’ opinions and preferences along with statistical data to solve subjective real-world problems. In FLeAC, experts take part in both constructing and reasoning of the classifier by assigning linguistic validity to each item. These validities are then aggregated using collective intelligence that determines final item validity. To examine the proposed framework, we extend an efficient and well-known FAC, CFAR, and present an extended <inline-formula> <tex-math notation="LaTeX">${f}$ </tex-math></inline-formula>-CFAR algorithm. Also, several variations of <inline-formula> <tex-math notation="LaTeX">${f}$ </tex-math></inline-formula>-CFAR are implemented to examine the effect of rule validity and different <inline-formula> <tex-math notation="LaTeX">${f}$ </tex-math></inline-formula>-transformation operators. We then run various nonparametric statistical tests, including Friedman, Nemenyi posthoc, and ROC tests on an actual medical dataset of burn patients from Ahwaz, Iran, to compare <inline-formula> <tex-math notation="LaTeX">${f}$ </tex-math></inline-formula>-CFAR performance with those of the original and nine other rule-based classifiers. Statistical analysis shows that <inline-formula> <tex-math notation="LaTeX">${f}$ </tex-math></inline-formula>-CFAR not only has a better overall diagnostic performance than CFAR but also it outperforms CFAR and the other rule-based classifiers in terms of the number of rules, the number of conditions, and the execution time, leading to a more compact and comprehensible classifier with comparable accuracy.
Morphology and Mechanical Properties of 3Y-TZP Nanofiber Mats

The mats of yttria-stabilized tetragonal zirconia nanofibers were prepared using electrospinning. The effect of calcination temperature in the range of 600–1200 °C on their microstructure, phase composition and mechanical properties was investigated. Phase composition of the nanofibers did not change in all ranges of the calcination temperatures, while the average grain size increased from 8 to 39 nm. Nanoindentation testing of the mats showed a decrease in the hysteresis loop energy in samples with higher calcination temperature. Hardness and the elastic modulus measured with the indentation technique were the highest for the mats calcined at 900 °C.
DOT-1.1-dependent H3K79 methylation promotes normal meiotic progression and meiotic checkpoint function in C. elegans

Epigenetic modifiers are emerging as important regulators of the genome. However, how they regulate specific processes during meiosis is not well understood. Methylation of H3K79 by the histone methyltransferase Dot1 has been shown to be involved in the maintenance of genomic stability in various organisms. In S. cerevisiae, Dot1 modulates the meiotic checkpoint response triggered by synapsis and/or recombination defects by promoting Hop1-dependent Mek1 activation and Hop1 distribution along unsynapsed meiotic chromosomes, at least in part, by regulating Pch2 localization. However, how this protein regulates meiosis in metazoans is unknown. Here, we describe the effects of H3K79me depletion via analysis of dot-1.1 or zfp-1 mutants during meiosis in Caenorhabditis elegans. We observed decreased fertility and increased embryonic lethality in dot-1.1 mutants suggesting meiotic dysfunction. We show that DOT-1.1 plays a role in the regulation of pairing, synapsis and recombination in the worm. Furthermore, we demonstrate that DOT-1.1 is an important regulator of mechanisms surveilling chromosome synapsis during meiosis. In sum, our results reveal that regulation of H3K79me plays an important role in coordinating events during meiosis in C. elegans.
The molluscan shell secretome : unlocking calcium pathways in a changing world

How do molluscs build their shells? Despite hundreds of years of human fascination, the processes underpinning mollusc shell production are still considered a black box. We know molluscs can alter their shell thickness in response to environmental factors, but we do not have a mechanistic understanding of how the shell is produced and regulated. In this thesis I used a combination of methodologies from traditional histology, to shell damage-repair experiments and ‘omics technologies to better understand the molecular mechanisms which control shell secretion in two species, the Antarctic clam Laternula elliptica and the temperate blunt-gaper clam Mya truncata. The integration of different methods was particularly useful for assigning putative biomineralisation functions to genes with no previous annotation. Each chapter of this thesis found reoccurring evidence for the involvement of vesicles in biomineralisation and for the duplication and subfunctionalisation of tyrosinase paralogues. Shell damage-repair experiments revealed biomineralisation in L. elliptica was variable, transcriptionally dynamic, significantly affected by age and inherently entwined with immune processes. The high amount of transcriptional variation across 78 individual animals was captured in a single mantle regulatory gene network, which was used to predict the regulation of “classic” biomineralisation genes, and identify novel biomineralisation genes. There were some general shared patterns in the molecular control of biomineralisation between the two species investigated in this thesis, but overall, the comparative work in this thesis, coupled to the growing body of literature on the evolution of molluscan biomineralisation, suggests that biomineralisation mechanisms are surprisingly divergent.