Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulation of cytotoxic drug-induced apoptosis by death receptor 5 in human colon cancer cells

5-Fluorouracil(5-FU)is a cytotoxic drug that is widely used for the treatment of colon cancer. However, 5-FU-resistance is still a common issue which needs to be overcome. Understanding the molecular pathway of 5-FU-induced apoptosis will help designing more effective cancer treatments. Chemotherapeutic drugs such as 5-FU are thought to trigger cell death via the intrinsic apoptosis pathway which involves caspase-9 activation as one of the initiating molecular events. However, our group recently found the new apoptotic pathways which are involved in 5-FU-induced apoptosisin which caspase-8 is an essential factor for 5-FU-induced cell death with caspase-9 being dispensable for this process. Aside from caspase-8, the death receptor TRAIL-R2 (DR5), which is usually involved in the extrinsic pathway of apoptosis, was found to be required for the execution of 5-FU-triggered cell death. Moreover,following 5-FU treatment, DR5 is not responsible for caspase-8 activation, but for the activation of c-Jun N-terminal kinases (JNK) without the involvement of its natural ligand TRAIL. In the current study, factors associated with DR5 that are involved in JNK activation are identified. Also, the involvement ofTRAF2, FADD, caspase-8, caspase-10 and RIP1 in JNK activation were examined. It was found that JNK is activated in HCT116, but not in DR5, caspase-8 and FADD knockdown cells after 5-FU treatment. Moreover, the absence of caspase-10, TRAF2 and RIP1 does not affect JNK activation.Also it was discovered that similar to 5-FU, when cells are treated with etoposide,another cytotoxic drug, JNK is also activated and initiated by DR5 and mediated by FADD and caspase-8. Thus, in the present study, the factors that are involved in activating JNK after 5-FU and etoposide treatment have been identified. The obtained results further clarify the mechanism of cell death in colon cancer cells after 5-FU and etoposide treatment which constitutes a novel regulating pathway of apoptosis.
Comparison of inexperienced operators and experts in γH2A.X and 53BP1 foci assay for high-throughput biodosimetry approaches in a mass casualty incident

Abstract Purpose In case of population exposure by ionizing radiation, a fast and reliable dose assessment of exposed and non-exposed individuals is crucial important. In initial triage, physicians have to take fast decisions whom to treat with adequate medical care. In addition, worries about significant exposure can be taken away from hundreds to thousands non- or low exposed individuals. Studies have shown that the γH2A. X radiation-induced foci assay is a promising test for fast triage decisions. However, in a large-scale scenario most biodosimetry laboratories will quickly reach their capacity limit. The aim of this study was to evaluate the benefit of inexperienced experimenters to speed up the foci assay and manual foci scoring. Materials and methods The participants of two training courses performed the radiation-induced foci assay (γH2A.X) under the guidance of experts and scored foci (γH2A.X and 53BP1) on sham-irradiated and irradiated blood samples (0.05–1.5 Gy). The outcome of laboratory experiments and manual foci scoring by 26 operators with basic experience in laboratory work was statistically analyzed in comparison to the results from experts. Results Inexperienced operators prepared slides with significant dose-effects (0, 0.1 and 1.0 Gy) for semi-automatic microscopic analyses. Manual foci scoring by inexperienced scorer resulted in a dose–effect curve for γH2A. X, 53BP1 and co-localized foci. In addition, inexperienced scorers were able to distinguish low irradiation doses from unirradiated cells. While 53BP1 foci scoring was in accordance to the expert counting, differences between beginners and expert increased for γH2A. X or co-localized foci. Conclusions In case of a large-scale radiation event, inexperienced staff is useful to support laboratories in slide preparation for semi-automatic foci counting as well as γH2A. X and 53BP1 manual foci scoring for triage-mode biodosimetry. Slides can be clearly classified in the non-, low- or high-exposed category.
JAM-A Acts via C/EBP-α to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function

Supplemental Digital Content is available in the text. Rationale: Intercellular tight junctions are crucial for correct regulation of the endothelial barrier. Their composition and integrity are affected in pathological contexts, such as inflammation and tumor growth. JAM-A (junctional adhesion molecule A) is a transmembrane component of tight junctions with a role in maintenance of endothelial barrier function, although how this is accomplished remains elusive. Objective: We aimed to understand the molecular mechanisms through which JAM-A expression regulates tight junction organization to control endothelial permeability, with potential implications under pathological conditions. Methods and Results: Genetic deletion of JAM-A in mice significantly increased vascular permeability. This was associated with significantly decreased expression of claudin-5 in the vasculature of various tissues, including brain and lung. We observed that C/EBP-α (CCAAT/enhancer-binding protein-α) can act as a transcription factor to trigger the expression of claudin-5 downstream of JAM-A, to thus enhance vascular barrier function. Accordingly, gain-of-function for C/EBP-α increased claudin-5 expression and decreased endothelial permeability, as measured by the passage of fluorescein isothiocyanate (FITC)-dextran through endothelial monolayers. Conversely, C/EBP-α loss-of-function showed the opposite effects of decreased claudin-5 levels and increased endothelial permeability. Mechanistically, JAM-A promoted C/EBP-α expression through suppression of β-catenin transcriptional activity, and also through activation of EPAC (exchange protein directly activated by cAMP). C/EBP-α then directly binds the promoter of claudin-5 to thereby promote its transcription. Finally, JAM-A–C/EBP-α–mediated regulation of claudin-5 was lost in blood vessels from tissue biopsies from patients with glioblastoma and ovarian cancer. Conclusions: We describe here a novel role for the transcription factor C/EBP-α that is positively modulated by JAM-A, a component of tight junctions that acts through EPAC to up-regulate the expression of claudin-5, to thus decrease endothelial permeability. Overall, these data unravel a regulatory molecular pathway through which tight junctions limit vascular permeability. This will help in the identification of further therapeutic targets for diseases associated with endothelial barrier dysfunction.
Nematicidal Activity of Holigarna caustica (Dennst.) Oken Fruit Is Due to Linoleic Acid

Holigarna caustica (Dennst.) Oken is used by the tribes of Northeast India for the treatment of intestinal problems. Therefore, the present study was undertaken to investigate the active principles of this plant responsible for its anthelmintic activity, using bioassay-guided fractionation. An ethanol extract of H. caustica fruit was fractionated on a silica gel column, followed by HPLC, while nematicidal activity was followed throughout on Caenorhabditis (C.) elegans as a model organism. Our study constitutes the first nematicidal report for this plant. Bioassay-guided purification led to the isolation of one compound (IC50 = 0.4 µM) as the only active constituent in the most active fraction. The compound was identified as linoleic acid based on spectroscopic data (1H and 13C NMR and ESI-MS). No cytotoxicity was observed in the crude extract or in linoleic acid (up to 356 µM). The results support the use of H. caustica for the treatment of intestinal problems by traditional healers in India.
Natural fire frequency for the eastern Canadian boreal forest: consequences for sustainable forestry

Given that fire is the most important disturbance of the boreal forest, climatically induced changes in fire frequency (i.e., area burnt per year) can have important consequences on the resulting forest mosaic age-class distribution and composition. Using archives and dendroecological data we reconstructed the fire frequency in four large sectors along a transect from eastern Ontario to central Quebec. Results showed a dramatic decrease in fire frequency that began in the mid-19th century and has been accentuated during the 20th century. Although all areas showed a similar temporal decrease in area burned, we observed a gradual increase in fire frequency from the west to Abitibi east, followed by a slight decrease in central Quebec. The global warming that has been oc- curring since the end of the Little Ice Age (∼1850) may have created a climate less prone to large forest fires in the eastern boreal forest of North America. This interpretation is corroborated by predictions of a decrease in for - est fires for that region of the boreal forest in the future. A longer fire cycle (i.e., the time needed to burn an area equivalent to the study area) has important consequences for sustainable forest management of the boreal for- est of eastern Canada. When considering the important proportion of overmature and old-growth stands in the landscape resulting from the elongation of the fire cycles, it becomes difficult to justify clear-cutting practices over all the entire area as well as short rotations as a means to emulate natural disturbances. Alternative practices involving the uses of variable proportion of clear, partial, and selective cutting are discussed.
Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema.

Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor (HIF)-1α, but a reduction of HIF-2α protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif-2α exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif-2α caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2α is an important mediator of lymphatic health. HIF-2α promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (Angpt1) gene therapy. Our study suggests that HIF-2α normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2α pathways in lymphedema could mitigate long-term pathology and disability.
Intracellular autoactivation of TMPRSS11A, an airway epithelial transmembrane serine protease

Type II transmembrane serine proteases (TTSPs) are a group of enzymes participating in diverse biological processes. Some members of the TTSP family are implicated in viral infection. TMPRSS11A is a TTSP expressed on the surface of airway epithelial cells, which has been shown to cleave and activate spike proteins of the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome coronaviruses (CoVs). In this study, we examined the mechanism underlying the activation cleavage of TMPRSS11A that converts the one-chain zymogen to a two-chain enzyme. By expression in human embryonic kidney 293, esophageal EC9706, and lung epithelial A549 and 16HBE cells, Western blotting, and site-directed mutagenesis, we found that the activation cleavage of human TMPRSS11A was mediated by autocatalysis. Moreover, we found that TMPRSS11A activation cleavage occurred before the protein reached the cell surface, as indicated by studies with trypsin digestion to remove cell surface proteins, treatment with cell organelle-disturbing agents to block intracellular protein trafficking, and analysis of a soluble form of TMPRSS11A without the transmembrane domain. We also showed that TMPRSS11A was able to cleave the SARS-CoV-2 spike protein. These results reveal an intracellular autocleavage mechanism in TMPRSS11A zymogen activation, which differs from the extracellular zymogen activation reported in other TTSPs. These findings provide new insights into the diverse mechanisms in regulating TTSP activation.
Antimicrobial Photodynamic Therapy in the Treatment of Chronic Adult Periodontitis

Objective: Antimicrobial photodynamic therapy (aPDT) is a new adjunctive therapy for chronic periodontitis. The study hypothesis was that aPDT applied as an adjunct to scaling and root planing (SRP) would improve 12-week clinical outcomes in the treatment of chronic adult periodontitis, compared to SRP alone. Methods: 34 patients diagnosed with chronic periodontitis were recruited into a randomized, examiner-blinded, parallel-group study with two equal cohorts (SRP alone and SRP + aPDT). Both cohorts were treated with SRP at all probing sites ≥ 5 mm that exhibited bleeding on probing (BOP). In the intervention group a single aPDT treatment was deployed following SRP. Results: Combination therapy (aPDT + SRP) produced significant gain in clinical attachment level (CAL) (0.53 mm, p=0.0017) and probing depth reductions (PD) (0.73 mm, p=0.0002) when averaged across all regions of the mouth, versus the SRP-only arm at 3 months. Treatment with adjunctive aPDT increased by 8-fold the number of patients experiencing >1.5 mm gain in CAL, versus the control arm (5.9% in the SRP arm, 47.1% in the aPDT arm, p=0.022) at 3 months. Conclusions: This study demonstrated that adjunctive aPDT provided significant gain in CAL and PD reduction, compared to SRP alone in the treatment of chronic adult periodontitis.
Small intestine development in chicks after hatch and in pigs around the time of weaning and its relation with nutrition: A review

Abstract The period after hatch in broilers and around the time of weaning in pigs is critical for development and for adaptation of the small intestine to the nutritional changes. In broilers, the small-intestinal weight relative to body weight and villous height increase rapidly during the first week after hatch. After the first week, the relative small-intestinal weight decreases gradually, but the villous height continues to increase. In pigs, at 4 d after weaning, villous height decreases to about 60% of the pre-weaning height when weaned between 1 and 4 wk of age. Two weeks after weaning, this recovers to similar values as in unweaned control animals independent of weaning age. Small-intestinal development after hatch and after weaning consistently deteriorates at low feed intake levels and with suboptimal protein nutrition. These findings stress the importance of applying an optimal nutritional strategy in these phases of life to reach optimal small-intestinal development.
Attach Me If You Can: Murine Norovirus Binds to Commensal Bacteria and Fungi

The presence of commensal bacteria enhances both acute and persistent infection of murine noroviruses. For several enteric viral pathogens, mechanisms by which these bacteria enhance infection involve direct interactions between the virus and bacteria. While it has been demonstrated that human noroviruses bind to a variety of commensal bacteria, it is not known if this is also true for murine noroviruses. The goal of this study was to characterize interactions between murine noroviruses and commensal bacteria and determine the impact of bacterial growth conditions, incubation temperature and time, on murine norovirus attachment to microbes that comprise the mammalian microbiome. We show that murine noroviruses bind directly to commensal bacteria and show similar patterns of attachment as human norovirus VLPs examined under the same conditions. Furthermore, while binding levels are not impacted by the growth phase of the bacteria, they do change with time and incubation temperature. We also found that murine norovirus can bind to a commensal fungal species, Candida albicans.
Fatty Acid Composition of Meat and Edible Offal from Free-Living Red Deer (Cervus elaphus)

The objective of the study was to characterize tissue-associated differences in the fatty acid composition of fat in skeletal muscles M. longissimus dorsi (loin), M. biceps femoris (hind quarter), and M. triceps brachii (shoulder), and internal organs (i.e., liver, heart, and kidney) from free-living red deer (Cervus elaphus) females (n = 11) hunted in Lithuania. Skeletal muscles were characterized by lower content of free fat compared with the offal. The highest percentage of saturated fatty acids was found in the liver fat, whereas the lowest percentage was in the heart. Red deer offal showed significantly lower and higher proportions of monounsaturated and polyunsaturated fatty acids compared to meat, respectively. Higher proportions of oleic fatty acid in the shoulder and hind quarter compared to the loin were the only significant differences between skeletal muscles. The lowest and the highest n-6 polyunsaturated/n-3 polyunsaturated fatty acids (n-6/n-3PUFA) ratio were found in the liver and heart, respectively. More favorable lower atherogenic index and higher hypocholesterolemic/hypercholesterolemic ratio found in the offal showed their high nutritional value, however, higher peroxidizability index indicated higher susceptibility to lipid peroxidation compared to skeletal muscles.
Breathing-focused Yoga as Augmentation for Unipolar and Bipolar Depression: A Randomized Controlled Trial: Le yoga axé sur la respiration comme traitement d’appoint pour la dépression unipolaire et bipolaire: Un essai randomisé contrôlé

Objective: Patients with depression frequently experience persistent residual symptoms even with optimal interventions. These patients often use complementary treatments, including yoga, as a preferred alternative or adjunctive treatment. There is evidence for the benefit of yoga for depression, but this has not been rigorously evaluated, particularly in bipolar depression. We aimed to determine the feasibility and benefit of manualized breathing-focused yoga in comparison to psychoeducation as augmentation to pharmacotherapy for improving residual symptoms of depression in unipolar and bipolar patients. Methods: Using a randomized single-blind crossover design, 72 outpatients with unipolar or bipolar depression were augmented with the two 8-week interventions at separate times, as add-ons to current first-line antidepressants and mood stabilizers. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale (MADRS). Due to the high dropout of participants after crossover at Week 8, analysis focused on between-group comparisons of yoga and psychoeducation during the initial 8 weeks of the study. Results: There was a significant decline in depressive symptoms, as measured by the MADRS, following 8 weeks of yoga. However, there was no significant difference in MADRS ratings between intervention groups. Similar improvements in self-rated depressive symptoms and well-being were also observed across time. Conclusions: Both yoga and psychoeducation may improve residual symptoms of unipolar and bipolar depression as add-on to medications. In-class group sessions and long study durations may reduce feasibility for this population. Larger trials with parallel group design and shorter duration may be more feasible.
Inhibition of Interleukin-1 in the Treatment of Selected Cardiovascular Complications.

BACKGROUND Interleukin-1 (IL-1) is a pro-inflammatory cytokine that is produced by endothelial cells, smooth muscle cells, and macrophages. It is an important regulator of a complex humoral and cellular inflammatory response. IL1β is known to be implicated in the development of chronic inflammatory disorders such as rheumatoid arthritis. We aimed to review the effects of IL-1β antagonists in various cardiovascular disorders and to discuss their effectiveness in such diseases. METHODS Major biomedical databases, including PubMed and Scopus, were searched for clinical studies regarding the treatment of cardiovascular diseases (CVD) using IL-1β antagonists. RESULTS The drugs currently used in clinical trials are anakinra, the monoclonal antibodies canakinumab and gevokizumab, and the soluble decoy receptor rilonacept. There are clinical trials and case reports of patients with CVD in which anakinra administration, at the standard dose, has caused rapid clinical improvement and recovery in a few months. Our comprehensive search revealed that IL-1β antagonists have beneficial effects in the treatment of various cardiovascular disorders such as myocarditis, pericarditis, heart failure, acute coronary syndrome, myocardial infarction, atherosclerosis, and Kawasaki disease. CONCLUSION The present review article shows that IL-1β has a major role in the pathophysiology of cardiovascular disorders, its antagonists have beneficial effects in these conditions, and their use should be considered in future studies.
Navigator Role for Promoting Adaptive Sports and Recreation Participation in Individuals With Disabilities

Objective The aims of the study were to gain a better understanding of the resources, barriers, and facilitators of participation in adaptive sport and recreational activities as a means of achieving physical activity recommendations in individuals with disability and to understand preferences for a patient navigator service to help mitigate the barriers. Design Clinical, academic, and community stakeholders applied a community-engaged research approach to develop online surveys and focus group questions for adults with a disability or parents of a child with a disability to meet study objectives. Results One hundred ninety-eight adults and 146 parents completed the online surveys. Sixteen adults and 18 parents took part in focus groups. Many participants lacked knowledge of available adaptive sport and recreational resources; other barriers were expense, limited number of trained volunteers, and need for instruction. Conversely, persons were facilitated by community, socialization, and words of encouragement/motivation. Participants strongly preferred a patient navigator to be a person active in adaptive sport and recreational or an informative resource-filled website. Conclusions Our findings suggest that physical activity programs including adaptive sport and recreational should be designed to offer people with disabilities opportunities to build social networks and strengthen social support. A patient navigator service could help increase participation in adaptive sport and recreational and physical activity within a community context.
Gene Expression Analysis of the Concomitant Existence of Lymphovascular and Perineural Invasion in Colorectal Cancer

The invasion of cancer cells into the peritumoral, lymph node and perineural system could be detrimental on cancer patients. In colorectal cancer (CRC) patients, the presence of lymphovascular (LVI) and/or perineural (PNI) invasion could significantly influence the survival rates, treatment options and recurrence tendencies. To date, no study has analysed the concomitant existence of LVI and PNI in CRC, particularly in relation to the molecular profiles. Here, we reanalysed The Cancer Genome Atlas (TCGA) CRC datasets and focused on cases where the information regarding LVI and PNI are available (n=176). We performed differential gene expression, methylation and microRNA analysis by comparing between the groups having both or either LVI and PNI with the control group (LVI negative and PNI negative). Although there were no significant difference in the methylation and miRNA profiles, we identified a number of differentially expressed genes (DEGs). The comparison between the LVI+PNI+ and LVI-PNI- groups revealed key DEGs including SFTA2, PHACTR3, CRABP2, ODZ3, GRP, HAP1 and HDAC9. Meanwhile, in the LVI-PNI+ vs LVI-PNI- group, some of the DEGs found were PTPRR, EFNA2, FGF20, IGFL4 and IGFBPL1. We believe that this study could be beneficial and add value to further understand the complex molecular profiles of CRC.