Miracle-dz/UniFAR-FTUs huggingface dataset:
Long Term Transcriptional Reactivation of Epigenetically Silenced Genes in Colorectal Cancer Cells Requires DNA Hypomethylation and Histone Acetylation

Epigenetic regulation of genes involves the coordination of DNA methylation and histone modifications to maintain transcriptional status. These two features are frequently disrupted in malignancy such that critical genes succumb to inactivation. 5-aza-2′-deoxycytidine (5-aza-dC) is an agent which inhibits DNA methyltransferase, and holds great potential as a treatment for cancer, yet the extent of its effectiveness varies greatly between tumour types. Previous evidence suggests expression status after 5-aza-dC exposure cannot be explained by the DNA methylation status alone. Aim We sought to identify chromatin changes involved with short and long term gene reactivation following 5-aza-dC exposure. Two colorectal cancer cell lines, HCT116 and SW480, were treated with 5-aza-dC and then grown in drug-free media to allow DNA re-methylation. DNA methylation and chromatin modifications were assessed with bisulfite sequencing and Chromatin Immuno-Precipitation analysis. Results Increased H3 acetylation, H3K4 tri-methylation and loss of H3K27 tri-methylation were associated with reactivation. Hypermethylated genes that did not show increased acetylation were transiently expressed with 5-aza-dC treatment before reverting to an inactive state. Three reactivated genes, CDO1, HSPC105 and MAGEA3, were still expressed 10 days post 5-aza-dC treatment and displayed localised hypomethylation at the transcriptional start site, and also an increased enrichment of histone H3 acetylation. Conclusions These observations suggest that hypomethylation alone is insufficient to reactivate silenced genes and that increased Histone H3 acetylation in unison with localised hypomethylation allows long term reversion of these epigenetically silenced genes. This study suggests that combined DNA methyltransferase and histone deacetylase inhibitors may aid long term reactivation of silenced genes.
Factors Associated with Outcomes of Percutaneous Transluminal Renal Angioplasty in Patients with Renal Artery Stenosis: A Retrospective Analysis of 50 Consecutive Cases

Background The results of recent trials have brought some confusion to the treatment strategy for renal artery stenosis (RAS). To evaluate the applicability of percutaneous transluminal renal angioplasty (PTRA) for RAS, we extracted the factors that may affect the effectiveness of PTRA from cases experienced at a hypertension center. Methods and Results We retrospectively assessed the blood pressure (BP) lowering effects and renoprotective effects in 50 consecutive patients that had hemodynamically significant RAS and had undergone PTRA and stenting during 2001–2005. Subjects were diagnosed with atherosclerotic RAS (42), fibromuscular dysplasia (6), or Takayasu disease (2). After PTRA, BP significantly lowered from 152.3/80.3 mmHg to 132.6/73.2 mmHg (p < 0.05), but the estimated glomerular filtration rate (eGFR) did not change significantly. There were no factors associated with the BP lowering effects of PTRA. The baseline resistive index (RI) was negatively correlated with the change in eGFR (p < 0.05). After correction for age, sex, BMI, and the dose of contrast medium, the association of RI with change in eGFR remained significant. Conclusion In cases with hemodynamically significant RAS, PTRA lowered BP but was not effective in improving renal function. Higher baseline RI may be a factor for predicting poor clinical course of renal function after PTRA.
Abnormal Intracellular Accumulation and Extracellular Aβ Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders

Background It has been shown that amyloid ß (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount. Methodology/Principal Findings In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Aβ load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Aβ load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly N-terminally truncated. Increased intraneuronal accumulation of Aβ17–40/42 in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aβ1–40/42 detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques. Conclusions/Significance The higher prevalence of excessive Aβ accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.
Pectin and Xyloglucan Influence the Attachment of Salmonella enterica and Listeria monocytogenes to Bacterial Cellulose-Derived Plant Cell Wall Models

ABSTRACT Minimally processed fresh produce has been implicated as a major source of foodborne microbial pathogens globally. These pathogens must attach to the produce in order to be transmitted. Cut surfaces of produce that expose cell walls are particularly vulnerable. Little is known about the roles that different structural components (cellulose, pectin, and xyloglucan) of plant cell walls play in the attachment of foodborne bacterial pathogens. Using bacterial cellulose-derived plant cell wall models, we showed that the presence of pectin alone or xyloglucan alone affected the attachment of three Salmonella enterica strains (Salmonella enterica subsp. enterica serovar Enteritidis ATCC 13076, Salmonella enterica subsp. enterica serovar Typhimurium ATCC 14028, and Salmonella enterica subsp. indica M4) and Listeria monocytogenes ATCC 7644. In addition, we showed that this effect was modulated in the presence of both polysaccharides. Assays using pairwise combinations of S. Typhimurium ATCC 14028 and L. monocytogenes ATCC 7644 showed that bacterial attachment to all plant cell wall models was dependent on the characteristics of the individual bacterial strains and was not directly proportional to the initial concentration of the bacterial inoculum. This work showed that bacterial attachment was not determined directly by the plant cell wall model or bacterial physicochemical properties. We suggest that attachment of the Salmonella strains may be influenced by the effects of these polysaccharides on physical and structural properties of the plant cell wall model. Our findings improve the understanding of how Salmonella enterica and Listeria monocytogenes attach to plant cell walls, which may facilitate the development of better ways to prevent the attachment of these pathogens to such surfaces.
Viral and Atypical Bacterial Detection in Acute Respiratory Infection in Children Under Five Years

Background Acute respiratory infection (ARI) is a leading cause of morbidity and mortality in children worldwide. This study aimed to determine the viral and atypical bacterial causes of different severities and clinical manifestations of ARI in preschool children from low-income families in North-East Brazil. Methods Clinical/demographic data and nasopharyngeal aspirates (NPA) were prospectively collected from children <5 years presenting with ARI over one year to a paediatric A&E department. Disease severity was grouped according to presence of lower respiratory tract signs, need for hospital admission and need for oxygen. Clinical manifestation of ARI was based on discharge diagnosis from hospital with four conditions predominating: bronchiolitis, pneumonia, episodic viral wheeze/asthma and upper respiratory tract infection. Multiplex PCR was used to detect 17 common respiratory viral and atypical bacterial pathogens in NPA. Findings 407 children with a median age of eight months were recruited. Pathogens were detected in 85·5% samples with co-infection being particularly common (39·5%). Respiratory Syncytial Virus (RSV; 37%), Adenoviruses (AdV; 25%), Rhinoviruses (hRV; 19%), Bocavirus (hBoV; 19%), human Meta-pneumovirus (hMPV; 10%) and Mycoplasma pneumoniae (Mpp; 10%) were most prevalent. Detection and co-infection rates were similar in all severities and clinical manifestations of ARI apart from RSV, which was associated with more severe disease and specifically more severe cases of bronchiolitis, and Mpp, which was associated with more severe cases of pneumonia. Mpp was detected in 17% of children admitted to hospital with pneumonia. Interpretation This study underlines the importance of viral and atypical bacterial pathogens in ARI in pre-school children and highlights the complex epidemiology of these pathogens in this age group. Generally, viruses and atypical bacteria were detected in all severities and clinical manifestations of ARI but RSV and Mpp were associated with more severe cases of bronchiolitis and pneumonia respectively.
Appetitive Aggression as a Resilience Factor against Trauma Disorders: Appetitive Aggression and PTSD in German World War II Veterans

Background Repeated exposure to traumatic stressors such as combat results in chronic symptoms of PTSD. However, previous findings suggest that former soldiers who report combat-related aggression to be appetitive are more resilient to develop PTSD. Appetitive Aggression should therefore prevent widespread mental suffering in perpetrators of severe atrocities even after decades. Methods and Findings To test the long-term relationship between trauma-related illness and attraction to aggression, we surveyed a sample of 51 German male World-War II veterans (age: M = 86.7, SD = 2.8). War-related appetitive aggression was assessed with the Appetitive Aggression Scale (AAS). Current- and lifetime PTSD symptoms were assessed with the PSS-I. In a linear regression analysis accounting for 31% of the variance we found that veterans that score higher on the AAS show lower PSS-I symptom severity scores across their whole post-war lifetime (β = − .31, p = .014). The effect size and power were sufficient (f 2 = 0.51, (1-β) = . 99). The same was true for current PTSD (β = − .27, p = .030). Conclusions Appetitive Aggression appears to be a resilience factor for negative long-term effects of combat experiences in perpetrators of violence. This result has practical relevance for preventing trauma-related mental suffering in Peace Corps and for designing adequate homecoming reception for veterans.
Frequent Arousal from Hibernation Linked to Severity of Infection and Mortality in Bats with White-Nose Syndrome

White-nose syndrome (WNS), an emerging infectious disease that has killed over 5.5 million hibernating bats, is named for the causative agent, a white fungus (Geomyces destructans (Gd)) that invades the skin of torpid bats. During hibernation, arousals to warm (euthermic) body temperatures are normal but deplete fat stores. Temperature-sensitive dataloggers were attached to the backs of 504 free-ranging little brown bats (Myotis lucifugus) in hibernacula located throughout the northeastern USA. Dataloggers were retrieved at the end of the hibernation season and complete profiles of skin temperature data were available from 83 bats, which were categorized as: (1) unaffected, (2) WNS-affected but alive at time of datalogger removal, or (3) WNS-affected but found dead at time of datalogger removal. Histological confirmation of WNS severity (as indexed by degree of fungal infection) as well as confirmation of presence/absence of DNA from Gd by PCR was determined for 26 animals. We demonstrated that WNS-affected bats aroused to euthermic body temperatures more frequently than unaffected bats, likely contributing to subsequent mortality. Within the subset of WNS-affected bats that were found dead at the time of datalogger removal, the number of arousal bouts since datalogger attachment significantly predicted date of death. Additionally, the severity of cutaneous Gd infection correlated with the number of arousal episodes from torpor during hibernation. Thus, increased frequency of arousal from torpor likely contributes to WNS-associated mortality, but the question of how Gd infection induces increased arousals remains unanswered.
MT2-MMP induces proteolysis and leads to EMT in carcinomas

Epithelial-mesenchymal transition (EMT) is critical for carcinoma invasiveness and metastasis. To investigate the role of membrane-type-2 matrix metalloproteinase (MT2-MMP) in EMT, we generated lentiviral constructs of wild-type (WT) and an inactive Glu260Ala (E260A) mutant MT2-MMP and derived stably transfected HCT116 and A549 cell lines. WT-transfected cells appeared mesenchymal-like, whereas cells transfected with the E260A mutant were epithelial-like, as were cells treated with an MMP inhibitor (GM6001). Expression of E-cadherin, β-catenin, and zonula occludens-1 was lower in cells transfected with WT MT2-MMP compared to vector controls, cells treated with GM6001, or cells transfected with the E260A mutant. An 80-kD N-terminal fragment of E-cadherin was immunoprecipitated in conditioned medium from WT MT2-MMP cells, but not in the medium from vector controls, cells treated with GM6001, or E260A mutant cells. When endogenous expression of MT2-MMP in A2780 human ovarian cancer cells was inhibited using GM6001 or MT2-MMP-specific siRNA, levels of the 80-kD E-cadherin fragment in conditioned medium were decreased. Chick embryo chorioallantoic membrane invasion assays demonstrated that cells transfected with WT MT2-MMP were more invasive than cells transfected with control vector, treated with GM6001, or transfected with the E260A mutant. These results suggest that MT2-MMP degrades adherens and tight junction proteins and results in EMT, making it a potential mediator of EMT in carcinomas.
Adverse Pregnancy Outcomes After Treatment for Cervical Intraepithelial Neoplasia

OBJECTIVE: To explore associations between specific treatments for intraepithelial or early invasive cervical lesions and adverse pregnancy outcomes. METHODS: We conducted a population-based cohort study in which treatment data from the Cancer Registry of Norway were linked to the Medical Birth Registry of Norway to identify adverse pregnancy outcomes. All women (n=545,243) with singleton births (N=943,321) in Norway during 1998–2014 were included; 9,554 of births were in women treated before delivery. Hazard ratios (HRs) with 95% confidence intervals (CIs) were derived from Cox regression models. RESULTS: There was a significant association between preterm birth and previous treatment of cervical lesions overall (9.7 compared with 5.3%; HR 1.8, 95% CI 1.7–2.0). The strongest associations were seen for cold knife (13 compared with 5.3%; HR 2.6, 95% CI 1.3–5.3) and laser conization (12 compared with 5.3%; HR 2.3, 95% CI 2.0–2.5). The association was stronger for preterm birth at earlier gestational ages and increased with amount of tissue excised. Furthermore, the association weakened with calendar year of treatment. There was also an association with increased risks of spontaneous abortion (0.5 compared with 0.2%; HR 2.5, 95% CI 1.7–3.7), and the strongest associations were seen for laser conization (0.6 compared with 0.2%; HR 3.0, 95% CI 1.8–5.3) and a loop electrosurgical excision procedure (LEEP) (0.4 compared with 0.2%; HR 2.3, 95% CI 1.3–4.0). CONCLUSION: Treatment with major excisional procedures, including LEEP, was associated with increased risks of preterm birth and spontaneous abortion. The risk of preterm birth was highest at early gestational ages and for those with the largest amount of tissue excised. Women should be informed about their future risk of adverse pregnancy outcomes, particularly preterm birth, after excisional treatment for cervical lesions.
A Long Preoperative Duration of Symptoms Is Associated With Worse Functional Outcomes After 1-Stage Arthroscopic Treatment of Rotator Cuff Tears With Shoulder Stiffness

Background: Rotator cuff tears with shoulder stiffness remain a difficult issue. Despite the reported satisfactory results of 1-stage surgery, little information is available regarding the factors that affect clinical outcomes. Purpose/Hypothesis: To evaluate the 1-stage arthroscopic treatment of rotator cuff tears with shoulder stiffness and to present the influence of duration of symptoms (DOS) on postoperative functional outcomes. The hypothesis was that a long preoperative DOS is related to worse functional outcomes. Hypothesis: A long preoperative DOS is related to worse functional outcomes. Study Design: Cohort study; Level of evidence, 2. Methods: A cohort study was performed with consecutive patients who underwent 1-stage surgery between January 2012 and July 2014. Forty-four patients were enrolled in the long DOS group (DOS ≥6 months or LDOS), and 38 were enrolled in the short DOS group (DOS <6 months or SDOS). There were no significant differences in the other variables between the groups. The patients were followed for a mean of 33.8 months, and the functional and radiographic outcomes were compared. Results: Both groups achieved apparent functional postoperative improvements in terms of range of motion, pain, strength, and functional scores (P < .001 for all). Despite the overall improvements, the patients in the SDOS group had significantly better outcomes according to all functional instruments. The mean postoperative abduction and external rotation at the side in the SDOS group were higher than in the LDOS group (abduction: 162.2° vs 152.8°, respectively [P = .002]; external rotation: 64.7° vs 56.9°, respectively [P = .004]). The mean postoperative functional scores in the SDOS group were all higher than in the LDOS group (American Shoulder and Elbow Surgeons [ASES] score: 91.1 vs 81.9, respectively; Constant-Murley score: 76.9 vs 71.8, respectively; Fudan University Shoulder Score [FUSS], 90.6 vs 81.1, respectively), and the mean postoperative visual analog scale (VAS) score for pain in the SDOS group was lower (0.7 vs 1.8, respectively) (P < .001 for all). The difference in the retear rates was not significant, with 7 retears in the SDOS group and 4 in the LDOS group (P = .216). Conclusion: One-stage surgery effectively achieved overall improvements. A preoperative DOS of ≥6 months led to poorer functional outcomes, which suggests that surgeons should propose a surgical treatment for this condition before symptoms persist for 6 months.
Invasion History of the Oriental Fruit Fly, Bactrocera dorsalis, in the Pacific-Asia Region: Two Main Invasion Routes

The oriental fruit fly, Bactrocera dorsalis, was initially recorded in Taiwan Island in 1912, and has dispersed to many areas in the Pacific-Asia region over the last century. The area of origin of the species may be confidently placed in South-East China. However, routes of range expansion to new areas and underlying population processes remain partially unclear, despite having been the subject of several studies. To explore the invasion history of this species, a partition of the cox1 gene of mitochondrial DNA was used to investigate genetic diversity, haplotype phylogeny and demographic history of 35 populations, covering China and South-East Asia and including marginal populations from Pakistan and Hawaii. Based on neighbor-joining tree analysis and the distribution of haplotypes, two main invasion routes are inferred: one from South-East China to Central China, another from South-East China to South-East Asia, with both routes probably coinciding in Central China. Populations in Taiwan Island and Hainan Island might have originated in South-East China. The marginal populations in Pakistan and Hawaii might have undergone founding events or genetic bottlenecks. Possible strategies for the control of this species are proposed based on the invasion history and reconstructed expansion routes.
Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases

Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD. DOI: http://dx.doi. org/10.7554/eLife.12813. 001
Dispersion and properties of cellulose nanowhiskers and layered silicates in cellulose acetate butyrate nanocomposites

The aim of this work was to develop well dispersed nanocomposites, in a non water soluble polymer using a non aqueous, low polarity solvent as a dispersion medium. The nanoreinforcements were cellulose whiskers and layered silicates (LSs) and matrix was cellulose acetate butyrate (CAB). Before nanocomposite processing, a homogenizer was used in combination with sonification to achieve full dispersion of the nanoreinforcements in a medium of low polarity (ethanol). After processing, the cellulose nanowhiskers (CNW) showed flow birefringence in both ethanol and dissolved CAB, which indicated well dispersed whiskers. The microscopy studies indicated that the processing was successful for both nanocomposites. The CNW showed a homogeneous dispersion on nanoscale. The LS nanocomposite contained areas with lower degree of dispersion and separation of the LS sheets and formed mainly an intercalated structure. The produced materials were completely transparent, which indicated good dispersion. Transparency measurements also indicated that the nanocomposite containing CNW showed similar performance as the pure CAB. Dynamic mechanical thermal analysis (DMTA) showed improved storage modulus for a wide temperature range for both nanocomposites compared with the pure CAB matrix. This study indicated that CNW have a potential application in transparent nanocomposites based on fully renewable resources. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009