67 research outputs found
Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins
No full textBACKGROUND: CtBP1 and CtBP2 are transcriptional co-repressors that modulate the activity of a large number of transcriptional repressors via the recruitment of chromatin modifiers. Many CtBP-regulated proteins are involved in pathways associated with tumorigenesis, including TGF-beta and Wnt signalling pathways and cell cycle regulators such as RB/p130 and HDM2, as well as adenovirus E1A. CtBP1 and CtBP2 are highly similar proteins, although evidence is emerging that their activity can be differentially regulated, particularly through the control of their subcellular localisation. CtBP2s from diverse species contain a unique N-terminus, absent in CtBP1 that plays a key role in controlling the nuclear-cytoplasmic distribution of the protein.RESULTS: Here we show that amino acids (a.a.) 4-14 of CtBP2 direct CtBP2 into an almost exclusively nuclear distribution in cell lines of diverse origins. Whilst this sequence contains similarity to known nuclear localisation motifs, it cannot drive nuclear localisation of a heterologous protein, but rather has been shown to function as a p300 acetyltransferase-dependent nuclear retention sequence. Here we define the region of CtBP2 required to co-operate with a.a. 4-14 to promote CtBP2 nuclear accumulation as being within a.a. 1-119. In addition, we show that a.a. 120-445 of CtBP2 can also promote CtBP2 nuclear accumulation, independently of a.a. 4-14. Finally, CtBP1 and CtBP2 can form heterodimers, and we show that the interaction with CtBP2 is one mechanism whereby CtBP1 can be recruited to the nucleus.CONCLUSION: Together, these findings represent key distinctions in the regulation of the functions of CtBP family members that may have important implications as to their roles in development, and cell differentiation and survival.<br/
Influence of conjugated linoleic acid enriched ghee feeding on cancer incidence and histopathological changes in 7,12-dimethyl-benz[a]anthracene induced mammary gland carcinogenesis in rats
Get PDFIstraživan je utjecaj davanja maslaca od bivoljega mlijeka obogaćenoga konjugiranom linolnom kiselinom na incidenciju i patohistološke promjene u nastanku raka mliječne žlijezde štakorica uzrokovanoga 7,12-dimetilbenz[a]antracenom. Wistar štakorice u dobi od 21 dana bile su nasumce podijeljene u tri skupine po 30 životinja. Prva skupina bila je hranjena hranom na bazi soje, dok je druga dobivala hranu na bazi bivoljega mlijeka s malom koncentracijom konjugirane linolne kiseline, a treća hranu s dodatkom veće količine konjugirane linolne kiseline. Sojino ulje i linolna kiselina dodavani su u hranu u količini od 20%. Hranidba navedenom hranom započela je na dan zalučenja. Svakoj je životinji peroralno dan 7,12-dimetilbenz[a]antracen (DMBA) u količini od 5 mg u dobi od 55 dana, a testirana hrana davana je do 32 tjedna nakon primjene DMBA. Sve su životinje bile žrvovane nakon 32 tjedna te pretražene na pojavnost i patohistološke značajke tumora. Incidencija tumora u I skupini bila je 83,33%, u II skupini 63,33% i u III skupini 46,07%. Patohistološki je ustanovljen fibrom, adenom i fibroadenom u štakorica svih skupina, dok je u štakorica I skupine ustanovljen i adenokarcinom. Rezultati su pokazali da je konjugirana linolna kiselina imala inhibirajući učinak i na dobroćudni i na zloćudni tumor.A study was conducted to investigate the influence of Conjugated Linoleic Acid (CLA) feeding on cancer incidence and histopathological changes in DMBA induced mammary gland carcinogenesis rats. Female Wistar rats of 21 days were taken for the study and the animals were randomly divided into three groups of 30 animals each. Group I animals were fed with a soybean based diet, whereas group II and group III animals were fed with a low CLA and high CLA ghee based diet, respectively. Soybean oil, low CLA and high CLA ghee were included at the level of 20 per cent in the animal diet. Feeding with test diets started on the day of weaning. The animals were given 7,12 dimethyl-benz[a]anthracene(DMBA) at 5 mg per animal as a single dose by oral intubation at the age of 55 days and the test diets were continued up to 32 weeks after DMBA administration. At the end of 32 weeks all the animals were sacrificed, tumour data recorded and histopathology performed. The tumour incidence in groups I, II and III was 83.33, 63.33 and 46.07 per cent respectively. Histopathology revealed fibroma, adenoma, fibroadenoma in all the groups whereas in group I showed adenocarcinoma. Therefore, the results of the present study showed CLA not only inhibited benign type tumours but malignant tumours as well
Singaporean mothers' perception of their three-year-old child's weight status: A cross-sectional study
Get PDFSingapore National Research Foundation; National Medical Research Council (NMRC), SingaporeFull Author List: Cheng T.S.; Cheng T.; Loy S.; Cheung Y.; Chan J.; Tint M.; Godfrey K.; Gluckman P.; Kwek K.; Saw S.; Chong Y.; Lee Y.; Yap F.; Lek N.; Sheppard A.; Chinnadurai A.; Goh A.; Rifkin-Graboi A.; Qiu A.; Biswas A.; Lee B.; Broekman B.; Quah B.; Shuter B.; Chng C.; Ngo C.; Hsu S.; Bong C.; Henry C.; Chee C.; Fok D.; Yeo G.; Inskip H.; Chen H.; Van Bever H.; Magiati I.; Wong I.; Lau I.; Kapur J.; Richmond J.; Holbrook J.; Gooley J.; Tan K.; Niduvaje K.; Singh L.; Su L.; Daniel L.; Shek L.; Fortier M.; Hanson M.; Chong M.; Rauff M.; Chua M.; Meaney M.; Teoh O.; Wong P.; Agarwal P.; Van Dam R.; Rebello S.; Chong S.; Cai S.; Soh S.; Lim S.; Rajadurai V.; Stunkel W.; Han W.; Pang W.; Goh Y.; Chan Y.</p
Optimizing pharmacodynamics and evaluating echocardiographic effects of alfaxalone sedation in bearded dragons (Pogona vitticeps) and prairie rattlesnakes (Crotalus viridis)
Get PDFAlfaxalone, a neurogenic steroid with action at the γ-aminobutyric acid A receptor, is an injectable sedative frequently utilized in squamate medicine. A novel formulation of alfaxalone was recently approved by the Food and Drug Administration for 28-day use after breaching the vial due to the addition of proprietary preservatives. Previous research performed in squamates focuses on evaluating one route of administration at one or more doses and monitoring the effects of alfaxalone on that species (i.e. heart rate, respiratory rate, depth of sedation (Bertelsen 2011, Ferreira 2019, James 2018, Strahl-Heldreth 2019, Jurox 2020, Perrin 2017, Scheelings 2011). This thesis research examines the use of the new formulation of alfaxalone in two species: the bearded dragon and the prairie rattlesnake. Bearded dragons (Pogona vitticeps), a popular zoological companion species, frequently require sedation for procedures. Prairie rattlesnakes (Crotalus viridis) act as a model for that species and other Viperidae housed in zoological institutions or studied in free-ranging populations that require sedation to facilitate safe handling, examination, and minimally invasive procedures. A group of bearded dragons (n=10) and prairie rattlesnakes (n=10) were respectively sedated with alfaxalone at 15 mg/kg and 20 mg/kg based on a pilot study that identified the optimal dose for each species. A complete cross-over design evaluated four routes of administration: intracoelomic, subcutaneous, intramuscular, and intravenous. The optimal route of administration, defined as the route that provided consistent deep sedation with loss of righting reflex, maintenance of spontaneous respiration, and a clinically normal heart rate, was identified as intravenous (coccygeal vein) in bearded dragons and intramuscular (epaxials cranial to the heart) in prairie rattlesnakes. Echocardiography evaluated whether the cardiac function of either species was significantly affected by alfaxalone administered at the optimal dose and route of administration. End systolic volume was the only echocardiographic parameter that significantly increased in bearded dragons indicating a decrease in cardiac contractility secondary to sedation. Prairie rattlesnake echocardiographic values were not affected. Administration of alfaxalone at 15 mg/kg intravenously in the coccygeal vein of bearded dragons and 20 mg/kg intramuscularly in the cranial epaxials of prairie rattlesnakes should facilitate safe handling and immobilization for minimally invasive procedures in each species.Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2023-05-01The student, Joanna Webb, accepted the attached license on 2021-04-02 at 08:20.The student, Joanna Webb, submitted this Thesis for approval on 2021-04-02 at 08:37.This Thesis was approved for publication on 2021-04-07 at 16:39.DSpace SAF Submission Ingestion Package generated from Vireo submission #16230 on 2021-09-16 at 20:08:00Made available in DSpace on 2021-09-17T04:04:07Z (GMT). No. of bitstreams: 2
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Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription
No full textThe transcription factor p53 lies at the center of a protein network that controls cell cycle progression and commitment to apoptosis. p53 is inactive in proliferating cells, largely because of negative regulation by the Hdm2/Mdm2 oncoprotein, with which it physically associates. Release from this negative regulation is sufficient to activate p53 and can be triggered in cells by multiple stimuli through diverse pathways. This diversity is achieved in part because Hdm2 uses multiple mechanisms to inactivate p53; it targets p53 for ubiquitination and degradation by the proteosome, shuttles it out of the nucleus and into the cytoplasm, prevents its interaction with transcriptional coactivators, and contains an intrinsic transcriptional repressor activity. Here we show that Hdm2 can also repress p53 activity through the recruitment of a known transcriptional corepressor, hCtBP2. This interaction, and consequent repression of p53-dependent transcription, is relieved under hypoxia or hypoxia-mimicking conditions that are known to increase levels of intracellular NADH. CtBP proteins can undergo an NADH-induced conformational change, which we show here results in a loss of their Hdm2 binding ability. This pathway represents a novel mechanism whereby p53 activity can be induced by cellular stress.<br/
Channeling Exciton Migration into Electron Transfer in Formamidinium Lead Bromide Perovskite Nanocrystal/Fullerene Composites
Get PDFHydrophobically capped nanocrystals of formamidinium lead bromide (FAPbBr(3)) perovskite (PNC) show bright and stable fluorescence in solution and thin-film states. When compared with isolated PNCs in a solution, closepacked PNCs in a thin film show extended fluorescence lifetime (ca. 4.2 mu s), which is due to hopping or migration of photogenerated excitons among PNCs. Both fluorescence quantum efficiency and lifetime decrease in a PNC thin film doped with fullerene (C-60), which is attributed to channeling of exciton migration into electron transfer to C-60. On the other hand, quenching of fluorescence intensity of a PNC solution is not accompanied by any change in fluorescence lifetime, indicating static electron transfer to C-60 adsorbed onto the hydrophobic surface of individual PNCs. Exciton migration among close-packed PNCs and electron transfer to C-60 places C-60-doped PNC thin films among cost-effective antenna systems for solar cells
Investigation of the diagnosis and treatment of Macrorhabdus ornithogaster in Budgerigars (Melopsittacus undulatus)
No full textSubmission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2027-05-01The student, Danielle Lang, accepted the attached license on 2025-04-22 at 22:18.The student, Danielle Lang, submitted this Thesis for approval on 2025-04-22 at 22:23.This Thesis was approved for publication on 2025-04-29 at 18:45.DSpace SAF Submission Ingestion Package generated from Vireo submission #21908 on 2025-10-19 at 19:15:26Macrorhabdus ornithogaster (MO) is a pathogenic yeast that can cause significant morbidity and mortality in both wild and captive birds. Budgerigars (Melopsittacus undulatus) are a commonly affected species, making this an important disease of client-owned birds and zoological collections. Antemortem diagnosis is difficult given variable shedding, lack of available diagnostic assays to quantify the pathogen, and inability to maintain this pathogen in any lab in the world. In addition, there is a lack of curative treatments for this pathogen. Given the broad avian taxonomic range in which this pathogen has been identified, the challenges with diagnosis, and inconsistent treatment results, we aimed to 1) develop a novel quantitative polymerase-chain reaction (qPCR) assay to quantify MO DNA from feces, 2) culture MO in vitro to test antifungal susceptibility, and 3) use the novel qPCR assay to assess the prevalence of MO in both wild and managed birds. A TaqMan qPCR assay targeting a 94 bp segment of MO 18S rRNA was developed and validated, performing with high efficiency (slope = -3.355, R2 = 0.999, efficiency = 98.622) and low intra- and inter-assay variability (coefficient of variation <2.63% at all dilutions). MO culture was successfully performed using proventricular-ventricular samples and feces from deceased, cytology-positive budgerigars using Basal Medium Eagle or chicken serum media, 20% fetal bovine serum, 5% sucrose, 100 units/mL penicillin, 100 µg/mL streptomycin, and 25 µg/mL chloramphenicol at pH 3-4 and 42°C under microaerophilic conditions. MO was successfully cultured from four different infected budgerigars using this culture protocol; however, cultures did not maintain long enough for antifungal susceptibility testing. Prevalence testing was performed using the novel qPCR, revealing an overall MO prevalence of 9.4% in a managed zoological budgerigar population, which was lower than in previous prevalence reports. No wild birds from northeastern Illinois tested positive for MO. Budgerigars that were positive for MO on qPCR had significantly lower weights than negative birds. These findings demonstrate the utility of a novel MO qPCR for antemortem diagnosis of MO in bird feces and the potential impact that MO presence has on the health of infected budgerigars. The low prevalence in this population prompts further investigation into improving diagnostic sensitivity for detecting this organism, especially with intermittent shedding
Targeting C-terminal binding proteins (CtBPs) using genetic selection
No full textThere are many protein-protein interactions that are vital for cellular processes such as signal transduction, structural organisation and apoptosis. In this study we decipher the role of the protein-protein interaction of C terminal Binding Proteins (CtBPs). CtBPs function as transcriptional co-repressors in the nucleus playing key roles in tumorigenesis and metastasis by regulating cellular processes, critical to cell survival, cell migration and senescence. CtBP proteins also play a role in the cytoplasm in regulating mitotic Golgi membrane fission Studies in which the expression or function of CtBPs has been inhibited have independently identified roles for CtBPs in both suppressing apoptosis and promoting cell cycle progression. Modulation of these interactions with small molecules is a potential therapeutic strategy with benefits over current methods. Our approach in studying protein-protein interactions and uncovering potential inhibitors involves constructing a bacterial Reverse Two Hybrid System (RTHS) linking the dimerisation of the target protein partners to the expression of reporter genes, whose regulation can be monitored via host survival. Subsequent screening of a cyclic peptide library for potential inhibitors was then carried out. The libraries were produced using Split Intein-mediated Circular Ligation Of Peptides and Proteins (SICLOPPS) technology, developed for intracellular synthesis of cyclic peptides. We have used this methodology to identify inhibitors of CtBP dimerisation and better understand the roles of this protein interaction in cell cycle regulation. Chapter 1 provides an introduction to the work carried out to study protein-protein interactions and finding potential inhibitors. Since our investigations involved the extensive use of the RTHS and SICLOPPS system, the background and work performed by others has been described in detail. A detailed review of CtBPs has also been carried out. Chapter 2 details our work investigating the homodimeric and heterodimeric protein-protein interaction of CtBPs using the RTHS. This work allowed us to optimise selection conditions and find cyclic peptide inhibitors of the homodimerisation of CtBP1 and CtBP2 using the SICLOPPS process. The synthesis of these inhibitors is described. Chapter 3 details our work carried out to develop ELISAs for in vitro analysis of the selected cyclic peptides. This involved the purification of His- and GST-tagged CtBP1 and CtBP2 proteins. The ELISA conditions were optimised to carry out CtBP homodimeric and hetrodimeric analysis. This work showed that the peptides lead to a reduction in CtBP homdimerisation and heterodimerisation in vitro. Chapter 4 details the in vivo effects of the uncovered CtBP dimerisation inhibitors. Using these cyclic peptide inhibitors we have demonstrated that CtBP dimerisation is essential for the regulation of mitotic fidelity, and that inhibition of CtBP dimerisation by the cyclic peptides leads to aberrant segregation of chromosomes during mitosis. We have also shown that inhibition of CtBP dimerisation leads to a reduction in migration of MCF-7 breast cancer cells. Chapter 5 details the experimental procedures used in this work and presents spectroscopic and analytical data for the compounds prepared
C-terminal binding proteins: Emerging roles in cell survival and tumorigenesis
Get PDFWithin a cell, the levels and activity of multiple pro- and anti-apoptotic molecules act in concert to regulate commitment to apoptosis. Whilst the balance between survival and death can be tipped by the effects of single molecules, cellular apoptosis control pathways very often incorporate key transcription factors that co-ordinately regulate the expression of multiple apoptosis control genes. C-terminal binding proteins (CtBPs), which were originally identified through their binding to the Adenovirus E1A oncoprotein, have been described as such transcriptional regulators of the apoptosis program. Specifically, CtBPs function as transcriptional co-repressors, and have been demonstrated to promote cell survival by suppressing the expression of several pro-apoptotic genes. In this review we summarize the evidence supporting a key role for CtBP proteins in cell survival. We also describe the known mechanisms of transcriptional control by CtBPs, and review the multiplicity of intracellular signaling and transcriptional control pathways with which they are known to be involved. Finally we consider these findings in the context of additional known roles of CtBP molecules, and the potential implications that this combined knowledge may have for our comprehension of diseases of cell survival, notably cance
PSYCHIATRIC COMORBIDITY AND QUALITY OF LIFE IMPAIRMENT IN ALCOHOL DEPENDENCE: A CROSS-SECTIONAL STUDY FROM A TERTIARY CARE COHORT
No full textObjective: The objective of the study is to determine the prevalence and pattern of anxiety and depression in patients with alcohol dependence syndrome (ADS) and to examine their association with quality of life (QoL) domains in a tertiary-care cohort.
Methods: This cross-sectional observational study enrolled 171 male patients diagnosed with ADS at a tertiary care center in India. Psychiatric morbidity was assessed using the Hospital Anxiety and Depression Scale (HADS), and QoL was measured using the World Health Organization QoL-BREF. Analyses included descriptive statistics, Mann–Whitney U and Kruskal–Wallis H tests, chi-square test for association between anxiety and depression severity, Spearman rank correlations, and multiple linear regression modeling. A comparative synthesis of published studies (2020–2025) was used to contextualize prevalence estimates.
Results: Using the standard HADS abnormal cut-off (≥11), abnormal anxiety was observed in 41.5% (n=71) and abnormal depression in 43.8% (n=75). When HADS caseness was defined as score ≥8, anxiety and depression caseness were present in 59.65% (n=102) and 59.06% (n=101), respectively, with comorbid anxiety–depression in 42.11% (n=72). Anxiety and depression caseness showed a significant association (χ2=13.88, p<0.001). Previous treatment history was not associated with lower current anxiety or depression severity; however, patients with prior treatment had significantly higher social well-being scores (mean difference=8.45, p=0.021). Correlations between psychiatric symptom severity and QoL domains were negligible (Spearman ρ<0.13), and regression models demonstrated low explanatory power (R2≤0.04).
Conclusion: Psychiatric comorbidity is common and clinically significant among tertiary-care ADS patients. The finding that previous treatment is linked to better social functioning despite persistent psychiatric symptoms suggests that treatment contact may confer durable social benefits independent of symptom remission. The weak symptom–QoL association and low model R2 values support the view that functional outcomes in ADS are multidetermined, underscoring the need for integrated dual-diagnosis care with explicit emphasis on sustained psychosocial rehabilitation and social reintegration
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