53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility

Double-strand breaks activate the ataxia telangiectasia mutated (ATM) kinase, which promotes the accumulation of DNA damage factors in the chromatin surrounding the break. The functional significance of the resulting DNA damage foci is poorly understood. Here we show that 53BP1 (also known as TRP53BP1), a component of DNA damage foci, changes the dynamic behaviour of chromatin to promote DNA repair. We used conditional deletion of the shelterin component TRF2 (also known as TERF2) from mouse cells (TRF2fl/-) to deprotect telomeres, which, like double-strand breaks, activate the ATM kinase, accumulate 53BP1 and are processed by non-homologous end joining (NHEJ). Deletion of TRF2 from 53BP1-deficient cells established that NHEJ of dysfunctional telomeres is strongly dependent on the binding of 53BP1 to damaged chromosome ends. To address the mechanism by which 53BP1 promotes NHEJ, we used time-lapse microscopy to measure telomere dynamics before and after their deprotection. Imaging showed that deprotected telomeres are more mobile and sample larger territories within the nucleus. This change in chromatin dynamics was dependent on 53BP1 and ATM but did not require a functional NHEJ pathway. We propose that the binding of 53BP1 near DNA breaks changes the dynamic behaviour of the local chromatin, thereby facilitating NHEJ repair reactions that involve distant sites, including joining of dysfunctional telomeres and AID (also known as AICDA)-induced breaks in immunoglobulin class-switch recombination

How university’s activities support the development of students’ entrepreneurial abilities: case of Slovenia and Croatia

The paper reports how the offered university activities support the development of students’ entrepreneurship abilities. Data were collected from 306 students from Slovenian and 609 students from Croatian universities. The study reduces the gap between theoretical researches about the academic entrepreneurship education and individual empirical studies about the student’s estimation of the offered academic activities for development of their entrepreneurial abilities. The empirical research revealed differences in Slovenian and Croatian students’ perception about (a) needed academic activities and (b) significance of the offered university activities, for the development of their entrepreneurial abilities. Additionally, the results reveal that the impact of students’ gender and study level on their perception about the importance of the offered academic activities is not significant for most of the considered activities. The main practical implication is focused on further improvement of universities’ entrepreneurship education programs through selection and utilization of activities which can fill in the recognized gaps between the students’ needed and the offered academic activities for the development of students’ entrepreneurial abilities

Anterior chest wall tuberculous abscess: a case report

The granulomatous inflammation of tuberculosis usually involves the lungs and the hilar lymph nodes. Musculoskeletal tuberculosis (TB) occurs in 1–3% of patients with TB, while TB of the chest wall constitutes 1% to 5% of all cases of musculoskeletal TB. Furthermore, nowadays it is rarer to find extrapulmonary TB in immunocompetent rather that non-immunocompetent patients. The present case reports a fifty-six-year-old immunocompetent man with an anterior chest wall tuberculous abscess. The rarity of the present case relates both to the localization of the tuberculous abscess, and to the fact that the patient was immunocompetent. The diagnosis of musculoskeletal tuberculous infection remains a challenge for clinicians and requires a high index of suspicion. The combination of indolent onset of symptoms, positive tuberculin skin test, and compatible radiographic findings, strongly suggests the diagnosis. TB, however, must be confirmed by positive culture or histologic proof. Prompt diagnosis and treatment are important to prevent serious bone and joint destruction

Links between maternal postpartum depressive symptoms, maternal distress, infant gender and sensitivity in a high-risk population

<p>Abstract</p> <p>Background</p> <p>Maternal postpartum depression has an impact on mother-infant interaction. Mothers with depression display less positive affect and sensitivity in interaction with their infants compared to non-depressed mothers. Depressed women also show more signs of distress and difficulties adjusting to their role as mothers than non-depressed women. In addition, depressive mothers are reported to be affectively more negative with their sons than with daughters.</p> <p>Methods</p> <p>A non-clinical sample of 106 mother-infant dyads at psychosocial risk (poverty, alcohol or drug abuse, lack of social support, teenage mothers and maternal psychic disorder) was investigated with EPDS (maternal postpartum depressive symptoms), the CARE-Index (maternal sensitivity in a dyadic context) and PSI-SF (maternal distress). The baseline data were collected when the babies had reached 19 weeks of age.</p> <p>Results</p> <p>A hierarchical regression analysis yielded a highly significant relation between the PSI-SF subscale "parental distress" and the EPDS total score, accounting for 55% of the variance in the EPDS. The other variables did not significantly predict the severity of depressive symptoms. A two-way ANOVA with "infant gender" and "maternal postpartum depressive symptoms" showed no interaction effect on maternal sensitivity.</p> <p>Conclusions</p> <p>Depressive symptoms and maternal sensitivity were not linked. It is likely that we could not find any relation between both variables due to different measuring methods (self-reporting and observation). Maternal distress was strongly related to maternal depressive symptoms, probably due to the generally increased burden in the sample, and contributed to 55% of the variance of postpartum depressive symptoms.</p

Deletion of the WD40 Domain of LRRK2 in Zebrafish Causes Parkinsonism-Like Loss of Neurons and Locomotive Defect

LRRK2 plays an important role in Parkinson's disease (PD), but its biological functions are largely unknown. Here, we cloned the homolog of human LRRK2, characterized its expression, and investigated its biological functions in zebrafish. The blockage of zebrafish LRRK2 (zLRRK2) protein by morpholinos caused embryonic lethality and severe developmental defects such as growth retardation and loss of neurons. In contrast, the deletion of the WD40 domain of zLRRK2 by morpholinos targeting splicing did not induce severe embryonic developmental defects; rather it caused Parkinsonism-like phenotypes, including loss of dopaminergic neurons in diencephalon and locomotion defects. These neurodegenerative and locomotion defects could be rescued by over-expressing zLRRK2 or hLRRK2 mRNA. The administration of L-dopa could also rescue the locomotion defects, but not the neurodegeneration. Taken together, our results demonstrate that zLRRK2 is an ortholog of hLRRK2 and that the deletion of WD40 domain of zLRRK2 provides a disease model for PD

Serum Calcium Levels Are Associated with Novel Cardiometabolic Risk Factors in the Population-Based CoLaus Study

BACKGROUND: Associations of serum calcium levels with the metabolic syndrome and other novel cardio-metabolic risk factors not classically included in the metabolic syndrome, such as those involved in oxidative stress, are largely unexplored. We analyzed the association of albumin-corrected serum calcium levels with conventional and non-conventional cardio-metabolic risk factors in a general adult population. METHODOLOGY/PRINCIPAL FINDINGS: The CoLaus study is a population-based study including Caucasians from Lausanne, Switzerland. The metabolic syndrome was defined using the Adult Treatment Panel III criteria. Non-conventional cardio-metabolic risk factors considered included: fat mass, leptin, LDL particle size, apolipoprotein B, fasting insulin, adiponectin, ultrasensitive CRP, serum uric acid, homocysteine, and gamma-glutamyltransferase. We used adjusted standardized multivariable regression to compare the association of each cardio-metabolic risk factor with albumin-corrected serum calcium. We assessed associations of albumin-corrected serum calcium with the cumulative number of non-conventional cardio-metabolic risk factors. We analyzed 4,231 subjects aged 35 to 75 years. Corrected serum calcium increased with both the number of the metabolic syndrome components and the number of non-conventional cardio-metabolic risk factors, independently of the metabolic syndrome and BMI. Among conventional and non-conventional cardio-metabolic risk factors, the strongest positive associations were found for factors related to oxidative stress (uric acid, homocysteine and gamma-glutamyltransferase). Adiponectin had the strongest negative association with corrected serum calcium. CONCLUSIONS/SIGNIFICANCE: Serum calcium was associated with the metabolic syndrome and with non-conventional cardio-metabolic risk factors independently of the metabolic syndrome. Associations with uric acid, homocysteine and gamma-glutamyltransferase were the strongest. These novel findings suggest that serum calcium levels may be associated with cardiovascular risk via oxidative stress

γ-H2AX Kinetics as a Novel Approach to High Content Screening for Small Molecule Radiosensitizers

Persistence of γ-H2AX after ionizing radiation (IR) or drug therapy is a robust reporter of unrepaired DNA double strand breaks in treated cells.DU-145 prostate cancer cells were treated with a chemical library ±IR and assayed for persistence of γ-H2AX using an automated 96-well immunocytochemistry assay at 4 hours after treatment. Hits that resulted in persistence of γ-H2AX foci were tested for effects on cell survival. The molecular targets of hits were validated by molecular, genetic and biochemical assays and in vivo activity was tested in a validated Drosophila cancer model.We identified 2 compounds, MS0019266 and MS0017509, which markedly increased persistence of γ-H2AX, apoptosis and radiosensitization in DU-145 cells. Chemical evaluation demonstrated that both compounds exhibited structurally similar and biochemical assays confirmed that these compounds inhibit ribonucleotide reductase. DNA microarray analysis and immunoblotting demonstrates that MS0019266 significantly decreased polo-like kinase 1 gene and protein expression. MS0019266 demonstrated in vivo antitumor activity without significant whole organism toxicity.MS0019266 and MS0017509 are promising compounds that may be candidates for further development as radiosensitizing compounds as inhibitors of ribonucleotide reductase

A Review of Time Courses and Predictors of Lipid Changes with Fenofibric Acid-Statin Combination

Fibrates activate peroxisome proliferator activated receptor α and exert beneficial effects on triglycerides, high-density lipoprotein cholesterol, and low density lipoprotein subspecies. Fenofibric acid (FA) has been studied in a large number of patients with mixed dyslipidemia, combined with a low- or moderate-dose statin. The combination of FA with simvastatin, atorvastatin and rosuvastatin resulted in greater improvement of the overall lipid profile compared with the corresponding statin dose. The long-term efficacy of FA combined with low- or moderate- dose statin has been demonstrated in a wide range of patients, including patients with type 2 diabetes mellitus, metabolic syndrome, or elderly subjects. The FA and statin combination seems to be a reasonable option to further reduce cardiovascular risk in high-risk populations, although trials examining cardiovascular disease events are missing