Everyday Life of Children with Intellectual and Developmental Disabilities in Albania

The focus of this master's thesis is children with Intellectual and Developmental Disabilities (IDDs) in Albania. It is exploratory research about the everyday lives and personal experiences of childhood and disability. The research took place in a private multi-functional daycare centre in Tirana. The primary participants were children with IDDs whereas the secondary participants were their parents, teacher and therapist who worked with them in the centre. This research draws on theories, concepts and models from interdisciplinary fields of research including childhood studies, disability studies, disabled children's childhood studies and intersectionality theory. The central value that guided the data collection process and analysis is the acknowledgement that children with IDDs are participants and active agents worthy of contributing to the co-creation of knowledge about their own lives. Utilising the mosaic approach and inspired by ethnographic and participatory methodology, I designed an inclusive, child-focused methodology for this research. I conducted participatory observation and activity-based interviews with the children, as well as semi-structured interviews with parents and professionals. The main contribution of this research is that it reveals the social construction of childhood disability by painting a more nuanced picture of the uniqueness of the experience of the participants' lives at the intersection of age, ability, gender, culture and socio-economic status. The findings of the study are threefold. First, whereas children with IDDs are very different from one another, they experience some similar challenges and share some basic needs. They enjoy going to school and being included in regular classrooms which allows them to make friends and socialise. However, they often struggle with receiving quality and consistent education that matches their lived realities. Second, the issues present in the healthcare services should be improved to comply with the demands stipulated by law. Raising a child with disabilities is a joyful and extraordinary experience but it is also difficult at times and presents many challenges for families. Caring for children with IDDs in Albania is influenced by the family's support from their relatives, their economic status, the geographic location and proximity to services and many other factors. Third, oftentimes children with IDDs become targets of stigma and prejudice based on a construction of disability as a 'misfortune' or problem informed by the normalcy and development paradigm. These findings have important social policy implications for supporting families and children with IDDs in Albania and beyond

Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories

Replication origins are licensed by loading MCM2-7 hexamers before entry into S phase. However, only ∼10% of licensed origins are normally used in S phase, with the others remaining dormant. When fork progression is inhibited, dormant origins initiate nearby to ensure that all of the DNA is eventually replicated. In apparent contrast, replicative stress activates ataxia telangiectasia and rad-3–related (ATR) and Chk1 checkpoint kinases that inhibit origin firing. In this study, we show that at low levels of replication stress, ATR/Chk1 predominantly suppresses origin initiation by inhibiting the activation of new replication factories, thereby reducing the number of active factories. At the same time, inhibition of replication fork progression allows dormant origins to initiate within existing replication factories. The inhibition of new factory activation by ATR/Chk1 therefore redirects replication toward active factories where forks are inhibited and away from regions that have yet to start replication. This minimizes the deleterious consequences of fork stalling and prevents similar problems from arising in unreplicated regions of the genome

Stochastic association of neighboring replicons creates replication factories in budding yeast

Peer reviewedPublisher PD

The telomerase reverse transcriptase elongates reversed replication forks at telomeric repeats

The telomerase reverse transcriptase elongates telomeres to prevent replicative senescence. This process requires exposure of the 3'-end, which is thought to occur when two sister telomeres are generated at replication completion. Using two-dimensional agarose gel electrophoresis (2D-gels) and electron microscopy, we found that telomeric repeats are hotspots for replication fork reversal. Fork reversal generates 3' telomeric ends before replication completion. To verify whether these ends are elongated by telomerase, we probed de novo telomeric synthesis in situ and at replication intermediates by reconstituting mutant telomerase that adds a variant telomere sequence. We found variant telomeric repeats overlapping with telomeric reversed forks in 2D-gels, but not with normal forks, nontelomeric reversed forks, or telomeric reversed forks with a C-rich 3'-end. Our results define reversed telomeric forks as a substrate of telomerase during replication

Pregnancy in myasthenia gravis: a retrospective analysis of maternal and neonatal outcome from a large tertiary care centre in Germany

Purpose: Myasthenia gravis (MG) is a rare, potentially life-threatening autoimmune disease with fluctuating muscle weakness frequently affecting women of childbearing age. MG can affect maternal as well as neonatal outcome with risk of worsening of myasthenic symptoms in the mothers and risk of transient neonatal myasthenia gravis (TNMG) and arthrogryposis multiplex congenita (AMC) or foetal acetylcholine receptor antibody-associated disorders (FARAD) in the neonates. Methods: Retrospective analysis of maternal and neonatal outcome in a cohort of pregnant MG patients treated at a tertiary care centre in Germany. Results: Overall, 66 pregnancies were analysed. During 40 (63%) pregnancies, women experienced a worsening of myasthenic symptoms, of whom 10 patients (15.7%) needed acute therapy with IVIg or plasma exchange. There was no case of myasthenic crisis. Rate of caesarean section was comparable to the overall C-section rate at our centre (38% vs. 40%). However, there was a slightly higher rate for operative vaginal delivery (15% vs. 10%) as potential indicator for fatiguing striated musculature in MG patients during the expulsion stage. Rate of TNMG as well as AMC was 3% (two cases each). Conclusions: Maternal and neonatal outcome in our cohort was favourable with a low rate of myasthenic exacerbations requiring acute therapies and a low rate of TNMG and AMC/FARAD. Our data might help neurologists and obstetricians to advice MG patients with desire to have children

Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

Background Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. Main body The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Conclusion Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.info:eu-repo/semantics/publishedVersio

The burden of disease in seronegative myasthenia gravis: a patient-centered perspective

ObjectiveMyasthenia gravis (MG) is an autoimmune disorder primarily caused by autoantibodies against the acetylcholine receptor (AChR). Approximately 15% of MG patients, categorized as seronegative (snMG), lack detectable antibodies. Due to the snMG status, there may be a diagnostic delay. Moreover, there are limited data on treatment response in comparison to AChR-Ab+ patients. This study examines the burden of disease, treatment response, and quality of life of snMG patients in comparison to AChR-ab+ MG patients and healthy controls.MethodsA questionnaire-based survey was conducted collecting sociodemographic and clinical data including antibody status, therapy, treatment response, and self-rated disease severity along with standardized assessments such as MG-ADL (activities of daily living) and the Short Form Health (SF-36, generic Health-Related Quality of Life, HRQoL). HRQoL was evaluated through matched-pairs analyses. Participants from a general health survey served as the control group. Negative binomial regression was applied to evaluate the impact of antibody status on MG-ADL.ResultsCompared to AChR-ab+ patients, snMG patients (n = 237) were younger at symptom onset [median age 42 (IQR 30.5/53) vs. 51 (31/64) years, p < 0.001] and had longer diagnostic delays. Complete stable remission was less frequent in snMG patients (15.9% vs. 27.8%, p < 0.001), and they reported higher disease severity (52.8% medium, 9.5% severe vs. 41.9% medium, 8.5% severe, p = 0.005). snMG patients had higher MG-ADL scores [median 5 (IQR 2/9) vs. 3 (1/6), p < 0.001] and more employment restrictions (64.4% vs. 49.3%, p < 0.001). Furthermore, compared to healthy controls, snMG patients showed worse outcomes in all domains of the SF-36.ConclusionThe burden of disease in snMG patients is higher compared to AChR-ab+ MG due to delay in diagnosis, worse treatment response, and sociodemographic factors. These findings highlight the challenges patients and treating physicians face in snMG. There is a high need for earlier diagnosis, improved diagnostic tools, and inclusion of snMG patients in clinical trials to address their unique therapeutic challenges.Clinical Trial Registrationclinicaltrials.gov, identifier NCT03979521. Registered 7 June 2019 (retrospectively registered)

The splicing-factor related protein SFPQ/PSF interacts with RAD51D and is necessary for homology-directed repair and sister chromatid cohesion

DNA double-stranded breaks (DSBs) are among the most severe forms of DNA damage and responsible for chromosomal translocations that may lead to gene fusions. The RAD51 family plays an integral role in preserving genome stability by homology directed repair of DSBs. From a proteomics screen, we recently identified SFPQ/PSF as an interacting partner with the RAD51 paralogs, RAD51D, RAD51C and XRCC2. Initially discovered as a potential RNA splicing factor, SFPQ was later shown to have homologous recombination and non-homologous end joining related activities and also to bind and modulate the function of RAD51. Here, we demonstrate that SFPQ interacts directly with RAD51D and that deficiency of both proteins confers a severe loss of cell viability, indicating a synthetic lethal relationship. Surprisingly, deficiency of SFPQ alone also leads to sister chromatid cohesion defects and chromosome instability. In addition, SFPQ was demonstrated to mediate homology directed DNA repair and DNA damage response resulting from DNA crosslinking agents, alkylating agents and camptothecin. Taken together, these data indicate that SFPQ association with the RAD51 protein complex is essential for homologous recombination repair of DNA damage and maintaining genome integrity

Lifelong leukocyte telomere dynamics and survival in a free-living mammal

Telomeres play a fundamental role in the maintenance of genomic integrity at a cellular level, and average leukocyte telomere length (LTL) has been proposed as a biomarker of organismal aging. However, studies tracking LTL across the entire life course of individuals are lacking. Here, we examined lifelong patterns of variation in LTL among four birth cohorts of female Soay sheep (Ovis aries) that were longitudinally monitored and sampled from birth to death. Over the first 4 months of life, there was within‐individual loss of LTL, consistent with findings in the human and primate literature, but there was little evidence of consistent LTL loss associated with age after this point. Overall, we observed only weak evidence of individual consistency in LTL across years and over the entire lifespan: Within‐individual variation was considerable, and birth cohorts differed markedly in their telomere dynamics. Despite the high levels of LTL variation within the lifetimes of individuals, there remained significant associations between LTL and longevity. Detailed analysis of the longitudinal data set showed that this association was driven by improved survival of individuals with longer LTL over the first 2 years of life. There was no evidence that LTL predicted survival in later adulthood. Our data provide the first evidence from a mammal that LTL can predict mortality and lifespan under natural conditions, and also highlight the potentially dynamic nature of LTL within the lifetimes of individuals experiencing a complex and highly variable environment