Apoptotic effect of bortezomib on pancreatic islet cells in STZ-induced diabetic rats

This study aimed to investigate the possible apoptotic role of bortezomib (BMZ) on pancreatic islets of streptozotocin (STZ)-induced diabetic rats.Methods: Sprague-Dawley rats were divided into groups that were administered BMZ alone or in combination with STZ. To evaluate the effect of BMZ on the development of diabetes, blood glucose levels were measured regularly in the animals. Islet cell viability was determined by staining the islets with fluorescein diacetate and propidium iodide. Expression of the Bcl-2 and bax genes was determined in islet cells by quantitative real-time polymerase chain reaction.Results: Administering STZ-induced hyperglycemia in the rats reduced the viability of islet cells and the bcl-2/bax ratio. In the group administered BMZ alone, the bcl-2/bax gene expression rate in islets increased significantly compared to the control group. BMZ co-administered with STZ significantly increased islet cell viability and the bcl-2/bax ratio compared to the diabetic group.Conclusions: This study demonstrates that BMZ may protect pancreatic islet cells from apoptosis by increasing islet viability and upregulating the bcl-2/bax gene expression ratio, even though it failed to protect against the destructive effect of STZ

Human inbreeding has decreased in time through the Holocene

The history of human inbreeding is controversial. In particular, how the development of sedentary and/or agricultural societies may have influenced overall inbreeding levels is unclear. Here we present an approach for reliable estimation of runs of homozygosity (ROH) in genomes with ≥3x mean sequence coverage across >1 million SNPs, and apply this to 411 ancient Eurasian genomes from the last 15,000 years. We show that the frequency of inbreeding, as measured by ROH, has decreased over time. The strongest effect is associated with the Neolithic transition, but the trend has since continued, indicating a population size effect on inbreeding prevalence. We further show that most inbreeding in our historical sample can be attributed to small population size instead of consanguinity. We observed singular cases of high consanguinity only among members of farming societies

A genomic snapshot of demographic and cultural dynamism in Upper Mesopotamia during the Neolithic Transition

Upper Mesopotamia played a key role in the Neolithic Transition in Southwest Asia through marked innovations in symbolism, technology, and foodways. We present thirteen ancient genomes (c.8500-7500 calBCE) from Pre-Pottery Neolithic Çayönü in the Tigris basin together with bioarchaeological and material culture data. Our findings reveal that Çayönü was a genetically diverse population, carrying a mixed ancestry from western and eastern Fertile Crescent, and that the community received immigrants. Our results further suggest that the community was organised along biological family lines. We document bodily interventions such as head-shaping and cauterization among the individuals examined, reflecting Çayönü's cultural ingenuity. Finally, we identify Upper Mesopotamia as the likely source of eastern gene flow into Neolithic Anatolia, in line with material culture evidence. We hypothesise that Upper Mesopotamia's cultural dynamism during the Neolithic Transition was the product not only of its fertile lands but also of its interregional demographic connections

Archaeogenetic analysis of Neolithic sheep from Anatolia suggests a complex demographic history since domestication

Yurtman, ozer, Yuncu et al. provide an ancient DNA data set to demonstrate the impact of human activity on the demographic history of domestic sheep. The authors demonstrate that there may have been multiple domestication events with notable changes to the gene pool of European and Anatolian sheep since the Neolithic. Sheep were among the first domesticated animals, but their demographic history is little understood. Here we analyzed nuclear polymorphism and mitochondrial data (mtDNA) from ancient central and west Anatolian sheep dating from Epipaleolithic to late Neolithic, comparatively with modern-day breeds and central Asian Neolithic/Bronze Age sheep (OBI). Analyzing ancient nuclear data, we found that Anatolian Neolithic sheep (ANS) are genetically closest to present-day European breeds relative to Asian breeds, a conclusion supported by mtDNA haplogroup frequencies. In contrast, OBI showed higher genetic affinity to present-day Asian breeds. These results suggest that the east-west genetic structure observed in present-day breeds had already emerged by 6000 BCE, hinting at multiple sheep domestication episodes or early wild introgression in southwest Asia. Furthermore, we found that ANS are genetically distinct from all modern breeds. Our results suggest that European and Anatolian domestic sheep gene pools have been strongly remolded since the Neolithic

The in vivo ınvestigation of the usage of proteasome inhibitor bortezomib in type 1 diabetes treatment

Tip 1 Diyabet, pankreasın langerhans adacıklarına inflamatuar hücrelerin infiltrasyonu ve sonrasında insülin salgılayan β hücrelerinin kaybı ile karakterize edilen otoimmün bir hastalıktır. İn vitro ve in vivo olarak yapılmış birçok çalışma, IL-1β, TNF-α ve IFN-γ gibi proinflamatuar sitokinlerin neden olduğu β hücre ölümünde Nüklear Faktör Kappa-B (NF-κB) sinyal yolağının rol aldığını göstermiştir. NF-κB'nin hücre büyümesi, hücre canlılığı, apoptozis ve inflamasyon gibi önemli biyolojik işlemlerde rol alan birçok genin ifadesini düzenleyen bir transkripsiyonel faktör olduğu bilinmektedir. Bu tez çalışmasının amacı, günümüzde multiple myeloma tedavisinde kullanılan ve klinikteki etkinliği NF-kB inhibisyonuna bağlı olan proteozom inhibitörü bortezomib´in, tip 1 diyabetin tedavisinde kullanılabilirliğini in vivo koşullarda araştırmaktır. Bunun için dişi Sprague Dawley cinsi rat bulunan beş farklı çalışma grubu (n=5-7) oluşturuldu. Bunlar, kontrol grubu, diyabet grubu (grup II), bortezomib verilen grup (grup III), STZ ve bortezomibin eş zamanlı verildiği grup (grup IV) ve STZ sonrası diyabetik olduğu doğrulanan ratlara bortezomib verilen tedavi grubudur (grup V). Bortezomib klinikte kullanıldığı şekilde 3 gün ara ile toplamda üç (0, 3, ve 7, gün) doz uygulanmıştır. İlaç uygulaması sonrası 24 saat kültüre edilmiş tüm adacıklarda hücre canlılığı, fluoresans mikroskopta saptanmıştır. Sonrasında kültür ortamından alınan adacıklardan RNA izolasyonu ve cDNA sentezi yapılarak apoptotik genlerden bcl-2, bax ve kaspaz 3 genlerinin ifade düzeyleri real time RT-PCR yöntemi kullanılarak araştırılmıştır. Bu tez çalışması sonucunda, STZ'nin pankreasın insülin salgılayan beta hücrelerinde apoptozise neden olduğu kan şekerlerindeki artış, adacıkların % canlılıklarındaki azalma ve apoptotik genlerin ifade düzeylerine bakılarak doğrulandı (bax/bcl-2=3.14 /1.99). Tek başına uygulanan bortezomib dozunun pankreasın β hücrelerinde sitotoksik olmadığı (%91) kontrol grubuna göre değişiklik göstermemesi ile saptandı. Bu grupta ayrıca apoptotik gen ifade düzeylerine (bax/bcl-2=0.83/1.69) bakıldığında Bor'in antiapoptotik etkiye neden olduğu gözlendi. STZ ve Bor'in eş zamanlı uygulandığı grup IV de, STZ uygulaması ile kan şekeri düzeyleri artmasına karşın, Bor'in β hücrelerinde anti-apoptotik etkiye sahip olduğu bax/bcl-2 (3.84/4.68) oranına bakılarak saptandı. STZ sonrası Bor verilen grup V'de Bor'in hem kan şekeri hem de adacık sayısı açısından bir iyileşmeye neden olmadığı apoptotik gen ifade düzeylerine bakıldığında (bax/bcl-2=4.45/3.30) proapoptotik etki gözlendi. Sonuç olarak, adacıkları tamamen harap olmamış diyabetik ratlarda Bor'in NF-kB sinyal yolağını bloke ederek hücrelerin apoptozise girmesini engelleyebileceği sonucuna varılmıştır.Tip 1 diabet is a otoimmüne disease that is characterizied as the infiltration of inflamatuar cells to pancreas langerhans islets and destruction of the insulin secreting β cells. The leukocytes, which is infiltrated to inner parts of islet, secrete proinflamatuar cytokines like IL-β, TNF-α and IFN-γ that causes death of the β cells. In most studies both in vitro and in vivo, it is showed that Nuclear Factor Kappa-B (NF-κB) pathway has a role in β cell death that is triggered by those cytokines. The objective of this these is investigate usability of bortezomib, a Proteozome inhibitor, whose effectiveness in clinical practise depends on NF-kB inhibition and which is nowadays used in treatment of multiple myeloma, in treatment of Type-1 Diabetes Mellitus in vivo. For this purpose, female Sprague Dawley rats which were not obese were comprised. These were the control group, the diabetes group for which streptozotocin (STZ) was injected (Group II), the group for which bortezomib was administered (Group III), the group for which STZ and bortezomib were administered simultaneously (Group IV) and the treatment group in which bortezomib was administered to the rats which were confirmed to be diabetic following STZ administration (Group V). Bortezomib was administered totally as three (0th, 3rd and 7th days) with 3-day interval, as it is used in clinical practice. Following drug administration, all islets which were cultured for 24 hours, cell viability was determined under fluorescence microscopy. In conclusion of this study, the fact that STZ causes apoptozis in insulin-secreting beta cells of pancreas was confirmed by increase in blood glucose levels, decrease in viability of islets and investigation of expression levels of apoptotic genes (bax/bcl-2=3.14 /1.99). The fact that bortezomib dosage that was administered alone was not cytotoxic for β cells (91%) did not demonstrate any alteration compared to the control group. When apoptotic gene expression levels were investigated in this group, it was determined that Bortezomib had anti-apoptotic effect. In group IV, in which STZ and BOR were administered simultaneously, although blood glucose increased with administration of STZ, the fact that Bortezomib had anti-apoptotic effect on β cells was determined by evaluating bax/bcl-2 (3.84/4.68) ratio. In group V, in which Bortezomib was administered following STZ, it was determined that there was no improvement in terms of neither blood glucose nor number of islets. In group V, when apoptotic gene expression levels were investigated (bax/bcl-2=4.45/3.30), as is in the Group II, it pro-apoptotic effect was determined. In conclusion, it was concluded that in diabetic rats whose islets were not completely destructed, Bortezomib may prevent cells to undergo apoptozis by inhibiting NF-kB signalling pathway

Zihinsel engelli çocuklara hayat bilgisi kavramlarının öğretiminde akıllı oyuncaklar.

In Turkey and all around the world, technology-supported learning environments for children with intellectual disability (ID) have not yet reached to a desired point and there are limited studies that investigate the effectiveness of advanced technologies in teaching social studies concepts to children with ID. For this purpose, the current study aims to investigate the effectiveness of smart toys in teaching social studies concepts to children with ID. The mentioned smart toys/technology enhanced learning environments were developed in the scope of this study. A multi-method research design was used to determine whether this study has a positive effect on teaching social studies concepts to children with ID. In addition, children’motivation were analyzed together with the usability of (effective, efficient and satisfactory) the technology from teachers’ point of view. Six individuals with IDs and four special education teachers formed the participants of the study.To be eligible for participation, individuals were expected to meet some requirements such as the ability to follow simple verbal instructions. Semi structured interviews were conducted with special education teachers to understand their opinions about the smart toy. Four kinds of data were collected, namely effectiveness, reliability, social validity, and usability. According to the results of the analysis of effectiveness data, smart toys have a positive effect in teaching social studies concepts to children with ID.Also, interview results revealed that, smart toys increased student motivation, and that smart toy technology developed in this study was effective, efficient, and satisfactory. Ph.D. - Doctoral Progra