Molecular and circuit analysis of stable contrast processing in the visual system

Visual perception gives us a reliable estimate of the world throughout the day, thanks to the computations implemented in visual circuits. In a given space or time, the relative change in luminance, contrast, forms the basis for many downstream computations like the detection of edges, shape, orientation and motion. Stable contrast estimation is challenged by the immensely changing lightning conditions that can slowly change throughout the day or much more rapidly when viewing natural scenes. To ensure reliable behavioral responses to the same (contrast) stimulus, visual systems face the monumental task of keeping contrast representations stable. Gain mechanisms operate across the nervous system to match neural responses to relevant stimulus distribution. In visual systems, photoreceptors have numerous mechanisms that implement sensory gain to keep contrast representations stable across the slow changes of luminance occurring throughout the day. However, major changes in luminance also occur at fast timescales due to the luminance distributions within natural scenes which we view or through which we navigate. The extend of photoreceptor gain is often insufficient in these conditions but vision can still operate luminance-invariantly as shown in human perception, neurons in the vertebrate cortex, lateral geniculate nucleus and the retina. This highlights the necessity of post-receptor luminance gain mechanisms and evidence from a few studies suggests that this happens in the retina. However, a detailed understanding of the underlying circuitry, including the contribution of different cell types, their specialization and the molecular mechanisms underlying the post-receptor gain, is not understood in any visual system. A recent study from Drosophila melanogaster showed that fly behavior to stimuli containing contrast decrements (OFF stimuli) is also luminance-invariant in rapidly changing conditions (Ketkar et al. 2020). Two second order neurons located in the lamina and post-synaptic to photoreceptors, L2 and L3, contribute to the OFF behavior by encoding contrast and luminance respectively. L3 neurons underlie the luminance-invariant behavior by providing a rapid luminance gain to the OFF pathway (Ketkar et al. 2020). This opened up the possibility of investigating post-receptor gain using the advanced fly genetic arsenal. In the first part of this thesis, we asked if the ON pathway also utilizes a post-receptor gain and which second-order neurons support this. The fly ON pathway was thought to receive major inputs only from a single second-order neuron type, L1 neurons, instead of the contrast and luminance sensitive parallel pathways formed by L2 and L3 within the OFF pathway. Using calcium imaging and behavioral paradigms, we revealed that all lamina neurons encode distinct features of the visual scenery and distribute these to both ON and OFF pathways showing that ON and OFF pathways only arise downstream of the lamina neurons. ON behavior also requires a luminance gain and this is provided by both L1 as well as L3 inputs. For the rapid luminance gain, L1 and L3 provide distinct contributions since their luminance encoding differ. Thus, a combination of temporal filtering leading to distinct contrast-luminance specializations in the second-order visual neurons is vital for downstream stable contrast processing. The bipolar cells, the second-order visual neurons of the vertebrate retina, also form parallel temporal channels suggesting that these specializations can serve distinct behavioral roles like in the fly visual system. In the second study, I investigated the molecular factors shaping the distinct feature encoding properties of the lamina cell-types. Biophysical properties of neurons that are largely shaped by ion channel expression underlie a significant fraction of their signal processing properties. Using RNA-seq data and endogenous protein tagging, I have identified a specific subtype of voltage gated potassium channels, the Ka channels Shaker and Shal, as being highly expressed in the contrast sensitive L2 neurons. Using pharmacological manipulations, I have revealed the circuit wide role of Ka channels in enhancing L2 contrast responses. Additionally using cell-type specific RNAi, I have shown that Ka channels are involved in sharpening the L2 contrast responses. Similarities in the other fly species suggest the conserved role of Ka channels in shaping distinct cell-types and conferring their computational role within visual circuits for contrast processing. In the third study I investigated visual circuits of the OFF pathway that implement the rapid luminance gain. I characterized the contrast encoding properties of all major celltypes in the OFF circuitry and identified the dendrites of two distinct third-order medulla neurons as the location where the rapid luminance gain arises. Using the specific features provided by the lamina neurons, the medulla neurons Tm1 and Tm9 implement a rapid luminance gain which scale their representations of contrast in distinct ways. Whereas Tm1 neurons reach luminance-invariant estimations of contrast, Tm9 neurons boost contrast signals in low luminances. Spatial pooling underlies the luminance gain in both neurons and both neurons receive wide glutamatergic signals yet use distinct molecular mechanisms to the implement luminance gain. Genetic analysis shows that Tm9 relies on inhibition mediated by GluClα channels whereas the molecular basis for luminanceinvariance in Tm1 remains yet to be identified. This study reveals the details of how visual systems implement a gain mechanisms vital for stable vision in natural scenes. A post-receptor gain acting specifically in dim light in vertebrates is also implemented in the third-order neurons suggesting the presence of convergent strategies for stable vision. Testing if distinct luminance gain channels exist in vertebrates and whether similar spatial and molecular properties underlie the luminance gain can reveal if convergent strategies are implemented for natural scene processing across species. My initial studies added to the numerous examples of convergent and divergent processing happening within neural circuits. One outcome of such complex wiring of neural circuits is that specific synaptic connections made between distinct synaptic partners, can contribute to information processing differently. To get a detailed causal understanding of specific cell-type to cell-type connections, manipulations restricted to specific synapses are necessary. However current manipulations maximally achieve specificity that affects all presynapses of one cell-type and thus limit the level of detail at which can understand neural circuit function. In my final study, we are developing a genetic tool, Synapse Targeted Activity Block (STAB), to manipulate synaptic connections between distinct partners. STAB is based on two components each expressed in one of the partners and only activates when these components coincide, which happens in the synaptic connections. One component is a viral protease (TEV protease - TEVp) which cleaves a conditionally integrated cleavage site (TEV cleavage site - TEVcs) in an endogenous synaptic protein which constitutes the second component. We generated TEVp fusion proteins that localize to synaptic regions and function extracellularly both in vitro and in vivo. Concentrating on the transsynaptic cleavage of postsynaptic receptors that are known to be essential for visual circuit function, in vitro experiments suggested that TEVp cleavage leads to degradation of post-synaptic receptor GluClα containing a TEVcs but the levels of degradation was not enough to recapitulate LOF phenotypes in vivo. We generated an optimized TEVp version which showed higher levels of GluClα degradation. STAB with the enhanced TEVp needs to be validated in vivo before applying it for investigating specific synaptic connections. STAB is the first example of synapse specific manipulations that opens up a door of highly specific investigations of neural circuits and get detailed causal insights on neural circuits, computations and behavior. Overall, my work thus combined the molecular and circuit analysis of stable contrast computation in dynamically changing environments. The development of the genetic STAB tool will allow circuit analysis at higher resolution than possible to date, and can be applied to studying visual computations, as well as any other type of circuit level analysis.2023-07-1

INTEREST RATES, FISHER EFFECT AND ECONOMIC DEVELOPMENT IN TURKEY, 1989-2011

This paper investigates the validity of the Fisher Hypothesis in Turkey coveringthe period 2003 – 2012. To test validity of Fisher Hypothesis, this paper uses anAutoregressive Distributed Lag test for threshold cointegration recently introduced in theliterature by Li and Lee (2010). The empirical results which are obtained from this paperindicate that Fisher hypothesis is valid for Turkey, meaning nominal interest rates wouldbe an important leading indicator for inflation

Government expenditures and economic growth in developing countries: Evidence from a panel data analysis

This paper re-estimates the two-sector growth model of Ram (1986), “Government Size and Economic Growth: A New Framework and Some Evidence from Cross-Section and Time-Series Data”, American Economic Review, 7(1), 191-203, by employing panel data techniques and using a more recent data set for thirtyfour developing countries. The estimation results confirm the cross-sectional findings of Ram: Government size is positively associated with the economic growth and economic performance of developing countries. The total effect of government size on economic growth is positive and quite large. In addition, the marginal externality effect of government size on non-government output is positive. Another finding of the study is that the country effects estimated for the models of Ram are positive for most of the Asian countries in the sample and negative for most of the Latin American and African countries.Publisher's Versio

ZIRHLI ARAÇ İMALATINDA KULLANILAN 5000 SERİSİ ALÜMİNYUM ALAŞIMLARIN ARK KAYNAĞINDA SÜRTÜNME KARIŞTIRMA YÖNTEMİ KULLANILARAK YORULMA DAYANCI İYİLEŞTİRME

ZIRHLI ARAÇ İMALATINDA KULLANILAN 5000 SERİSİ ALÜMİNYUM ALAŞIMLARIN ARK KAYNAĞINDA SÜRTÜNME KARIŞTIRMA YÖNTEMİ KULLANILARAK YORULMA DAYANCI İYİLEŞTİRM

Effect of microstructural modification on damage tolerance of 34CrMo4 shaft steel

Overall damage tolerances of the heat-treated 34CrMo4 steels having ferritic-pearlitic, bainitic, and tempered-martensitic microstructures were evaluated based on their threshold stress intensity factor prior to small crack propagation, fatigue strength, and fracture toughness under static loading. Kitagawa-Takahashi diagrams were constructed to determine the limiting size of small crack propagation. The micromechanical effects of carbide morphology and phase distribution on quasi-static and dynamic mechanical properties were also elaborated. Fractographic investigations were carried out on the notched fatigue test specimens to distinguish deterioration and deformation mechanism of the microstructure under reversed cyclic loads. Finally, improvements in the damage tolerance were discussed to present the advantages and disadvantages of each heat treatment procedure to minimize in-service fatigue failures

Molecular dynamics simulations provide molecular insights into the role of HLA-B51 in Behcet's disease pathogenesis

Behcet's disease is an inflammatory disorder of unknown etiology. Genetic tendency has an important role in its pathogenesis, and HLA-B51, a class I MHC antigen, has been recognized as the strongest susceptibility factor for Behcet's disease. Despite the confirmation of the association of HLA-B51 with Behcet's disease in different populations, its pathogenic mechanisms remain elusive. HLA-B51 differs in only two amino acids from HLA-B52, other split antigen of HLA-B5, which is not associated with Behcet's disease. These two amino acids are located in the B pocket of the antigen-binding groove, which occupies the second amino acids of the bound peptides. To understand the nature of the HLA-peptide interactions, differences in structure and dynamics of two HLA alleles were investigated by molecular dynamics simulations using YAYDGKDYI, LPRSTVINI, and IPYQDLPHL peptides. For HLA-B51, all bound peptides fluctuated to larger extent than HLA-B52. Free energy profiles of unbinding process for YAYDGKDYI by steered molecular dynamics simulations showed that unbinding from HLA-B52 results in greater free energy differences than HLA-B51. These results suggest the possibility of an instability of HLA-B51 associated with the repertoire of peptides, and this finding may provide significant insight to its pathogenic role in Behcet's disease

Vehbi Koç ve Ankara Araştırmaları Merkezi

Ankara : İhsan Doğramacı Bilkent Üniversitesi İktisadi, İdari ve Sosyal Bilimler Fakültesi, Tarih Bölümü, 2014.This work is a student project of the The Department of History, Faculty of Economics, Administrative and Social Sciences, İhsan Doğramacı Bilkent University.by Ünsal, Mehmet Süha

The study of the somatotypes of the Turkish National Rafting Team

Aim: In the study, it was aimed to determine the somatotype characteristics of the male athletes of the Turkish National Rafting Team. 8 male rafting athletes from the Turkish National Rafting Team voluntarily participated in the study during the national team camp in Rize before 2015 World Rafting Champs-Indonesia. Material and Methods: The age, height, weight, skinfold thickness, circumference, and width measurements of the athletes participated in the study were taken at the Performance Lab of Physical Education and Sports Academy, Karadeniz Technical University. Heath-Carter method was used to determine their somatotypes. The statistical analyses of the measurements were carried out by using SPSS 13. Results: The mean values of the participant male rafting athletes of the Turkish National Rafting Team (n=8) were found as follows; mean age 21 years old; mean height 175.68±3.32 cm; mean body weight 76.00±7.96kg. The mean values of the somatotype components of the athletes were found as endomorphy 2.23±0.88, mesomorphy 5.04±0.91, ectomorphy 1.92±0.94. Although there are various studies on determining somatotype characteristics in Sports Science, those related to rafting are limited in number. Conclusion: We are of the opinion that our study, in addition to determining the somatotype characteristics of the male rafting athletes of the Turkish National Rafting Team, will also contribute to the studies carried out in this field

Behiç Erkin ve TCDD tarihi

Ankara : İhsan Doğramacı Bilkent Üniversitesi İktisadi, İdari ve Sosyal Bilimler Fakültesi, Tarih Bölümü, 2013.This work is a student project of the The Department of History, Faculty of Economics, Administrative and Social Sciences, İhsan Doğramacı Bilkent University.by Melike Ünal.Ünal, Melike. HIST 200-17ÜNAL HIST 200-17/8 2012-1