A study of walkability in Surabaya urban park utilizing the space syntax

The urban parks are open spaces that accommodate people to do various activities. One of the most popular activities is walking. Human experience essentially leads pedestrians to have specific spatial dimensions and configurations in a park. Space syntax exists as a tool to explore the characteristics of the spatial configuration and the influence of the visitors on their activities through their perceptions. Space syntax has been widely applied in urban and human movement studies, despite rarely applied within the scope of urban parks. This study aims to address the debate and offers a new technique in applying the space syntax method. This research employed quantitative methods in interpreting the concept of Walkability and evaluated the design of urban parks by spatial exploration. The result determined the scope of research within the park, the configurational relationships between spaces as well as the visual connection and continuity of the human line of sight. This principle was developed and illustrated based on the three urban parks in Surabaya.

Structural dissection of sequence recognition and catalytic mechanism of human LINE-1 endonuclease

Long interspersed nuclear element-1 (L1) is an autonomous non-LTR retrotransposon comprising ∼20% of the human genome. L1 self-propagation causes genomic instability and is strongly associated with aging, cancer and other diseases. The endonuclease domain of L1’s ORFp2 protein (L1-EN) initiates de novo L1 integration by nicking the consensus sequence 5′-TTTTT/AA-3′. In contrast, related nucleases including structurally conserved apurinic/apyrimidinic endonuclease 1 (APE1) are non-sequence specific. To investigate mechanisms underlying sequence recognition and catalysis by L1-EN, we solved crystal structures of L1-EN complexed with DNA substrates. This showed that conformational properties of the preferred sequence drive L1-EN’s sequence-specificity and catalysis. Unlike APE1, L1-EN does not bend the DNA helix, but rather causes ‘compression’ near the cleavage site. This provides multiple advantages for L1-EN’s role in retrotransposition including facilitating use of the nicked poly-T DNA strand as a primer for reverse transcription. We also observed two alternative conformations of the scissile bond phosphate, which allowed us to model distinct conformations for a nucleophilic attack and a transition state that are likely applicable to the entire family of nucleases. This work adds to our mechanistic understanding of L1-EN and related nucleases and should facilitate development of L1-EN inhibitors as potential anticancer and antiaging therapeutics.

A line through the brain: implementation of human line-scanning at 7T for ultra-high spatiotemporal resolution fMRI

Functional magnetic resonance imaging (fMRI) is a widely used tool in neuroscience to detect neurally evoked responses, e.g. the blood oxygenation level-dependent (BOLD) signal. Typically, BOLD fMRI has millimeter spatial resolution and temporal resolution of one to few seconds. To study the sub-millimeter structures and activity of the cortical gray matter, the field needs an fMRI method with high spatial and temporal resolution. Line-scanning fMRI achieves very high spatial resolution and high sampling rate, at the cost of a sacrifice in volume coverage. Here, we present a human line-scanning implementation on a 7T MRI system. First, we investigate the quality of the saturation pulses that suppress MR signal outside the line. Second, we established the best coil combination for reconstruction. Finally, we applied the line-scanning method in the occipital lobe during a visual stimulation task, showing BOLD responses along cortical depth, every 250 µm with a 200 ms repetition time (TR). We found a good correspondence of t-statistics values with 2D gradient-echo echo planar imaging (GE-EPI) BOLD fMRI data with the same temporal resolution and voxel volume (R = 0.6 ± 0.2). In summary, we demonstrate the feasibility of line-scanning in humans and this opens line-scanning fMRI for applications in cognitive and clinical neuroscience.

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition.

CYTOTOXIC EFFECT OF NEWLY SYNTHESIZED NANOMATERIALS FOR POTENTIAL DENTAL APPLICATION

Introduction: Biocompatibility is an essential feature of any dental material. Few materials can be said to be biologically inert since most contain potentially harmful or irritating ingredients. This study aimed to determine the cytocompatibility of newly synthesized nanomaterials based on calcium aluminates and calcium silicates for potential dental applications. Material and methods: The cytotoxicity of calcium aluminate-based nanomaterials (ALBO-CA), calcium silicate (ALBO-CS) and calcium silicate hydroxyapatite (ALBO-CSHA) was examined using the MTT test on the human line of human fibroblasts (MRC-5) according to ISO standard (ISO 10993- 5: 2009) in comparison with the calcium aluminate cements EndoBinder (Binder was, São Carlos, SP, Brazil). For the analysis, the eluates of the investigated materials in the growth medium were diluted to a concentration of 4.7, 9.4, 18.8, 37.5 and 75, 0 mg. Qualitative verification of results was performed by a light microscope (Carl Zeiss). The mean values and standard deviations of the MTT test results were done in Microsoft Excel. Results: All tested concentrations of ALBO-CA, ALBO-CS, and EndoBinder resulted in a high survival of cells in culture. The strongest cytotoxic effect was ALBO-CSHA with IC50 = 46.44 after the first cycle of testing; IC50 = 55.52 after the second cycle; or IC50 = 55.42 after the third repetition of the MTT test. Conclusion: ALBO-CA and ALBO-CS nanomaterials have shown a cytocompatible effect comparable to EndoBinder. The obtained results are certainly encouraged to continue researching these materials in the future and other experimental and clinical studies.

Human TRIM5α senses and restricts LINE-1 elements

Mobile genetic elements have significantly shaped our genomic landscape. LINE-1 retroelements are the only autonomously active elements left in the human genome. Since new insertions can have detrimental consequences, cells need to efficiently control LINE-1 retrotransposition. Here, we demonstrate that the intrinsic immune factor TRIM5α senses and restricts LINE-1 retroelements. Previously, rhesus TRIM5α has been shown to efficiently block HIV-1 replication, while human TRIM5α was found to be less active. Surprisingly, we found that both human and rhesus TRIM5α efficiently repress human LINE-1 retrotransposition. TRIM5α interacts with LINE-1 ribonucleoprotein complexes in the cytoplasm, which is essential for restriction. In line with its postulated role as pattern recognition receptor, we show that TRIM5α also induces innate immune signaling upon interaction with LINE-1 ribonucleoprotein complexes. The signaling events activate the transcription factors AP-1 and NF-κB, leading to the down-regulation of LINE-1 promoter activity. Together, our findings identify LINE-1 as important target of human TRIM5α, which restricts and senses LINE-1 via two distinct mechanisms. Our results corroborate TRIM5α as pattern recognition receptor and shed light on its previously undescribed activity against mobile genetic elements, such as LINE-1, to protect the integrity of our genome.

The Female Line in the Bible. Ratzinger’s Deepening of the Church’s Understanding of Tradition and Mary

This paper explores the female line in the Bible that Joseph Ratzinger identifies as running in parallel to, and being indispensable for, the male line in the Bible. This female line expands the understanding of Salvation History as described by Dei Verbum so that it runs not just from Adam through to Jesus, but also from Adam and Eve to Mary and Jesus, the final Adam. Ratzinger’s female line demonstrates that women are at the heart of God’s plan for humanity. I illustrate that this line is evident when Ratzinger’s method of biblical interpretation is applied to the women of Scripture. Its full potential comes into view through Ratzinger’s development of the Christian notion of person: Person as revealed by Jesus Christ is relatedness without reserve with God and is fully applicable to the human being through Christ. I argue that together, the male and female lines in the Bible form the human line in the Bible, in which the male line represents “the humanity”, every human being, while the female line represents the communal aspect of humanity. Moreover, I contend that Christianity’s notion of mother in relation to God (as Father, Son and Holy Spirit) should be understood through Mary’s response at the Annunciation. Mother in relation to God is to be understood through the Incarnation when Mary, as person, lived her life wholly in relation with and for God.

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

ABSTRACTNearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We found that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data uncover a new role for let-7, one of the most relevant microRNAs, which is to maintain somatic genome integrity by restricting L1 retrotransposition.

Lung genotoxicity of benzo(a)pyrene in vivo involves reactivation of LINE-1 retrotransposon and early reprogramming of oncogenic regulatory networks

Several lines of evidence have implicated long interspersed nuclear element-1 (LINE-1) retroelement in the onset and progression of lung cancer. Retrotransposition-dependent mechanisms leading to DNA mobilization give rise to insertion mutations and DNA deletions, whereas retrotransposition-independent mechanisms disrupt epithelial programming and differentiation. Previous work by our group established that tobacco carcinogens such as benzo(a)pyrene (BaP) reactivate LINE-1 in bronchial epithelial cells through displacement of nucleosome remodeling and deacetylase (NuRD) corepressor complexes and interference with retinoblastoma-regulated epigenetic signaling. Whether LINE-1 in coordination with other genes within its regulatory network contributes to the in vivo genotoxic response to BaP remains largely unknown. Evidence is presented here that intratracheal instillation of ORFeusLSL mice with BaP alone or in combination with adenovirus (adeno)-CRE recombinase is genotoxic to the lung and associated with activation of the human LINE-1 transgene present in these mice. LINE-1 reactivation modulated the expression of genes involved in oncogenic signaling, and these responses were most pronounced in female mice compared with males and synergized by adeno-CRE recombinase. This is the first report linking LINE-1 and genes within its oncogenic regulatory network with early sexually dimorphic responses of the lung in vivo.