Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome.

We have previously shown that the paired-box transcription factors Pax1 and Pax9 synergistically act in the proper formation of the vertebral column. Nevertheless, downstream events of the Pax1/Pax9 action and their target genes remain to be elucidated. We show, by analyzing Pax1;Pax9 double mutant mice, that expression of Bapx1 in the sclerotome requires the presence of Pax1 and Pax9, in a gene dose-dependent manner. By using a retroviral system to overexpress Pax1 in chick presomitic mesoderm explants, we show that Pax1 can substitute for Shh in inducing Bapx1 expression and in initiating chondrogenic differentiation. Furthermore, we demonstrate that Pax1 and Pax9 can transactivate regulatory sequences in the Bapx1 promoter and that they physically interact with the Bapx1 promoter region. These results strongly suggest that Bapx1 is a direct target of Pax1 and Pax9. Together, we conclude that Pax1 and Pax9 are required and sufficient for the chondrogenic differentiation of sclerotomal cells

Dynamic cumulative activity of transcription factors as a mechanism of quantitative gene regulation

By combining information on the yeast transcription network and high-resolution time-series data with a series of factors, support is provided for the concept that dynamic cumulative regulation is a major principle of quantitative transcriptional control

Embryonic development of selectively vulnerable neurons in Parkinson’s disease

A specific set of brainstem nuclei are susceptible to degeneration in Parkinson’s disease. We hypothesise that neuronal vulnerability reflects shared phenotypic characteristics that confer selective vulnerability to degeneration. Neuronal phenotypic specification is mainly the cumulative result of a transcriptional regulatory program that is active during the development. By manual curation of the developmental biology literature, we comprehensively reconstructed an anatomically resolved cellular developmental lineage for the adult neurons in five brainstem regions that are selectively vulnerable to degeneration in prodromal or early Parkinson’s disease. We synthesised the literature on transcription factors that are required to be active, or required to be inactive, in the development of each of these five brainstem regions, and at least two differentially vulnerable nuclei within each region. Certain transcription factors, e.g., Ascl1 and Lmx1b, seem to be required for specification of many brainstem regions that are susceptible to degeneration in early Parkinson’s disease. Some transcription factors can even distinguish between differentially vulnerable nuclei within the same brain region, e.g., Pitx3 is required for specification of the substantia nigra pars compacta, but not the ventral tegmental area. We do not suggest that Parkinson’s disease is a developmental disorder. In contrast, we consider identification of shared developmental trajectories as part of a broader effort to identify the molecular mechanisms that underlie the phenotypic features that are shared by selectively vulnerable neurons. Systematic in vivo assessment of fate determining transcription factors should be completed for all neuronal populations vulnerable to degeneration in early Parkinson’s disease

A roadmap towards personalized immunology.

Big data generation and computational processing will enable medicine to evolve from a "one-size-fits-all" approach to precise patient stratification and treatment. Significant achievements using "Omics" data have been made especially in personalized oncology. However, immune cells relative to tumor cells show a much higher degree of complexity in heterogeneity, dynamics, memory-capability, plasticity and "social" interactions. There is still a long way ahead on translating our capability to identify potentially targetable personalized biomarkers into effective personalized therapy in immune-centralized diseases. Here, we discuss the recent advances and successful applications in "Omics" data utilization and network analysis on patients' samples of clinical trials and studies, as well as the major challenges and strategies towards personalized stratification and treatment for infectious or non-communicable inflammatory diseases such as autoimmune diseases or allergies. We provide a roadmap and highlight experimental, clinical, computational analysis, data management, ethical and regulatory issues to accelerate the implementation of personalized immunology

Connecting environmental exposure and neurodegeneration using cheminformatics and high resolution mass spectrometry: potential and challenges

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary approach. Rapid developments in analytical and data technologies, such as non-target high resolution mass spectrometry (NT-HR-MS), have opened up new possibilities to accomplish this, inconceivable 20 years ago. While NT-HR-MS is being applied to increasingly complex research questions, there are still many unidentified chemicals and uncertainties in linking exposures to human health outcomes and environmental impacts. In this perspective, we explore the possibilities and challenges involved in using cheminformatics and NT-HR-MS to answer complex questions that cross many scientific disciplines, taking the identification of potential (small molecule) neurotoxicants in environmental or biological matrices as a case study. We explore capturing literature knowledge and patient exposure information in a form amenable to high-throughput data mining, and the related cheminformatic challenges. We then briefly cover which sample matrices are available, which method(s) could potentially be used to detect these chemicals in various matrices and what remains beyond the reach of NT-HR-MS. We touch on the potential for biological validation systems to contribute to mechanistic understanding of observations and explore which sampling and data archiving strategies may be required to form an accurate, sustained picture of small molecule signatures on extensive cohorts of patients with chronic neurodegenerative disorders. Finally, we reflect on how NT-HR-MS can support unravelling the contribution of the environment to complex diseases

Large-scale validation of miRNAs by disease association, evolutionary conservation and pathway activity.

The validation of microRNAs (miRNAs) identified by next generation sequencing involves amplification-free and hybridization-based detection of transcripts as criteria for confirming valid miRNAs. Since respective validation is frequently not performed, miRNA repositories likely still contain a substantial fraction of false positive candidates while true miRNAs are not stored in the repositories yet. Especially if downstream analyses are performed with these candidates (e.g. target or pathway prediction), the results may be misleading. In the present study, we evaluated 558 mature miRNAs from miRBase and 1,709 miRNA candidates from next generation sequencing experiments by amplification-free hybridization and investigated their distributions in patients with various disease conditions. Notably, the most significant miRNAs in diseases are often not contained in the miRBase. However, these candidates are evolutionary highly conserved. From the expression patterns, target gene and pathway analyses and evolutionary conservation analyses, we were able to shed light on the complexity of miRNAs in humans. Our data also highlight that a more thorough validation of miRNAs identified by next generation sequencing is required. The results are available in miRCarta ( https://mircarta.cs.uni-saarland.de )

DJ-1 depletion slows down immunoaging in T-cell compartments

Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7 /DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly delayed immunoaging in both human and mice. Compared with two gender-matched unaffected sibling carriers of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled frequencies of non-senescent T cells. The observation of a ‘younger’ immune system in the index patient was further consolidated by the results in aged DJ-1 knockout mice. Our data from bone marrow chimera models and adoptive transfer experiments demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases

PENGARUH TEKANAN KETAATAN DAN KOMPLEKSITAS TUGAS TERHADAP AUDIT JUDGMENT (Survey Terhadap Lima Kantor AkuntanPublik di Kota Bandung)

ABSTRAK Seperti yang kita ketahui bahwa seorang auditor dalam melakukan tugasnya membuat audit judgment dipengaruhi banyak faktor, baik bersifat teknis dan non teknis. Salah satu faktor non teknis adalah aspek perilaku individual. Aspek perilaku individu, sebagai salah satu faktor yang banyak mempengaruhi pembuatan audit judgment. Pada penelitian ini ada beberapa faktor yang mempengaruhi audit judgment yaitu tekanan ketaatan dan kompleksitas tugas. Dalam penelitian ini penullis ingin mengetahui sejauh mana “tekanan ketaatan dan kompleksitas tugas terhadap audit judgment”. Sedangkan tujuan dari penelitian ini adalah untuk mengetahui dan mempelajari tekanan ketaatan dan kompleksitas tugas terhadap audit judgment. Hipotesis yang diuji dalam penelitian ini adalah “ jika tekanan ketaatan dan kompleksitas tugas baik, maka audit judgment akan meningkat ( baik pula)”. Hipotesis ini berdasarkan asumsi bahwa tekanan ketaatan dan kompleksitas tugas berpengaruh terhadap audit judgment.dalam penelitian ini penulis menggunakan metode deskriptif asosiatif dengan pendekatan survey dan tes statistik. Penelitian ini terdiri dari atas variabel X1 dan X2 dan audit judgment sebagai veriabel Y atau variabel independen. Uji statistik dilakukan dengan mengolah data dari hasil jawaban kuesioner. Dalam penelitian ini, peulis menyebarkan angket kepada 5 Kantor Akuntan Publik di Kota Bandung khusunya untuk para auditor. Pengumpulan data dilakukan dengan cara penyebaran kuesioner yang telah diuji validitasnya dan reabilitasnya. Penelitian ini dilakukan di 5 KAP di Kota Bandung. Pengambilan sampel ini menggunakan purposive sampling berukuran 28 orang responden. Untuk uji hipotesis penelitian, penulis melakukannya dengan uji t untuk masing-masing variabel X1,X2, dan Y. Dari hasil uji tHitung tekanan ketaatan terhadap audit judgment tHitung =4,178>ttabel = 1.705 kompleksitas tugas terhadap audit judgment 5 tHitung = 3.364 > ttabel = 1,705. Maka, dari hasil uji hipotesis tersebut penulis menyimpulkan bahwa hipotesis penelitian diterima (Ho ditolak, Ha diterima) artinya terdapat pengaruh antara terkanan ketaatan terhadap audit judgment dan kompleksitas tugas terhadap audit judgment Untuk mencari besarnya pengaruh Tekanan ketaatan dan Kompleksitas Tugas terhadap Audit Judgment secara simultan penulis melakukannya dengan uji f dengan koefisien determinasi (KD). Dari hasil uji fhitung dan > f table yaitu 16,182>3,370. Kata kunci : Tekanan Ketaatan dan Kompleksitas tugas Terhadap Audit Judgmen