Protein Folding Database (PFD 2.0): an online environment for the International Foldeomics Consortium

The Protein Folding Database (PFD) is a publicly accessible repository of thermodynamic and kinetic protein folding data. Here we describe the first major revision of this work, featuring extensive restructuring that conforms to standards set out by the recently formed International Foldeomics Consortium. The database now adopts standards for data acquisition, analysis and reporting proposed by the consortium, which will facilitate the comparison of folding rates, energies and structure across diverse sets of proteins. Data can now be easily deposited using a rich set of deposition tools. Enhanced search tools allow sophisticated searching and graphical data analysis affords simple data analysis online. PFD can be accessed freely at

Ferritin Levels in the Cerebrospinal Fluid Predict Alzheimer\u27s Disease Outcomes and Are Regulated by APOE

Brain iron elevation is implicated in Alzheimer\u27s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer\u27s risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD

A blood-based predictor for neocortical Aβ burden in Alzheimer\u27s disease: results from the AIBL study

Dementia is a global epidemic with Alzheimer’s disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aβ (extracellular β-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aβ accumulation, therefore, providing a platform for developing a population-based scree

Identification of leukocyte surface P2X7 as a biomarker associated with Alzheimer\u27s disease

Alzheimer\u27s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ -ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline

Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE.

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD

Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE

Brain iron elevation is implicated in Alzheimer’s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer’s risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD

REKONSEPTUALISASI HAK KONSTITUSIONAL CALON PERSEORANGAN MENUJU PEMERINTAHAN DAERAH YANG EFEKTIF

Penelitian disertasi ini dilatar belakangi oleh kecenderungan adanya diskriminasi dan ketidakadilan dalam regulasi calon perseorangan dan adanya kekhawatiran adanya implikasi negatif terhadap calon perseorangan dalam penyelenggaraan pemerintahan di daerah apabila calon perseorangan memenangkan dalam pemilukada. Oleh karena itu permasalahan dalam penelitian ini adalah mengapa terjadi pergeseran pola pengisian jabatan kepala daerah/wakil kepala daerah; mengapa regulasi calon perseorangan saat ini cenderung diskriminatif dan tidak adil, serta implikasinya dalam penyelenggaraan pemerintahan di daerah; dan bagaimana konsep baru hak calon perseorangan. Paradigma penelitian yang digunakan adalah legal constructivisme, dengan pendekatan penelitian hermeneutik. Penelitian ini merupakan penelitian socio-legal, sehingga jenis data yang digunakan meliputi data primer yang diperoleh melalui wawancara dan observasi dan data sekunder yang diperoleh melalui studi dokumen. Data yang diperoleh dianalisis dengan menggabungkan logika induktif (data primer) dan logika deduktif (data sekunder) atau yang disebut abduksi. Adapun teknik pengecekan keabsahan data akan dipakai teknik triangulasi data. Hasil penelitian menunjukkan, bahwa (1) Pergeseran pola pengisian jabatan kepala daerah/wakil kepala daerah terjadi karena perubahan paradigma hak dalam pemilihan kepala daerah/wakil kepala daerah, bahwa hak itu tidak terbagi habis oleh parpol tetapi memberikan hak kepada perseorangan untuk ikut dalam pemilihan kepala daerah/wakil kepala daerah, sehingga calon perseorangan diperbolehkan; (2)a. Beberapa bentuk diskriminasi dan ketidakadilan dalam regulasi calon perseorangan yakni terdapat dalam sanksi bagi calon perseorangan yang mengundurkan diri dan syarat dukungan. Faktor penyebabnya ialah adanya penyimpangan pada saat pembentukan peraturan dan penyimpangan terhadap makna calon perseorangan oleh pembentuk undang-undang; (2)b. Terpilihnya kepala daerah yang berasal dari calon perseorangan ternyata memiliki implikasi yang positif dalam penyelenggaraan pemerintahan di daerah ; (3) Konsep baru tentang hak konstitusional calon perseorangan, bahwa hak itu diberikan harus berbasis pada nilai keadilan, tidak diskriminatif dan jangan sampai menutup kembali hak yang telah diberikan, serta diberikannya kewenangan pada pemerintah pusat untuk menyelesaikan konflik dalam relasi antara kepala daerah dan DPRD. Implikasi secara teoretik bahwa diperbolehkannya calon perseorangan karena adanya pergeseran paradigma hak dalam pemilihan kepala daerah/wakil kepala daerah dan implikasi secara praktis bahwa perlunya amandemen regulasi calon perseorangan dengan berbasis pada nilai keadilan dan tidak diskriminatif, serta diberikannya kewenangan pada pemerintah pusat untuk menyelesaikan konflik dalam relasi antara kepala daerah dan DPRD. Kata Kunci : Rekonseptualisasi, Hak Konstitusional, Calon Perseorangan. Background of this dissertation research is tendency of discrimination and injustice of regulation on individual candidate and negative implication to individual candidate in the management of local government if individual candidate elected in local election (pemilukada). The problems of this research is why happened friction of admission filling pattern of chief and deputy of local government; why recent regulation on individual candidate tends to discriminative and unjust, and its implication in the management of local government; and how to make new concep of individual candidate rights. Research paradigm applied is legal of constructivism, with hermeneutic reaserch-approach. This is a socio-legal research, so that data type applied covers primary data obtained through interview and observation, and secondary data obtained through documentary study. Data obtained will be analyzed by joint inductive logic (primary data) and deductive logic (secondary data) or abduksi. Triangulation of data will be used as a technique of checking data validity. The research result shows, that (1) already happened change of rights paradigm that the rights not divided pot by political party but the rights gives individual candidate rights to be a nominator in local election as a chief of local government; (2)a. Some discrimination form and unjustice in regulation individual of nomination who is resign and support promise. The cause of tendency of discrimination and injustice is deviation at the time of regulation making and negative perception of regulation maker on individual candidate; (2)b. The eligible head of a district whose come from individual candidate has positive implication in the management of local government; (3) New concept about constitutional rights individual candidate, that the right it to be given must base of justice value, undiscriminative and don’t be close again which already to be given, and necessary to be given authority to the central goverment to resolve every conflict in the relationship and the regional head of parliement thet could impact on goverment instability in the region. Implication on as teoretic that to be permitted the individual candidate cause it was like paradigm rubbing rights in election head/deputy of a district and implication as practical that necessary regulation of amandement individual candidate with base of justice value and undescriminative and to be given authority to the central goverment to resolve every conflict in the relationship and the regional head of parliement thet could impact on goverment instability in the region. Keyword: Reconceptualisation, Constitutional rights, individual candidate