Cryo-EM structures of tau filaments from Alzheimer's disease

Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases

Is missing maxillary lateral incisor in complete cleft lip and palate a product of genetics or local environment?

Objective: To test the null hypothesis: Subjects with isolated complete unilateral cleft lip and palate (UCLP) show no differences in overall frequency of tooth agenesis (hypodontia), comparing a subsample with cleft-side maxillary lateral incisor (MxI2) agenesis to a subsample without cleftside MxI2 agenesis. Findings could clarify the origins of cleft-side MxI2 agenesis. Materials and Methods: Tooth agenesis was identified from dental radiographs of 141 subjects with UCLP. The UCLP cohort was segregated into four categories according to the status and location of MxI2 in the region of the unilateral cleft: group M: subjects with one tooth, located on the mesial side of the alveolar cleft; group D: subjects with one tooth, located on the distal side of the alveolar cleft; group MD: subjects with two teeth present, one mesial and one distal to the cleft; and group ABS: subjects with lateral incisor absent (agenesis) in the cleft area. Results: The null hypothesis was rejected. Among UCLP subjects, there was a twofold increase (P < .0008) in overall frequency of tooth agenesis outside the cleft region in a subsample with cleftside MxI2 agenesis (ABS), compared to a subsample presenting with no agenesis of the cleft-side MxI2 (M+D+MD). Conclusions: Cleft-side MxI2 agenesis in CLP subjects appears to be largely a genetically controlled anomaly associated with cleft development, rather than a collateral environmental consequence of the adjacent cleft defect, since increased hypodontia involving multiple missing teeth observed remote from a cleft clearly has a significant genetic basis. (Angle Orthod. 2012;82:959-963.

Structures of filaments from Pick's disease reveal a novel tau protein fold

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain-three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer's disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254-Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer's disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick's disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer's disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers

Predictive factors for pressure ulcers in the ambulatory stage of spinal cord injury patients

Study Design: Case control study. Objective: To determine the main risk factors for pressure ulcer (PU) in ambulatory spinal cord injury (SCI) patients. Setting: Hospital del Trabajador, Santiago, (ACHS (Chilean Security Association), Chile. Methods: We studied 41 patients for traumatic SCI, from Santiago, Chile, cared for in our hospital. The clinical histories were reviewed from first discharge to 1996. The patients were categorized into two groups: 18 cases with a previous history of PU, and 23 patients with no history of PU were considered as controls. Univariate analysis was performed, 18 variables per case, 10 of which were psychosocial factors. Results: There were 37 men and four women. Average age was 41.7 years. Duration of SCI on average was 6.7 years. The distribution was complete paraplegia (CPP) 22 patients (54%), complete tetraplegia three patients (7%), incomplete paraplegia 11 patients (27%) and incomplete tetraplegia, five patients (12%). Four variables of the univariate analysis were significant: duration of cord injury (SCI time) >5 years, completeness of cord injury, paraplegia and not able to practice regular standing. There was a significant association in body morphology (endo or ectomorphic), being able to practice regular standing and personality disorder in CPP. Conclusions: The risk for developing PU was 4.3 times greater in CPP patients than is any other type of SCI. CPP patients who do not practice standing periodically, who have a personality disorder and have an ecto/endomorphic corporal morphology have a greater risk of suffering PU

Superimposition of maxillary digital models using the palatal rugae: Does ageing affect the reliability?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150535/1/ocr12309.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150535/2/ocr12309_am.pd