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Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer’s disease (AD) has facilitated advancement of the amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc box-dependent-interacting protein 1, clusterin, and presenilin-1 . U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein. Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.

Background Detergent-insoluble protein accumulation and aggregation in the brain is one of the pathological hallmarks of neurodegenerative diseases. Here, we describe the identification of septin 11 (SEPT11), an enriched component of detergent-resistant fractions in frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (FTLD-U), using large-scale unbiased proteomics approaches. Results We developed and applied orthogonal quantitative proteomic strategies for the unbiased identification of disease-associated proteins in FTLD-U. Using these approaches, we proteomically profiled detergent-insoluble protein extracts prepared from frontal cortex of FTLD-U cases, unaffected controls, or neurologic controls (i.e. Alzheimer's disease; AD). Among the proteins altered specifically in FTLD-U, we identified TAR DNA binding protein-43 (TDP-43), a known component of ubiquitinated inclusions. Moreover, we identified additional proteins enriched in detergent-resistant fractions in FTLD-U, and characterized one of them, SEPT11, in detail. Using independent highly sensitive targeted proteomics approaches, we confirmed the enrichment of SEPT11 in FTLD-U extracts. We further showed that SEPT11 is proteolytically cleaved into N-terminal fragments and, in addition to its prominent glial localization in normal brain, accumulates in thread-like pathology in affected cortex of FTLD-U patients. Conclusions The proteomic discovery of insoluble SEPT11 accumulation in FTLD-U, along with novel pathological associations, highlights a role for this cytoskeleton-associated protein in the pathogenesis of this complex disorder.

The Huntington disease (HD) phenotype is associated with expansion of a trinucleotide repeat in the IT15 gene, which is predicted to encode a 348-kDa protein named huntingtin. We used polyclonal and monoclonal anti-fusion protein antibodies to identify native huntingtin in rat, monkey, and human. Western blots revealed a protein with the expected molecular weight which is present in the soluble fraction of rat and monkey brain tissues and lymphoblastoid cell lines from control cases. In lymphoblastoid cell lines from juvenile-onset heterozygote HD cases, both normal and mutant huntingtin are expressed, and increasing repeat expansion leads to lower levels of the mutant protein. Immunocytochemistry indicates that huntingtin is located in neurons throughout the brain, with the highest levels evident in larger neurons. In the human striatum, huntingtin is enriched in a patch-like distribution, potentially corresponding to the first areas affected in HD. Subcellular localization of huntingtin is consistent with a cytosolic protein primarily found in somatodendritic regions. Huntingtin appears to particularly associate with microtubules, although some is also associated with synaptic vesicles. On the basis of the localization of huntingtin in association with microtubules, we speculate that the mutation impairs the cytoskeletal anchoring or transport of mitochondria, vesicles, or other organelles or molecules.

Reidemeister torison of R[Γ]-complexes associated to certain pairs of ∞-dimensional unitary representations of Γ is dicussed. A qusi-analytical formula for this torison is determined and the resulting extension of the Ray-Singer-Cheeger-Müller Theorem is conjectured.

In this randomized, sham-controlled trial, MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor who had not had a response to medication. Adverse effects of the procedure included sensory deficits and gait disturbances. Essential tremor, the most common movement disorder, 1 is characterized by a distinctive postural and intention tremor typically affecting the hands more than the legs, trunk, head, or voice. 2 , 3 Essential tremor does not shorten life expectancy, but it can affect quality of life, functional activities, mood, and socialization. 4 – 6 Class I evidence exists for propranolol and primidone as first-line medications that reduce tremor by approximately 60% in 50% of patients. 7 – 11 If resistance to medications develops or side effects are unacceptable, neurosurgical intervention is considered, primarily targeting the nucleus ventralis intermedius of the thalamus, a component of tremor circuitry that . . .

No consensus exists on whether preoperative blood transfusions are beneficial in patients with sickle-cell disease. We assessed whether perioperative complication rates would be altered by preoperative transfusion. We did a multicentre, randomised trial. Eligible patients were aged at least 1 year, had haemoglobin SS or Sβ0thalassaemia sickle-cell-disease subtypes, and were scheduled for low-risk or medium-risk operations. Patients were randomly assigned no transfusion or transfusion no more than 10 days before surgery. The primary outcome was the proportion of clinically important complications between randomisation and 30 days after surgery. Analysis was by intention to treat. 67 (96%) of 70 enrolled patients—33 no preoperative transfusion and 34 preoperative transfusion—were assessed. 65 (97%) of 67 patients had the haemoglobin SS subtype and 54 (81%) were scheduled to undergo medium-risk surgery. 13 (39%) of 33 patients in the no-preoperative-transfusion group had clinically important complications, compared with five (15%) in the preoperative-transfusion group (p=0·023). Of these, 10 (30%) and one (3%), respectively, had serious adverse events. The unadjusted odds ratio of clinically important complications was 3·8 (95% CI 1·2–12·2, p=0·027). 10 (91%) of 11 serious adverse events were acute chest syndrome (nine in the no-preoperative-transfusion group and one in the preoperative-transfusion group). Duration of hospital stay and readmission rates did not differ between study groups. Preoperative transfusion was associated with decreased perioperative complications in patients with sickle-cell disease in this trial. This approach could, therefore, be beneficial for patients with the haemoglobin SS subtype who are scheduled to undergo low-risk and medium-risk surgeries. NHS Blood and Transplant.

The crystal structure of a putative metal-chelate-type adenosine triphosphate (ATP)-binding cassette (ABC) transporter encoded by genes HI1470 and HI1471 of Haemophilus influenzae has been solved at 2.4 angstrom resolution. The permeation pathway exhibits an inward-facing conformation, in contrast to the outward-facing state previously observed for the homologous vitamin B₁₂ importer BtuCD. Although the structures of both HI1470/1 and BtuCD have been solved in nucleotide-free states, the pairs of ABC subunits in these two structures differ by a translational shift in the plane of the membrane that coincides with a repositioning of the membrane-spanning subunits. The differences observed between these ABC transporters involve relatively modest rearrangements and may serve as structural models for inward- and outward-facing conformations relevant to the alternating access mechanism of substrate translocation.

A high-resolution crystallographic analysis of the nitrogenase MoFe-protein reveals a previously unrecognized ligand coordinated to six iron atoms in the center of the catalytically essential FeMo-cofactor. The electron density for this ligand is masked in structures with resolutions lower than 1.55 angstroms, owing to Fourier series termination ripples from the surrounding iron and sulfur atoms in the cofactor. The central atom completes an approximate tetrahedral coordination for the six iron atoms, instead of the trigonal coordination proposed on the basis of lower resolution structures. The crystallographic refinement at 1.16 angstrom resolution is consistent with this newly detected component being a light element, most plausibly nitrogen. The presence of a nitrogen atom in the cofactor would have important implications for the mechanism of dinitrogen reduction by nitrogenase.

Complex iron-sulfur metalloclusters form the active sites of the enzymes that catalyze redox transformations of N2, CO, and H2, which are likely components of Earth's primordial atmosphere. Although these centers reflect the organizational principles of simpler iron-sulfur clusters, they exhibit extensive elaborations that confer specific ligand-binding and catalytic properties. These changes were probably achieved through evolutionary processes, including the fusion of small clusters, the addition of new metals, and the development of cluster assembly pathways, driven by selective pressures resulting from changes in the chemical composition of the biosphere.

Adenosine triphosphate (ATP) hydrolysis in the nitrogenase complex controls the cycle of association and dissociation between the electron donor adenosine triphosphatase (ATPase) (Fe-protein) and its target catalytic protein (MoFe-protein), driving the reduction of dinitrogen into ammonia. Crystal structures in different nucleotide states have been determined that identify conformational changes in the nitrogenase complex during ATP turnover. These structures reveal distinct and mutually exclusive interaction sites on the MoFe-protein surface that are selectively populated, depending on the Fe-protein nucleotide state. A consequence of these different docking geometries is that the distance between redox cofactors, a critical determinant of the intermolecular electron transfer rate, is coupled to the nucleotide state. More generally, stabilization of distinct docking geometries by different nucleotide states, as seen for nitrogenase, could enable nucleotide hydrolysis to drive the relative motion of protein partners in molecular motors and other systems.