Structure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.

Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD

Nonlinear Femtosecond Pulse Reshaping in Waveguide Arrays

We observe nonlinear pulse reshaping of femtosecond pulses in a waveguide array due to coupling between waveguides. Amplified pulses from a mode-locked fiber laser are coupled to an AlGaAs core waveguide array structure. The observed power-dependent pulse reshaping agrees with theory, including shortening of the pulse in the central waveguide

Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases.

BACKGROUND: Brain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases. MATERIALS AND METHODS: We compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM. RESULTS: The most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB ( CONCLUSIONS: Our findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM

The structure of Herpesvirus Fusion Glycoprotein B-Bilayer Complex reveals the protein-membrane and lateral protein-protein interaction

Glycoprotein B (gB) is a key component of the complex herpesvirus fusion machinery. We studied membrane interaction of two gB ectodomain forms and present an electron cryotomography structure of the gB-bilayer complex. The two forms differed in presence or absence of the membrane proximal region (MPR) but showed an overall similar trimeric shape. The presence of the MPR impeded interaction with liposomes. In contrast, the MPR-lacking form interacted efficiently with liposomes. Lateral interaction resulted in coat formation on the membranes. The structure revealed that interaction of gB with membranes was mediated by the fusion loops and limited to the outer membrane leaflet. The observed intrinsic propensity of gB to cluster on membranes indicates an additional role of gB in driving the fusion process forward beyond the transient fusion pore opening and subsequently leading to fusion pore expansion

Amicus Brief: Kumho Tire v. Carmichael

This brief addresses the issue of jury performance and jury responses to expert testimony. It reviews and summaries a substantial body of research evidence about jury behavior that has been produced over the past quarter century. The great weight of that evidence challenges the view that jurors abdicate their responsibilities as fact finders when faced with expert evidence or that they are pro-plaintiff, anti-defendant, and anti-business. The Petitioners and amici on behalf of petitioners make a number of overlapping, but empirically unsupported, assertions about jury behavior in response to expert testimony, namely that juries are frequently incapable of critically evaluation expert testimony, are easily confused, give inordinate weight to expert testimony, are awed by science, defer to the opinions of unreliable experts, and, implicitly, that in civil trials juries tilt in favor of plaintiffs and against corporations

Telomere length, antioxidant status and incidence of ischaemic heart disease in type 2 diabetes

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of ischaemic heart disease (IHD). An accelerated process of vascular ageing induced by an increased oxidative stress exposure is suggested as potential pathway accounting for this association. However, no studies have explored the relationship between markers of vascular ageing, measures of oxidative stress and risk of IHD in T2D. OBJECTIVES: To explore the association between plasma antioxidant status, marker of cellular ageing (leukocyte telomere length, LTL) and 10years risk of IHD in patients with T2D. METHODS: Between 2001 and 2002, 489 Caucasians subjects with T2D were enrolled at the diabetic clinic, University College London Hospital. Plasma total anti-oxidant status (TAOS) and LTL were measured by photometric microassay and RT-PCR, respectively. The incidence of IHD over 10years was determined through linkage with the national clinical audit of acute coronary syndrome in UK. RESULTS: At baseline, TAOS was associated with LTL (age adjusted: r=0.106, p=0.024). After 10years, 61 patients developed IHD. Lower TAOS and shorter LTL at baseline predicted an increased IHD risk at follow-up (age adjusted: p=0.033 and p=0.040, respectively). These associations were independent of age, gender, cardiovascular risk factors, circulating levels of CRP and medication differences. CONCLUSIONS: Reduced TAOS and short LTL are interrelated pathways which predict risk of IHD in patients with T2D. Our findings suggest that antioxidant defences are important to maintain telomere integrity, potentially reducing the progression of vascular ageing in patients with T2D

Returns to physician human capital: Evidence from patients randomized to physician teams

Physicians play a major role in determining the cost and quality of healthcare, yet estimates of these effects can be confounded by patient sorting. This paper considers a natural experiment where nearly 30,000 patients were randomly assigned to clinical teams from one of two academic institutions. One institution is among the top medical schools in the U.S., while the other institution is ranked lower in the distribution. Patients treated by the two programs have similar observable characteristics and have access to a single set of facilities and ancillary staff. Those treated by physicians from the higher ranked institution have 10–25% less expensive stays than patients assigned to the lower ranked institution. Health outcomes are not related to the physician team assignment. Cost differences are most pronounced for serious conditions, and they largely stem from diagnostic-testing rates: the lower ranked program tends to order more tests and takes longer to order them