Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification ...of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer's Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.
Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's remarkable antitumor efficacy in ...preclinical models has yet to be replicated in humans. Early clinical trials in the mid-1990's showed that systemic delivery of IL-12 incurred dose-limiting toxicities. Nevertheless, IL-12's pleiotropic activity, i.e., its ability to engage multiple effector mechanisms and reverse tumor-induced immunosuppression, continues to entice cancer researchers. The development of strategies which maximize IL-12 delivery to the tumor microenvironment while minimizing systemic exposure are of increasing interest. Diverse IL-12 delivery systems, from immunocytokine fusions to polymeric nanoparticles, have demonstrated robust antitumor immunity with reduced adverse events in preclinical studies. Several localized IL-12 delivery approaches have recently reached the clinical stage with several more at the precipice of translation. Taken together, localized delivery systems are supporting an IL-12 renaissance which may finally allow this potent cytokine to fulfill its considerable clinical potential. This review begins with a brief historical account of cytokine monotherapies and describes how IL-12 went from promising new cure to ostracized black sheep following multiple on-study deaths. The bulk of this comprehensive review focuses on developments in diverse localized delivery strategies for IL-12-based cancer immunotherapies. Advantages and limitations of different delivery technologies are highlighted. Finally, perspectives on how IL-12-based immunotherapies may be utilized for widespread clinical application in the very near future are offered.
Photoemission spectroscopy is central to understanding the inner workings of condensed matter, from simple metals and semiconductors to complex materials such as Mott insulators and superconductors
. ...Most state-of-the-art knowledge about such solids stems from spectroscopic investigations, and use of subfemtosecond light pulses can provide a time-domain perspective. For example, attosecond (10
seconds) metrology allows electron wave packet creation, transport and scattering to be followed on atomic length scales and on attosecond timescales
. However, previous studies could not disclose the duration of these processes, because the arrival time of the photons was not known with attosecond precision. Here we show that this main source of ambiguity can be overcome by introducing the atomic chronoscope method, which references all measured timings to the moment of light-pulse arrival and therefore provides absolute timing of the processes under scrutiny. Our proof-of-principle experiment reveals that photoemission from the tungsten conduction band can proceed faster than previously anticipated. By contrast, the duration of electron emanation from core states is correctly described by semiclassical modelling. These findings highlight the necessity of treating the origin, initial excitation and transport of electrons in advanced modelling of the attosecond response of solids, and our absolute data provide a benchmark. Starting from a robustly characterized surface, we then extend attosecond spectroscopy towards isolating the emission properties of atomic adsorbates on surfaces and demonstrate that these act as photoemitters with instantaneous response. We also find that the tungsten core-electron timing remains unchanged by the adsorption of less than one monolayer of dielectric atoms, providing a starting point for the exploration of excitation and charge migration in technologically and biologically relevant adsorbate systems.
Microsatellites have been popular molecular markers ever since their advent in the late eighties. Despite growing competition from new genotyping and sequencing techniques, the use of these versatile ...and cost‐effective markers continues to increase, boosted by successive technical advances. First, methods for multiplexing PCR have considerably improved over the last years, thereby decreasing genotyping costs and increasing throughput. Second, next‐generation sequencing technologies allow the identification of large numbers of microsatellite loci at reduced cost in non‐model species. As a consequence, more stringent selection of loci is possible, thereby further enhancing multiplex quality and efficiency. However, current practices are lagging behind. By surveying recently published population genetic studies relying on simple sequence repeats, we show that more than half of the studies lack appropriate quality controls and do not make use of multiplex PCR. To make the most of the latest technical developments, we outline the need for a well‐established strategy including standardized high‐throughput bench protocols and specific bioinformatic tools, from primer design to allele calling.
Overexpression of membrane proteins is often essential for structural and functional studies, but yields are frequently too low. An understanding of the physiological response to overexpression is ...needed to improve such yields. Therefore, we analyzed the consequences of overexpression of three different membrane proteins (YidC, YedZ, and LepI) fused to green fluorescent protein (GFP) in the bacterium Escherichia coli and compared this with overexpression of a soluble protein, GST-GFP. Proteomes of total lysates, purified aggregates, and cytoplasmic membranes were analyzed by one- and two-dimensional gel electrophoresis and mass spectrometry complemented with flow cytometry, microscopy, Western blotting, and pulse labeling experiments. Composition and accumulation levels of protein complexes in the cytoplasmic membrane were analyzed with improved two-dimensional blue native PAGE. Overexpression of the three membrane proteins, but not soluble GST-GFP, resulted in accumulation of cytoplasmic aggregates containing the overexpressed proteins, chaperones (DnaK/J and GroEL/S), and soluble proteases (HslUV and ClpXP) as well as many precursors of periplasmic and outer membrane proteins. This was consistent with lowered accumulation levels of secreted proteins in the three membrane protein overexpressors and is likely to be a direct consequence of saturation of the cytoplasmic membrane protein translocation machinery. Importantly accumulation levels of respiratory chain complexes in the cytoplasmic membrane were strongly reduced. Induction of the acetate-phosphotransacetylase pathway for ATP production and a down-regulated tricarboxylic acid cycle indicated the activation of the Arc two-component system, which mediates adaptive responses to changing respiratory states. This study provides a basis for designing rational strategies to improve yields of membrane protein overexpression in E. coli.
Many applications require diagnostics that can quantify the distribution of chemical gas species and gas temperature along a single line-of-sight, which is challenging in process environments with ...limited optical access. To this end, we present an approach that combines time-of-flight Light Detection and Ranging (LiDAR) with Tunable Diode Laser Absorption Spectroscopy (TDLAS) to scan individual gas molecular transition lines. This method is applicable in situations where scattering objects are distributed along the beam path, such as solid fuel combustion, or when dealing with multiple gas volumes separated by weakly reflecting windows. The approach is demonstrated through simulation studies and an initial experimental proof of concept for separated gas volumes.
The flat-spectrum radio quasar CTA 102 (redshift 1.037) exhibited a tremendously bright four-month-long outburst from late 2016 to early 2017. In a previous paper, we interpreted the event as the ...ablation of a gas cloud by the relativistic jet. The multiwavelength data have been reproduced very well within this model using a leptonic emission scenario. Here we expand that work by using a hadronic scenario, which gives us greater freedom with respect to the location of the emission region within the jet. This is important, since the inferred gas cloud parameters depend on the distance from the black hole. While the hadronic model faces the problem of invoking super-Eddington jet luminosities, it reproduces well the long-term trend and also days-long subflares. While the latter result in inferred cloud parameters that match those expected for clouds of the broad-line region, the long-term trend is not compatible with such an interpretation. We explore the possibilities that the cloud is from the atmosphere of a red giant star or comes from a star-forming region that passes through the jet. The latter could also explain the much longer-lasting activity phase of CTA 102 from late 2015 until early 2018.
Geographic atrophy (GA) is a vision-threatening manifestation of age-related macular degeneration (AMD), one of the leading causes of blindness globally. Objective, rapid, reliable, and scalable ...quantification of GA from optical coherence tomography (OCT) retinal scans is necessary for disease monitoring, prognostic research, and clinical endpoints for therapy development. Such automatically quantified biomarkers on OCT are likely to further elucidate structure-function correlation in GA and thus the pathophysiological mechanisms of disease development and progression. In this work, we aimed to predict visual function with machine-learning applied to automatically acquired quantitative imaging biomarkers in GA. A post-hoc analysis of data from a clinical trial and routine clinical care was conducted. A deep-learning automated segmentation model was applied on OCT scans from 476 eyes (325 patients) with GA. A separate machine learning prediction model (Random Forest) used the resultant quantitative OCT (qOCT) biomarkers to predict cross-sectional visual acuity under standard (VA) and low luminance (LLVA). The primary outcome was regression coefficient (r
) and mean absolute error (MAE) for cross-sectional VA and LLVA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters. OCT parameters were predictive of VA (r
0.40 MAE 11.7 ETDRS letters) and LLVA (r
0.25 MAE 12.1). Normalised random forest feature importance, as a measure of the predictive value of the three constituent features of GA; retinal pigment epithelium (RPE)-loss, photoreceptor degeneration (PDR), hypertransmission and their locations, was reported both on voxel-level heatmaps and ETDRS-grid subfields. The foveal region (46.5%) and RPE-loss (31.1%) had greatest predictive importance for VA. For LLVA, however, non-foveal regions (74.5%) and PDR (38.9%) were most important. In conclusion, automated qOCT biomarkers demonstrate predictive significance for VA and LLVA in GA. LLVA is itself predictive of GA progression, implying that the predictive qOCT biomarkers provided by our model are also prognostic.
In late 2016 and early 2017, the flat spectrum radio quasar CTA 102 exhibited a very strong and long-lasting outburst. The event can be described by a roughly two-month long increase of the baseline ...flux in the monitored energy bands (optical to γ-rays) by a factor 8, and a subsequent decrease over another two months back to pre-flare levels. The long-term trend was superseded by short but very strong flares, resulting in a peak flux that was a factor 50 above pre-flare levels in the γ-ray domain and almost a factor 100 above pre-flare levels in the optical domain. In this paper, we explain the long-term evolution of the outburst by the ablation of a gas cloud penetrating the relativistic jet. The slice-by-slice ablation results in a gradual increase of the particle injection until the center of the cloud is reached, after which the injected number of particles decreases again. With reasonable cloud parameters, we obtain excellent fits of the long-term trend.
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