Detection and Analysis of Protein Aggregation with Confocal Single Molecule Fluorescence Spectroscopy

The misfolding and aggregation of proteins is a common phenomenon both in the cell, in in vitro protein refolding, and the corresponding biotechnological applications. Most importantly, it is involved in a wide range of diseases, including some of the most prevalent neurodegenerative disorders. However, the range of methods available to analyze this highly heterogeneous process and the resulting aggregate structures has been very limited. Here we present an approach that uses confocal single molecule detection of FRET-labeled samples employing four detection channels to obtain information about diffusivity, anisotropy, fluorescence lifetimes and Förster transfer efficiencies from a single measurement. By combining these observables, this method allows the separation of subpopulations of folded and misfolded proteins in solution with high sensitivity and a differentiation of aggregates generated under different conditions. We demonstrate the versatility of the method with experiments on rhodanese, an aggregation-prone two-domain protei

Controlled generation of a pn-junction in a waveguide integrated graphene photodetector

With its electrically tunable light absorption and ultrafast photoresponse, graphene is a promising candidate for high-speed chip-integrated photonics. The generation mechanisms of photosignals in graphene photodetectors have been studied extensively in the past years. However, the knowledge about efficient light conversion at graphene pn-junctions has not yet been translated into high-performance devices. Here, we present a graphene photodetector integrated on a silicon slot-waveguide, acting as a dual-gate to create a pn-junction in the optical absorption region of the device. While at zero bias the photo-thermoelectric effect is the dominant conversion process, an additional photoconductive contribution is identified in a biased configuration. Extrinsic responsivities of 35 mA/W, or 3.5 V/W, at zero bias and 76 mA/W at 300 mV bias voltage are achieved. The device exhibits a 3 dB-bandwidth of 65 GHz, which is the highest value reported for a graphene-based photodetector.Comment: 19 pages, 16 figure

A compositional framework for energy management of a smart grid: A scalable stochastic hybrid model for cooling of a district network

The goal of this paper is to introduce a compositional modeling framework for the energy management of a smart grid that operates connected to the main grid. The focus is on the cooling of a district network composed of multiple buildings that possibly share resources such as storages, chillers, combined heat and power units, and renewable power generators. We adopt a modular perspective where components are described in terms of energy fluxes and interact by exchanging energy. Model dimension and complexity depend on the number and type of components that are present in the specific configuration. Energy management problems like the minimization of the electrical energy cost or the tracking of some electrical energy profile can be addressed in the proposed framework via different control strategies and architectures

Pilot evaluation of a perfused robot-assisted partial nephrectomy procedural simulation platform for single port robotic retroperitoneal approaches

Objective: In this study our objective was to develop a simulation platform for use cases in Laparoendoscopic Single Site (LESS) Surgery intended for patient-specific rehearsal prior to Robot-assisted Partial nephrectomy procedures. Patients and Surgical Procedure: This represents a simulation platform requiring no patients, although the fabrication process allows for the platform to be patient-specific. Tissue phantom 3D models were developed from de-identified CT imaging fulfilling the criteria of tumors located in the posterior lower pole of the kidney. Results: Respondents completed surveys on platform novelty and effectiveness. Agreement on simulator novelty was unanimously positive (100% agree or better). Performance evaluations reached a minimum of 80% agreement for all categories, with zero respondents. Conclusions: We have developed a highly realistic simulation platform for use in single-port robot-assisted partial nephrectomy that can be produced in a patient specific manner, which we believe will be highly useful for trainees as well as experts attempting to transfer skills to the newer platform

Look-ahead cyclic pitch control using LIDAR

LIDAR (Light detection and ranging) systems are able to provide preview information of wind disturbances at various distances in front of wind turbines. This information can be used to improve the control of wind turbines. This paper compares a predictive feedforward control structure combined with common PI controllers to a baseline controller and to an H∞ approach showing the advantage of look-ahead control to reduce wind turbine loads. The control design is verified by simulations with a turbulent wind field and a full nonlinear model of the wind turbine

To Participate and Elect: Section 2 of the Voting Rights Act at 40

This paper provides an overview of cases decided under Section 2 of the Voting Rights Act between September 1, 1982 and December 31, 2021. It updates our 2006 study documenting Section 2 litigation through 2005. Of note is the substantial decline in the number of Section 2 cases decided and diminished success for the plaintiffs who bring them. While recent litigation (including Brnovich and Merrill v. Milligan) suggests that Section 2 is likely to occupy, at best, a diminished role in future electoral disputes, this paper shows that Section 2’s reach had already declined significantly prior to recent disputes. It documents a steep drop in the number of Section 2 decisions involving vote dilution. So too, while plaintiffs bringing dilution claims found notable success in the first decade after Congress amended Section 2 in 1982, they have seen a steady decline in success ever since. Meanwhile, plaintiffs bringing Section 2 non-dilution claims—i.e., alternatively labelled “vote denial” or “time, place and manner” restrictions—have seen less success overall, and, as with dilution claims, a steady decline in success over time. The Report and underlying dataset can be found at www.voting.law.umich.ed

The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects