A Novel Neurofilament Light Chain ELISA Validated in Patients with Alzheimer’s Disease,Frontotemporal Dementia,and Subjective Cognitive Decline,and the Evaluation of Candidate Proteins for Immunoassay Calibration

Neurofilament light chain (Nf-L) is a well-known biomarker for axonal damage; however, the corresponding circulating Nf-L analyte in cerebrospinal fluid (CSF) is poorly characterized. We therefore isolated new monoclonal antibodies against synthetic peptides, and these monoclonals were characterized for their specificity on brain-specific intermediate filament proteins. Two highly specific antibodies, ADx206 and ADx209, were analytically validated for CSF applications according to well-established criteria. Interestingly, using three different sources of purified Nf-L proteins, a significant impact on interpolated concentrations was observed. With a lower limit of analytical sensitivity of 100 pg/mL using bovine Nf-L as the calibrator, we were able to quantify the Nf-L analyte in each sample, and these Nf-L concentrations were highly correlated to the Uman diagnostics assay (Spearman rho = 0.97, p < 0.001). In the clinical diagnostic groups, the new Nf-L ELISA could discriminate patients with Alzheimer’s disease (AD, n = 20) from those with frontotemporal lobe dementia (FTD, n = 20) and control samples with subjective cognitive decline (SCD, n = 20). Henceforth, this novel Nf-L ELISA with well-defined specificity and epitopes can be used to enhance our understanding of harmonizing the use of Nf-L as a clinically relevant marker for neurodegeneration in CSF.     

Adaptation of Oxidative Phosphorylation Machinery Compensates for Hepatic Lipotoxicity in Early Stages of MAFLD

Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. We addressed this question using a transgenic mouse model with increased hepatic insulin resistance and DNL due to constitutively active human SREBP-1c. The abundance of ETC complex subunits and components of key metabolic pathways are regulated in the liver of these animals. Further omics approaches combined with functional assays in isolated liver mitochondria and primary hepatocytes revealed that the SREBP-1c-forced fatty liver induced a substrate limitation for oxidative phosphorylation, inducing enhanced complex II activity. The observed increased expression of mitochondrial genes may have indicated a counteraction. In conclusion, a shift of available substrates directed toward activated DNL results in increased electron flows, mainly through complex II, to compensate for the increased energy demand of the cell. The reorganization of key compounds in energy metabolism observed in the SREBP-1c animal model might explain the initial increase in mitochondrial function observed in the early stages of human MAFLD.     

SARS-CoV-2 Infection Dysregulates Cilia and Basal Cell Homeostasis in the Respiratory Epithelium of Hamsters

Similar to many other respiratory viruses, SARS-CoV-2 targets the ciliated cells of the respiratory epithelium and compromises mucociliary clearance, thereby facilitating spread to the lungs and paving the way for secondary infections. A detailed understanding of mechanism involved in ciliary loss and subsequent regeneration is crucial to assess the possible long-term consequences of COVID-19. The aim of this study was to characterize the sequence of histological and ultrastructural changes observed in the ciliated epithelium during and after SARS-CoV-2 infection in the golden Syrian hamster model. We show that acute infection induces a severe, transient loss of cilia, which is, at least in part, caused by cilia internalization. Internalized cilia colocalize with membrane invaginations, facilitating virus entry into the cell. Infection also results in a progressive decline in cells expressing the regulator of ciliogenesis FOXJ1, which persists beyond virus clearance and the termination of inflammatory changes. Ciliary loss triggers the mobilization of p73⁺ and CK14⁺ basal cells, which ceases after regeneration of the cilia. Although ciliation is restored after two weeks despite the lack of FOXJ1, an increased frequency of cilia with ultrastructural alterations indicative of secondary ciliary dyskinesia is observed. In summary, the work provides new insights into SARS-CoV-2 pathogenesis and expands our understanding of virally induced damage to defense mechanisms in the conducting airways.     

Blind decentralized projection receiver for asynchronous CDMA in multipath channels

An asynchronous direct sequence code division multiple access (DS-CDMA) system employing periodic spreading sequences is considered to be operating in a frequency selective channel. The cyclostationary spread signal is received at multiple sensors and/or is sampled multiple times per chip (oversampling), leading to a stationary vector-valued received signal. Hence, such a model represents a very particular multi-input multi-output (MIMO) system with plentiful side information in terms of distinct spreading waveforms for the input signals. Depending upon the finite impulse response (FIR) length of the propagation channel, and the processing gain, the channel of a certain user spans a certain number of symbol periods, thus inducing memory or intersymbol interference (ISI) in the received signal in addition to the multiple-access interference (MAI) contributed by concurrent users. The desired user’s multipath channel estimate is obtained by means of a new blind technique which exploits the spreading sequence of the user and the second-order statistics of the received signal. The blind minimum mean square error-zero forcing (MMSE-ZF) receiver or projection receiver is subsequently obtained. This receiver represents the proper generalization of the anchored MOE receiver [1] to the asynchronous case with delay spread. Classification of linear receivers obtained by various criteria is provided and the MMSE-ZF receiver is shown to be obtainable in a decentralized fashion by proper implementation of the unbiased minimum output energy (MOE) receiver, leading to the minimum variance distortionless response (MVDR) receiver for the signal of the desired user. This MVDR receiver is then adapted blindly by applying Capon’s principle. A channel impulse response is obtained as a by-product. Lower bounds on the receiver filter length are derived, giving a measure of the ISI and MAI tolerable by the receiver and ensuring its identifiability.     

Upscaling and automation of electrophysiology: toward high throughput screening in ion channel drug discovery

Effective screening of large compound libraries in ion channel drug discovery requires the development of new electrophysiological techniques with substantially increased throughputs compared to the conventional patch clamp technique. Sophion Bioscience is aiming to meet this challenge by developing two lines of automated patch clamp products, a traditional pipette-based system called Apatchi-1, and a silicon chip-based system QPatch. The degree of automation spans from semi-automation (Apatchi-1) where a trained technician interacts with the system in a limited way, to a complete automation (QPatch 96) where the system works continuously and unattended until screening of a full compound library is completed. The performance of the systems range from medium to high throughputs.     

A Practical Cross-Layer Mechanism For Fairness in 802.11 Networks

Many companies, organizations and communities are providing wireless hotspots that provide networking access using 802.11b wireless networks. Since wireless networks are more sensitive to variations in bandwidth and environmental interference than wired networks, most networks support a number of transmission rates that have different error and bandwidth properties. Access points can communicate with multiple clients running at different rates, but this leads to unfair bandwidth allocation. If an access point communicates with a mix of clients using both 1 Mb/s and 11 Mb/s transmission rates, the faster clients are effectively throttled to 1 Mb/s as well. This happens because the 802.11 MAC protocol approximate “station fairness”, with each station given an equal chance to access the media. We provide a solution to provide “rate proportional fairness”, where the 11 Mb/s stations receive more bandwidth than the 1 Mb/s stations. Unlike previous solutions to this problem, our mechanism is easy to implement, works with common operating systems and requires no change to the MAC protocol or the stations. Joseph Dunn received an M.S. in computer science from the University of Colorado at Boulder in 2003, and B. S. in coputer science and mathematics from the University of Arizona in 2001. His research interests are in the general area of computer systems, primarily focusing on security and scalability in distributed systems. He is currently working on his Ph.D. in computer science from the University of Colorado at Boulder. Michael Neufeld received a Ph.D. in Computer Science from the University of Colorado at Boulder in December of 2004, having previously received an M.S. in Computer Science from the University of Colorado at Boulder in 2000 and an A.B. in Computer Science from Princeton University in 1993. His research interests are in the general area of computer system, specifically concentrating on wireless networking, software defind/cognitive radio, and streerable antennas. He is currently a postdoc in the Computer Science department at the University of Calorado at Boulder pursuing research related to software defined radio and new MAC protocols for steerable phase array antennas. Anmol Sheth is a Ph.D. student in Computer Science at the University of Colorado at Boulder. He received his B.S. in Computer Science from the University of Pune, India in 2001. He has been co-leading the development of the MANTIS operating system. He has co-authored three papers include MAC layer protocol design, energy-efficient wireless communication, and adapting communications to mobility. Dirk Grunwald received his Ph.D. from the University of Illinois in 1989 and joined the University of Colorado the same year. His work addresses research and teaching in the broad area of “computer systems”, which includes computer architecture, operating systems, networks, and storage systems. His interests also include issues in pervasive computing, novel computing models, and enjoying the mountains. He is currently an Associate Professor in the Department of Computer Science and in Electrical and Computer Engineering and is also the Director of the Colorado Center for Information Storage. John Bennett is a Professor of Computer Science with a joint appointment in Electrical and Computer Engineering at the University of Colorado at Boulder. He also serves as Associate Dean for Education in the College of Engineering and Applied Science. He joined the CU-Boulder faculty in 2000, after serving on the faculty of Rice University for 11 years. While at Rice, Bennett pioneered a course in engineering design for both engineering and non-engineering students that has been emulated at several universities and high schools. In addition to other teaching awards, Bennett received the Keck Foundation National Award for Engineering Teaching Excellence for his work on this course. Bennett received his Ph.D. in 1988 from the University of Washington. Prior to completing his doctoral studies, he was a U.S. Naval Officer for several years and founded and served as President of Pacific Mountain Research, Inc., where he supervised the design and development of a number of commercial computing systems. Bennett's primary research interests are broadly focused in the area of distributed systems, and more narrowly in distributed information management and distributed robotic macrosensors.     

Solving the trade-off between fairness and throughput: Token bucket and leaky bucket-based weighted fair queueing schedulers

In this article, we present two efficient weighted fair queueing (WFQ) scheduling algorithms leaned on the well-known token bucket and leaky bucket shaping/policing algorithms. The performance of the presented algorithms is compared to those of the state-of-the-art WFQ approximations such as weighted round robin (WRR) and the recently proposed bin sort fair queueing (BSFQ). Our simulation results show that the proposed algorithms provide a better fairness at a lower implementation complexity while simultaneously achieving a comparable network utilization.     

Enhancing Planar Inverted Perovskite Solar Cells with Innovative Dumbbell-Shaped HTMs: A Study of Hexabenzocoronene and Pyrene-BODIPY-Triarylamine Derivatives

Dumbbell-shaped systems based on PAHs-BODIPY-triarylamine hybrids TM-(01-04) are designed as novel and highly efficient hole-transporting materials for usage in planar inverted perovskite solar cells. BODIPY is employed as a bridge between the PAH units, and the effects of the conjugated π-system's covalent attachment and size are investigated. Fluorescence quenching, 3D fluorescence heat maps, and theoretical studies support energy transfer within the moieties. The systems are extremely resistant to UVC 254 nm germicidal light sources and present remarkable thermal stability at degradation temperatures exceeding 350 °C. Integrating these systems into perovskite solar cells results in outstanding power conversion efficiency (PCE), with TM-02-based devices exhibiting a PCE of 20.26%. The devices base on TM-01, TM-03, and TM-04 achieve PCE values of 16.98%, 17.58%, and 18.80%, respectively. The long-term stability of these devices is measured for 600 h, with initial efficiency retention between 94% and 86%. The TM-04-based device presents noticeable stability of 94%, better than the reference polymer PTAA with 91%. These findings highlight the exciting potential of dumbbell-shaped systems based on PAHs-BODIPY-triarylamine derivatives for next-generation photovoltaics.