Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice

<p>Abstract</p> <p>Background</p> <p>Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Researchers have identified 44 mutations in the <it>TARDBP </it>gene that encode TDP-43 as causative for cases of sporadic and familial ALS <url>http://www.molgen.ua.ac.be/FTDMutations/</url>. Certain mutant forms of TDP-43, such as M337V, are associated with increased low molecular weight (LMW) fragments compared to wild-type (WT) TDP-43 and cause neuronal apoptosis and developmental delay in chick embryos. Such findings support a direct link between altered TDP-43 function and neurodegeneration.</p> <p>Results</p> <p>To explore the pathogenic properties of the M337V mutation, we generated and characterized two mouse lines expressing human TDP-43 (hTDP-43_M337V) carrying this mutation. hTDP-43_M337Vwas expressed primarily in the nuclei of neurons in the brain and spinal cord, and intranuclear and cytoplasmic phosphorylated TDP-43 aggregates were frequently detected. The levels of TDP-43 LMW products of ~25 kDa and ~35 kDa species were also increased in the transgenic mice. Moreover, overexpression of hTDP-43_M337Vdramatically down regulated the levels of mouse TDP-43 (mTDP-43) protein and RNA, indicating TDP-43 levels are tightly controlled in mammalian systems. TDP-43_M337Vmice displayed reactive gliosis, widespread ubiquitination, chromatolysis, gait abnormalities, and early lethality. Abnormal cytoplasmic mitochondrial aggregates and abnormal phosphorylated tau were also detected in the mice.</p> <p>Conclusion</p> <p>Our novel TDP-43_M337Vmouse model indicates that overexpression of hTDP-43_M337Valone is toxic <it>in vivo</it>. Because overexpression of hTDP-43 in wild-type TDP-43 and TDP-43_M337Vmouse models produces similar phenotypes, the mechanisms causing pathogenesis in the mutant model remain unknown. However, our results suggest that overexpression of the hTDP-43_M337Vcan cause neuronal dysfunction due to its effect on a number of cell organelles and proteins, such as mitochondria and TDP-43, that are critical for neuronal activity. The mutant model will serve as a valuable tool in the development of future studies designed to uncover pathways associated with TDP-43 neurotoxicity and the precise roles TDP-43 RNA targets play in neurodegeneration.</p

Peguero Electrocardiographic Left Ventricular Hypertrophy Criteria and Risk of Mortality

Background: Peguero electrocardiographic left ventricular hypertrophy (ECG-LVH) criteria are newly developed criteria that have shown better diagnostic performance than the traditional Cornell-voltage and Sokolow-Lyon criteria. However, prediction of poor outcomes rather than detection of increased left ventricular mass is becoming the primary use for ECG-LVH criteria which requires investigating any new ECG-LVH criteria in terms of prediction.Aims: To examine the prognostic significance of the newly developed Peguero ECG-LVH criteria.Methods: We compared the prognostic significance of Peguero ECG-LVH with Cornell-voltage and Sokolow-Lyon ECG-LVH criteria in 7,825 participants (age 59.8 ± 13.4 years; 52.7% women) from the third National Health and Nutrition Examination Survey who were free of major intraventricular conduction defects. ECG-LVH criteria were derived from digital ECG tracings processed at a central core laboratory.Results: At baseline, ECG-LVH was detected in 11.8% by Peguero; in 4.3% by Cornell voltage and in 6.4% by Sokolow-Lyon. During a median follow up of 13.8 years, 2,796 all-cause mortality events occurred. In multivariable models adjusted for demographics and cardiovascular risk factors, presence of Peguero ECG-LVH was associated with increased risk of all-cause mortality [HR (95% CI): 1.29 (1.16, 1.44)]. This association was not significantly different from the associations of Cornell voltage-LVH or Sokolow-Lyon LVH with all-cause mortality [HR (95%CI): 1.32 (1.12, 1.55) and 1.24 (1.07, 1.43), respectively; p-values for comparisons of these HRs with the HR of Peguero ECG-LVH 0.817 and 0.667, respectively]. Similar patterns of associations were observed with cardiovascular, ischemic heart disease and heart failure mortalities.Conclusion: Peguero ECG-LVH is predictive of increased risk of death similar to the traditional ECG-LVH criteria

Light, fluidics and their applications in global sustainability and health

204 pagesSupplemental file(s) description: The assembly view of HI-Light reactor.The microscopic precision in simultaneous delivery of light and fluids by optofluidics offers great potential for global sustainability and health applications. Light drives photocatalytic reactions in a gas/liquid environment containing catalyst nanoparticles and reactants in global sustainability applications. The relevant efforts in this dissertation include: (1) a “shell-and-tube” glass waveguide-based photoreactor technology for converting CO2 to fuels, (2) a “gradient etching” approach to enable uniform light scattering of waveguides for enhanced photocatalytic degradation of methylene blue dyes, and (3) the optimization of both design and operating parameters of waveguide-based photoreactors via Multiphysics simulations. In global health applications, the fluidic environment involves various bodily fluids, such as serum, plasma, or human whole blood samples. Light irradiation by the optical reader excites the signals on test and control lines, and these line intensities are collected for later quantification of analyte concentrations. The health-related efforts in this dissertation include: (1) an iPad-based multiplexed lateral flow assay (LFA) system to differentially detect human malaria species with a single test line, (2) an optical reader-based multiplexed LFA system for differential diagnosis of malaria and typhoid infections, and (3) a fluorescence reader-based multiplexed LFA system for differentiating bacterial and viral infections.2024-01-0

Reconfigurable integrated structures with functions of Fabry–Perot antenna and wideband liquid absorber for radar system stealth

Abstract This paper proposes a functionally reconfigurable integrated structure of a Fabry–Perot (FP) antenna and wideband liquid absorber. First, a two-layer partial reflecting surface (PRS) has been designed. Then, a patch antenna is used to act as the source antenna. By combining the source antenna with the PRS, an FP antenna has been designed. What’s more, taking full advantage of the reflective properties of PRS, a liquid broadband absorber is then designed. Last, the integrated structure with two functions has been realized. It can be used as the FP antenna or the liquid absorber through the extraction and injection of ethanol. In this way, it is effective to switch between stealth and detection states which can be used in different electromagnetic environments. The PRS is elaborately tailored to serve as both a component of the FP antenna and the metal ground of the broadband liquid absorber. Then the integrated structure is realized by combining the FP antenna with the liquid absorber. The PRS is composed of patches on the top layer of the substrate and the square loop on the bottom. The liquid absorber is composed of a 3-D printed container, 45% ethanol layer and the PRS is used to serve as the metal ground. The formula of Mie resonance theory has been extended and used to design the liquid absorber. The gain of the antenna is 19.7 dBi when the ethanol is extracted. When the ethanol is injected, a wideband liquid absorber is achieved. The absorption band (S 11 < − 10 dB) ranges from 4 to 18 GHz. The absorption bandwidth is over 133%. The monostatic RCS reduction bands of the structure with ethanol range from 4 to 18 GHz and the average RCS reduction is 28.4 dBsm. The measured and simulated results are in good agreement

Rotor Fault Diagnosis Method Based on VMD Symmetrical Polar Image and Fuzzy Neural Network

Rotor fault diagnosis has attracted much attention due to its difficulties such as non-stationarity of fault signals, difficulty in fault feature extraction and low diagnostic accuracy of small samples. In order to extract fault feature information of rotors more effectively and to improve fault diagnosis precision, this paper proposed a fault diagnosis method based on variational mode decomposition (VMD) symmetrical polar image and fuzzy neural network. Firstly, the original rotor vibration signal is decomposed by using the VMD method and the relevant parameter selection algorithm of the VMD method is also proposed. Secondly, the intrinsic mode functions (IMF), which are sensitive to the signal characteristics, are selected for signal reconstruction based on a comprehensive evaluation factor method. As well, the reconstructed signal is transformed into a two-dimensional snowflake image through using the symmetrical polar coordinate method. Finally, the image features are extracted by the gray level co-occurrence matrix to form the state feature vector, which is input into the fuzzy neural network to realize the rotor fault diagnosis. Through the analysis of measured signals, the experimental results show that the proposed method can reach a higher recognition rate of 98% and the k-cross-validation experiment is used to demonstrate the robustness of the fuzzy neural network, and the average recognition accuracy of this experiment is 99.2%. Compared with some similar methods, the proposed method still has the highest fault recognition precision 98.4%, and the smallest standard deviation 0.5477

Investigation of Reaction Mechanism of Amino Acids and Phosphorus Trichloride by P-31 NMR and ESI-MS/MS

National Natural Science Foundation of China [20672104, 20732004]The reaction of amino acids and phosphorus trichloride in THF was studied by P-31 NMR tracing and ESI-MS/MS. A series of hydridophoranes and cyclic dipeptides were obtained. The reaction presented interesting diversity and the reaction mechanism was proposed. The mechanism suggests that phosphorus plays an important role in the synthesis of amino acid hydridophorane and cyclic dipeptides. The results also show that P-31 NMR and ESI-MS/MS are useful tools for the investigation of reaction mechanism