TDP-43 inclusions are found in many Alzheimer's disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical ...oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ's ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.
Oxide-supported noble metal catalysts have been extensively studied for decades for the water gas shift (WGS) reaction, a catalytic transformation central to a host of large volume processes that ...variously utilize or produce hydrogen. There remains considerable uncertainty as to how the specific features of the active metal-support interfacial bonding-perhaps most importantly the temporal dynamic changes occurring therein-serve to enable high activity and selectivity. Here we report the dynamic characteristics of a Pt/CeO
system at the atomic level for the WGS reaction and specifically reveal the synergistic effects of metal-support bonding at the perimeter region. We find that the perimeter Pt
- O vacancy-Ce
sites are formed in the active structure, transformed at working temperatures and their appearance regulates the adsorbate behaviors. We find that the dynamic nature of this site is a key mechanistic step for the WGS reaction.
•A novel binary-addition tree (BAT) algorithm is proposed.•BAT is simple to understand, easy to code, and flexible to made-to-fit.•A fast algorithm to calculate the binary-state network ...reliability.•BAT outperforms path- and cut-based algorithms from the time complexity.•BAT outperforms QIE which is the best related algorithm from the experiments.
Network structures and models have been widely adopted, e.g., for Internet of Things, wireless sensor networks, smart grids, transportation networks, communication networks, social networks, and computer grid systems. Network reliability is an effective and popular technique to estimate the probability that the network is still functioning. Networks composed of binary-state (e.g., working or failed) components (arcs and/or nodes) are called binary-state networks. The binary-state network is the fundamental type of network; thus, there is always a need for a more efficient algorithm to calculate the network reliability. Thus, a novel binary-addition tree (BAT) algorithm that employs binary addition for finding all the possible state vectors and the path-based layered-search algorithm for filtering out all the connected vectors is proposed for calculating the binary-state network reliability. According to the time complexity and numerical examples, the efficiency of the proposed BAT is higher than those of traditional algorithms for solving the binary-state network reliability problem.
Single‐ and few‐layer MoS2 nanoflowers are first discovered to have a piezo‐catalyst effect, exhibiting an ultra‐high degradation activity in the dark by introducing external mechanical strains. The ...degradation ratio of the Rhodamine‐B dye solution reaches 93% within 60 s under ultrasonic‐wave assistance in the dark.
Sleep apnea (SA) has been associated with cognitive impairment. However, no data regarding the risk of dementia in patients with SA has been reported in the general population. This retrospective ...matched-control cohort study was designed to estimate and compare the risk of dementia in SA and non-SA patients among persons aged 40 and above over a 5-year period follow-up.
We conducted a nationwide 5-year population-based study using data retrieved from the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan. The study cohort comprised 1414 patients with SA aged 40 years who had at least 1 inpatient service claim or 1 ambulatory care claim. The comparison cohort comprised 7070 randomly selected patients who were matched with the study group according to sex, age, and index year. We performed Cox proportional-hazards regressions to compute the 5-year dementia-free survival rates after adjusting for potentially confounding factors.
The SA patients in this study had a 1.70-times greater risk of developing dementia within 5 years of diagnosis compared to non-SA age- and sex-matched patients, after adjusting for other risk factors (95% confidence interval (CI) = 1.26-2.31; P < .01). For the gender-dependent effect, only females with SA were more likely to develop dementia (adjust HR: 2.38, 95% CI =1.51-3.74; P < .001). For the age-dependent effect of different genders, males with SA aged 50-59 years had a 6.08 times greater risk for developing dementia (95% CI = 1.96-18.90), and females with SA aged ≥ 70 years had a 3.20 times greater risk of developing dementia (95% CI =1.71-6.00). For the time-dependent effect, dementia may be most likely to occur in the first 2.5 years of follow-up (adjusted HR:2.04, 95% CI =1.35-3.07).
SA may be a gender-dependent, age-dependent, and time-dependent risk factor for dementia.
The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and ...immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1
TIM-3
T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3
cytotoxic CD8 T cells and immunosuppressive regulatory T cells (T
cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes T
cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon β and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.
Several lines of evidence implicate the protein tau in the pathogenesis of multiple brain disorders, including Alzheimer's disease, other neurodegenerative conditions, autism, and epilepsy. Tau is ...abundant in neurons and interacts with microtubules, but its main functions in the brain remain to be defined. These functions may involve the regulation of signaling pathways relevant to diverse biological processes. Informative disease models have revealed a plethora of abnormal tau species and mechanisms that might contribute to neuronal dysfunction and loss, but the relative importance of their respective contributions is uncertain. This knowledge gap poses major obstacles to the development of truly impactful therapeutic strategies. The current expansion and intensification of efforts to translate mechanistic insights into tau-related therapeutics should address this issue and could deliver better treatments for a host of devastating conditions.
Optical super-resolution microscopy allows nanoscale imaging of protein molecules in intact biological tissues. However, it is still challenging to perform large volume super-resolution imaging for ...entire animal organs. Here we develop a single-wavelength Bessel lightsheet method, optimized for refractive-index matching with clarified specimens to overcome the aberrations encountered in imaging thick tissues. Using spontaneous blinking fluorophores to label proteins of interest, we resolve the morphology of most, if not all, dopaminergic neurons in the whole adult brain (3.64 × 10
µm
) of Drosophila melanogaster at the nanometer scale with high imaging speed (436 µm
per second) for localization. Quantitative single-molecule localization reveals the subcellular distribution of a monoamine transporter protein in the axons of a single, identified serotonergic Dorsal Paired Medial (DPM) neuron. Large datasets are obtained from imaging one brain per day to provide a robust statistical analysis of these imaging data.
Calcium sulfate, an injectable and biodegradable bone‐void filler, is widely used in orthopedic surgery. Based on clinical experience, bone‐defect substitutes can also serve as vehicles for the ...delivery of drugs, for example, antibiotics, to prevent or to treat infections such as osteomyelitis. However, antibiotic additions change the characteristics of calcium sulfate cement. Moreover, high‐dose antibiotics may also be toxic to bony tissues. Accordingly, cefazolin at varying weight ratios was added to calcium sulfate samples and characterized in vitro. The results revealed that cefazolin changed the hydration reaction and prolonged the initial setting times of calcium sulfate bone cement. For the crystalline structure identification, X‐ray diffractometer revealed that cefazolin additive resulted in the decrease of peak intensity corresponding to calcium sulfate dihydrate which implying incomplete phase conversion of calcium sulfate hemihydrate. In addition, scanning electron microscope inspection exhibited cefazolin changed the morphology and size of the crystals greatly. A relatively higher amount of cefazolin additive caused a faster degradation and a lower compressive strength of calcium sulfate compared with those of uploaded samples. Furthermore, the extract of cefazolin‐impregnated calcium sulfate impaired cell viability, and caused the death of osteoblast‐like cells. The results of this study revealed that the cefazolin additives prolonged setting time, impaired mechanical strength, accelerated degradation, and caused cytotoxicity of the calcium sulfate bone‐void filler. The aforementioned concerns should be considered during intra‐operative applications.
Network reliability is an important index to the provision of useful information for decision support in the modern world. There is always a need to calculate symbolic network reliability functions ...(SNRFs) due to dynamic and rapid changes in network parameters. In this brief, the proposed squeezed artificial neural network (SqANN) approach uses the Monte Carlo simulation to estimate the corresponding reliability of a given designed matrix from the Box-Behnken design, and then the Taguchi method is implemented to find the appropriate number of neurons and activation functions of the hidden layer and the output layer in ANN to evaluate SNRFs. According to the experimental results of the benchmark networks, the comparison appears to support the superiority of the proposed SqANN method over the traditional ANN-based approach with at least 16.6% improvement in the median absolute deviation in the cost of extra 2 s on average for all experiments.
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