In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and ...neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.
A sub‐population of chemoresistant cells exhibits biological properties similar to cancer stem cells (CSCs), and these cells are believed to be a main cause for tumor relapse and metastasis. In our ...study, we explored the role of SOX8 and its molecular mechanism in the regulation of the stemness properties and the epithelial mesenchymal transition (EMT) of cisplatin‐resistant tongue squamous cell carcinoma (TSCC) cells. We found that SOX8 was upregulated in cisplatin‐resistant TSCC cells, which displayed CSC‐like properties and exhibited EMT. SOX8 was also overexpressed in chemoresistant patients with TSCC and was associated with higher lymph node metastasis, advanced tumor stage and shorter overall survival. Stable knockdown of SOX8 in cisplatin‐resistant TSCC cells inhibited chemoresistance, tumorsphere formation, and EMT. The Wnt/β‐catenin pathway mediated the cancer stem‐like properties in cisplatin‐resistant TSCC cells. Further studies showed that the transfection of active β‐catenin in SOX8 stable‐knockdown cells partly rescued the SOX8 silencing‐induced repression of stem‐like features and chemoresistance. Through chromatin immunoprecipitation and luciferase assays, we observed that SOX8 bound to the promoter region of Frizzled‐7 (FZD7) and induced the FZD7‐mediated activation of the Wnt/β‐catenin pathway. In summary, SOX8 confers chemoresistance and stemness properties and mediates EMT processes in chemoresistant TSCC via the FZD7‐mediated Wnt/β‐catenin pathway.
What's new?
Tongue cancer frequently spreads to the lymph nodes, and while chemotherapy with cisplatin has improved 5‐year survival rates, all too often the cancer becomes resistant to chemotherapy and returns. Here, the authors show that tongue squamous cell carcinoma (TSCC) cells that have acquired cisplatin resistance express more SOX‐8 mRNA than their parent TSCC cells. Getting rid of SOX‐8, they showed, hampered the cells' chemoresistance as well as the epithelial to mesenchymal transition. Adding active beta‐catenin to the cells lacking SOX‐8 partially restored these properties, showing that SOX‐8 acts through the Wnt/beta‐catenin pathway.
Loop Current warming by Hurricane Wilma Oey, L.-Y.; Ezer, T.; Wang, D.-P. ...
Geophysical research letters,
April 2006, Volume:
33, Issue:
8
Journal Article
Peer reviewed
Open access
Hurricanes mix and cool the upper ocean, as shown here in observations and modeling of the Caribbean Sea and the Gulf of Mexico during the passage of hurricane Wilma. Curiously, the upper ocean ...around the Loop Current warmed prior to Wilma's entrance into the Gulf. The major cause was increased volume and heat transports through the Yucatan Channel produced by storm‐induced convergences in the northwestern Caribbean Sea. Such oceanic variability may have important impacts on hurricane predictions.
A novel polysaccharide isolated from
Angelica sinensis, named APS-1d showed cytotoxic activity towards several cancer cell lines
in vitro. However, the precise antitumor mechanisms of this compound ...are unknown. In this study, we investigated the pro-apoptotic effects of APS-1d in human cervical cancer HeLa cells both
in vitro and
in vivo, and further elucidated the mechanisms of this action. Inhibition of HeLa cell proliferation was determined by MTT assay and the therapeutic efficacy of APS-1d was evaluated by human cancer xenografts in nude mice. Cell apoptosis was examined with flow cytometry and TUNEL assay. The mechanism of action of APS-1d was investigated by Western blot analysis. APS-1d decreased HeLa cell proliferation in a concentration- and time-dependent manner
in vitro. In addition, APS-1d significantly inhibited tumor growth in athymic nude mice. Characteristic manifestations of apoptosis including apoptotic morphological features and the sub- G
0/G
1 peaks were observed when the cells were treated with APS-1d. Further analysis showed that APS-1d-induced apoptosis was associated with the regulation of Bcl-2 family protein expression, a decrease in the mitochondrial membrane potential, and an increase in the cytosolic cytochrome
c levels. Sequentially, APS-1d increased the activities of caspase-9, -3, and poly (ADP-ribose) polymerase in a concentration-dependent manner, however, no obvious activation of Bid and caspase-8 was observed. Pretreatment with Z-LEHD-FMK, a specific inhibitor of caspase-9, significantly attenuated APS-1d-induced cell apoptosis, and activation of caspase-3. Taken together, our studies indicate that APS-1d is capable of inhibiting HeLa cell proliferation and inducing apoptosis in these cells which primarily involves the activation of the intrinsic mitochondrial pathway.
Purpose
To assess the efficacy of neck cooling on cognitive performance following exertional hyperthermia.
Methods
Twelve healthy men completed two experimental trials control (CON) and neck cooling ...collar (NCC) in a counter-balanced design. They ran on a treadmill at 70 %
V
O
2peak
under warm and humid conditions (dry bulb temperature: 30.2 ± 0.3 °C, relative humidity: 71 ± 2 %) for 75 min or until volitional exhaustion. Gastrointestinal, neck and skin temperatures, heart rate and subjective ratings were assessed. Serum brain-derived neurotrophic factor (BDNF) levels were measured before and after each run. Cognitive performance comprising symbol digit matching, search and memory, digit span, choice reaction time and psychomotor vigilance test (PVT) were assessed before and after exercise.
Results
Mean gastrointestinal temperature was similar after exercise between trials (CON: 39.5 ± 0.4 °C vs. NCC: 39.6 ± 0.3 °C;
p
= 0.15). Mean neck temperature was lowered in NCC compared to CON after the run (36.4 ± 1.6 °C vs. NCC: 26.0 ± 0.3 °C;
p
< 0.001). Exercise-induced hyperthermia improved mean reaction time in the symbol digit matching test (−134 ± 154 ms;
p
< 0.05) and the PVT (−18 ± 30 ms;
p
< 0.05). Maximum span was increased in the digit span test (1 ± 2;
p
< 0.05). Application of NCC reduced the number of search errors made in level 3 of the search and memory test (
p
< 0.05). Mean serum BDNF levels were increased following exercise-induced hyperthermia in both trials (
p
< 0.05).
Conclusion
Exercise-induced hyperthermia improves working memory and alertness. Neck cooling may only enhance performance in tasks of higher complexity.
We study the process e^{+}e^{-}→Λ_{c}^{+}Λover ¯_{c}^{-} at twelve center-of-mass energies from 4.6119 to 4.9509 GeV using data samples collected by the BESIII detector at the BEPCII collider. The ...Born cross sections and effective form factors (|G_{eff}|) are determined with unprecedented precision after combining the single and double-tag methods based on the decay process Λ_{c}^{+}→pK^{-}π^{+}. Flat cross sections around 4.63 GeV are obtained and no indication of the resonant structure Y(4630), as reported by Belle, is found. In addition, no oscillatory behavior is discerned in the |G_{eff}| energy dependence of Λ_{c}^{+}, in contrast to what is seen for the proton and neutron cases. Analyzing the cross section together with the polar-angle distribution of the Λ_{c}^{+} baryon at each energy point, the moduli of electric and magnetic form factors (|G_{E}| and |G_{M}|) are extracted and separated. For the first time, the energy dependence of the form factor ratio |G_{E}/G_{M}| is observed, which can be well described by an oscillatory function.
ABSTRACT
High time resolution and accuracy are of critical importance in the studies of timing analysis and time delay localization of gamma-ray bursts (GRBs), soft gamma-ray repeaters (SGRs) and ...pulsars. The Gravitational wave high-energy Electromagnetic Counterpart All-sky Monitor (GECAM) consisting of two micro-satellites, GECAM-A and GECAM-B, launched on 2020 December 10, is aimed at monitoring and locating X-ray and GRBs all over the sky. To achieve its scientific goals, GECAM is designed to have the highest time resolution (0.1 $\mu {\rm s}$) among all GRB detectors ever flown. Here, we make a comprehensive time calibration campaign including both on-ground and on-orbit tests to derive not only the relative time accuracy of GECAM satellites and detectors, but also the absolute time accuracy of GECAM-B. Using the on-ground calibration with a $\rm ^{22}Na$ radioactive source, we find that the relative time accuracy between GECAM-A and GECAM-B is about 0.15 $\mu {\rm s}$ (1σ). To measure the relative time accuracy between all detectors of a single GECAM satellite, cosmic-ray events detected on orbit are utilized since they could produce many secondary particles simultaneously record by multiple detectors. We find that the relative time accuracy among all detectors onboard GECAM-B is about 0.12 $\mu {\rm s}$ (1σ). Finally, we use the novel Li-CCF method to perform the absolute time calibration with Crab pulsar and SGR J1935+2154, both of which were jointly observed by GECAM-B and Fermi/GBM, and obtain that the time difference between GECAM-B and Fermi/GBM is 3.06 ± 6.04 $\mu {\rm s}$ (1σ).
The flower perianth has various, non‐mutually exclusive functions, such as visual signalling to pollinators and protecting the reproductive organs from the elements and from florivores, but how ...different perianth structures and their different sides play a role in these functions is unclear. Intriguingly, in many species there is a clear colour difference between the different sides of the perianth, with colour patterns or pigmentation present on only one side. Any adaptive benefit from such colour asymmetry is unclear, as is how the asymmetry evolved. In this viewpoint paper, we address the phenomenon of flowers with differently coloured inner and outer perianth sides, focusing on petals of erect flowers. Guided by existing literature and our own observations, we delineate three non‐mutually exclusive evolutionary hypotheses that may explain the factors underlying differently coloured perianth sides. The pollen‐protection hypothesis predicts that the outer side of petals contributes to protect pollen against UV radiation, especially during the bud stage. The herbivore‐avoidance hypothesis predicts that the outer side of petals reduces the flower's visibility to herbivores. The signalling‐to‐pollinators hypothesis predicts that flower colours evolve to increase conspicuousness to pollinators. The pollen‐protection hypothesis, the herbivore‐avoidance hypothesis, and the signalling‐to‐pollinators hypothesis generate largely but not entirely overlapping predictions about the colour of the inner and outer side of the petals. Field and laboratory research is necessary to disentangle the main drivers and adaptive significance of inner–outer petal side colour asymmetry.
Evolutionary hypotheses aimed at explaining why inner and outer sides of petals are often differently coloured.
Using the non-equilibrium Green’s function method combined with the density functional theory, we investigate the magnetism and spin-dependent transport properties of symmetric and asymmetric ...zigzag–edged graphene nanoribbons (ZGNRs) passivated by monohydrogenation with 1, −1 magnetism configuration. The symmetric model H–6ZGNR–H shows a dual spin filter effect, but asymmetric H–5ZGNR–H behaves as a conductor with linear current–voltage relationships. We also investigate the magnetism and spin-dependent transport properties of H2–ZGNR–H with asymmetric edge hydrogenations, the perfect dual spin filtering effect is observed in both H2–5ZGNR–H and H2–6ZGNR–H. The transmission pathways and PDOS demonstrate that the edge of C-H2 bonds have important effects on the magnetism and spin-dependent transport properties as compared with the edge of C–H bonds.
Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) ...aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas.
A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world.
MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance.
In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers.
•MCDBT-1 had a sensitivity of 69.1% and a specificity of 98.9% in detecting six cancers.•In the real world, MCDBT-1 decreased late-stage incidence by 38.7%-46.4% and increased 5-year survival rate by 33.1%-40.4%.•In parallel, MCDBT-2 was set at a lower specificity but a higher sensitivity than MCDBT-1 and had an ideal performance.
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