Mark4 ablation attenuates pathological phenotypes in a mouse model of tauopathy.

Accumulation of abnormally phosphorylated tau proteins is linked to various neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. Microtubule affinity-regulating kinase 4 (MARK4) has been genetically and pathologically associated with Alzheimer's disease and reported to enhance tau phosphorylation and toxicity in Drosophila and mouse traumatic brain-injury models but not in mammalian tauopathy models. To investigate the role of MARK4 in tau-mediated neuropathology, we crossed P301S tauopathy model (PS19) and Mark4 knockout mice. We performed behaviour, biochemical and histology analyses to evaluate changes in PS19 pathological phenotype with and without Mark4. Here, we demonstrated that Mark4 deletion ameliorated the tau pathology in a mouse model of tauopathy. In particular, we found that PS19 with Mark4 knockout showed improved mortality and memory compared with those bearing an intact Mark4 gene. These phenotypes were accompanied by reduced neurodegeneration and astrogliosis in response to the reduction of pathological forms of tau, such as those phosphorylated at Ser356, AT8-positive tau and thioflavin S-positive tau. Our data indicate that MARK4 critically contributes to tau-mediated neuropathology, suggesting that MARK4 inhibition may serve as a therapeutic avenue for tauopathies.

A cell-penetrating peptide derived from SARS-CoV-2 protein Orf9b allosterically inhibits MARK4 activity and mitigates tau toxicity.

Abnormal activation of microtubule affinity-regulating kinase 4 (MARK4) and its phosphorylation of the microtubule-associated protein tau are believed to play a role in the pathogenesis of Alzheimer's disease, and MARK4 inhibition can be a strategy to develop disease-modifying therapy. Here we report the development of a membrane-permeable peptide that inhibits MARK4 activity in an allosteric manner. The SARS-CoV-2-derived protein Orf9b inhibited MARK4-mediated tau phosphorylation in primary neurons and Drosophila. Orf9b inhibited MARK4 activity in an allosteric manner and did not inhibit the activity of MARK2, which is another MARK family member and is closely related to MARK4. Co-expression of Orf9b in the fly retina expressing human tau and MARK4 suppressed phosphorylation of tau at the microtubule-binding repeats and tau-induced neurodegeneration. We identified the minimal sequence of Orf9b required to suppress MARK4 activity and fused it to a cell-permeable sequence (TAT-Orf9b10-18_78-95). Extracellular supplementation of TAT-Orf9b10-18_78-95 inhibited MARK4 activity in primary neurons, and feeding TAT-Orf9b10-18_78-95 to a fly model of tauopathy lowered phospho-tau levels and suppressed neurodegeneration. These results suggest that TAT-Orf9b10-18_78-95 is a unique class of MARK4 inhibitor and can be used to modify tau toxicity.

129I in the SE-Dome ice core, Greenland: A new candidate golden spike for the Anthropocene.

The Anthropocene is a proposed geological epoch that will mark the time when humans have irreversibly affected the Earth. One of the primary requirements to formally establish this is a Global Boundary Stratotype Section and Point or "golden spike" - a record of a planetary signal marking the new epoch's beginning. The leading candidates for the Anthropocene's golden spike are the fallout peaks of 14C (T1/2 = 5730 y) and 239Pu (T1/2 = 24,110 y) from nuclear weapons testing in the 1960s. However, these radionuclides' half-lives may not be long enough for their signals to be observable in the far future and are, thus, not durable. In this regard, here we show the 129I time series record (1957-2007) of the SE-Dome ice core, Greenland. We find that 129I in SE-Dome records almost the entire history of the nuclear age in excellent detail at a time resolution of about four months. More specifically, 129I in SE-Dome reflects signals from nuclear weapons testing in 1958, 1961, and 1962, the Chernobyl Accident in 1986, and various signals from nuclear fuel reprocessing within the same year or a year after. The quantitative relationships between 129I in SE-Dome and these human nuclear activities were established using a numerical model. Similar signals are observed in other records from various environments worldwide, such as sediments, tree rings, and corals. This global ubiquity and synchronicity are comparable to those of the 14C and 239Pu bomb signals, but the much longer half-life of 129I (T1/2 = 15.7 My) makes it a more durable golden spike. For these reasons, the 129I record of the SE-Dome ice core can be considered an excellent candidate for the Anthropocene golden spike.

3D X-ray computed tomography gray value and age model datasets of coral cores Baler 2 and 3 (Philippines).

The datasets here contain the 3D X-ray computed tomography (3DXCT) gray values and age models of coral cores Baler 2 and 3, taken from Baler, Aurora, Philippines. 3DXCT was used to analyze 5 mm-thick slabs of the coral cores. From the resulting 3DXCT images, gray values were determined per pixel from top to bottom of the slabs. The gray value profiles across the length of the slabs were then matched with records of sea surface temperature (SST) of the Baler site to construct the age model of the coral cores. Daily SST records from October 2018 to February 1982 were from the Optimum Interpolation Sea Surface Temperature or OISST [1,2], while monthly SST records from February 1982 to May 1945 were from the Extended Reconstructed Sea Surface Temperature or ERSST [3]. The gray value datasets of coral cores Baler 2 and 3 present historical records of the corals' response to changing environments through the years and may be used in studies related to such. An example of this can be seen in the relationship between coral gray values and SST. Furthermore, the age model datasets of Baler 2 and 3 serve as the basis for interpretation for all current and future studies on these coral cores. These datasets were originally produced for the research work titled "A historical record of the impact of nuclear activities based on 129I in coral cores in Baler, Philippines: an update" [4].

A historical record of the impact of nuclear activities based on 129I in coral cores in Baler, Philippines: An update.

In a previous study in 2016, we presented how 129I in coral cores from the east (Baler) and west (Parola) sides of the Philippines recorded the impacts of human nuclear activities, including nuclear weapons testing, nuclear fuel reprocessing, and nuclear accidents. However, the 2016 Baler dataset only had a two-year time resolution and a crude age model based on growth band counting. Here we present a new 2020 Baler 129I/127I atomic ratio dataset that features at least annual time resolution and a more accurate age model constructed using 3D X-ray Computed Tomography. Results show that the bomb peaks in Baler primarily came from the Pacific Proving Grounds or PPG with a time lag of about 1.8 years (or more specifically, between 1.3 and 2.4 years). Moreover, a review of the Parola dataset shows that PPG signals may have been transported to Parola in the West Philippine Sea via two pathways: the northward and southward bifurcations of the North Equatorial Current, reaching Parola about 4.5 and 8.5 years after detonation, respectively. Moreover, a prominent peak in the year 2014.7 in Baler possibly came from the 2011 Fukushima Accident, transported by the Kuroshio Recirculation Gyre and the North Pacific Mode Waters with a 3.5-year time lag. This study contributes to the understanding of the impact and transport of human-made radionuclides to the Philippines and the relevant oceanographic processes in the Western Equatorial Pacific region.