Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability

Tau is a neuronal microtubule associated protein whose main biological functions are to promote microtubule self-assembly by tubulin and to stabilize those already formed. Tau also plays an important role as an axonal microtubule protein. Tau is an amazing protein that plays a key role in cognitive processes, however, deposits of abnormal forms of tau are associated with several neurodegenerative diseases, including Alzheimer disease (AD), the most prevalent, and Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI), the most recently associated to abnormal tau. Tau post-translational modifications (PTMs) are responsible for its gain of toxic function. Alonso et al. (1996) were the first to show that the pathological tau isolated from AD brains has prion-like properties and can transfer its toxic function to the normal molecule. Furthermore, we reported that the pathological changes are associated with tau phosphorylation at Ser199 and 262 and Thr212 and 231. This pathological version of tau induces subcellular mislocalization in cultured cells and neurons, and translocates into the nucleus or accumulated in the perinuclear region of cells. We have generated a transgenic mouse model that expresses pathological human tau (PH-Tau) in neurons at two different concentrations (4% and 14% of the total endogenous tau). In this model, PH-Tau causes cognitive decline by at least two different mechanisms: one that involves the cytoskeleton with axonal disruption (at high concentration), and another in which the apparent neuronal morphology is not grossly affected, but the synaptic terminals are altered (at lower concentration). We will discuss the putative involvement of tau in proteostasis under these conditions. Understanding tau’s biological activity on and off the microtubules will help shed light to the mechanism of neurodegeneration and of normal neuronal function

Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability

Tau is a neuronal microtubule associated protein whose main biological functions are to promote microtubule self-assembly by tubulin and to stabilize those already formed. Tau also plays an important role as an axonal microtubule protein. Tau is an amazing protein that plays a key role in cognitive processes, however, deposits of abnormal forms of tau are associated with several neurodegenerative diseases, including Alzheimer disease (AD), the most prevalent, and Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI), the most recently associated to abnormal tau. Tau post-translational modifications (PTMs) are responsible for its gain of toxic function. Alonso et al. (1996) were the first to show that the pathological tau isolated from AD brains has prion-like properties and can transfer its toxic function to the normal molecule. Furthermore, we reported that the pathological changes are associated with tau phosphorylation at Ser199 and 262 and Thr212 and 231. This pathological version of tau induces subcellular mislocalization in cultured cells and neurons, and translocates into the nucleus or accumulated in the perinuclear region of cells. We have generated a transgenic mouse model that expresses pathological human tau (PH-Tau) in neurons at two different concentrations (4% and 14% of the total endogenous tau). In this model, PH-Tau causes cognitive decline by at least two different mechanisms: one that involves the cytoskeleton with axonal disruption (at high concentration), and another in which the apparent neuronal morphology is not grossly affected, but the synaptic terminals are altered (at lower concentration). We will discuss the putative involvement of tau in proteostasis under these conditions. Understanding tau’s biological activity on and off the microtubules will help shed light to the mechanism of neurodegeneration and of normal neuronal function

Quantum Gas Mixtures and Dual-Species Atom Interferometry in Space

The capability to reach ultracold atomic temperatures in compact instruments has recently been extended into space. Ultracold temperatures amplify quantum effects, while free-fall allows further cooling and longer interactions time with gravity - the final force without a quantum description. On Earth, these devices have produced macroscopic quantum phenomena such as Bose-Einstein condensation (BECs), superfluidity, and strongly interacting quantum gases. Quantum sensors interfering the superposition of two ultracold atomic isotopes have tested the Universality of Free Fall (UFF), a core tenet of Einstein's classical gravitational theory, at the $10^{-12}$ level. In space, cooling the elements needed to explore the rich physics of strong interactions and preparing the multiple species required for quantum tests of the UFF has remained elusive. Here, utilizing upgraded capabilities of the multi-user Cold Atom Lab (CAL) instrument within the International Space Station (ISS), we report the first simultaneous production of a dual species Bose-Einstein condensate in space (formed from $^{87}$Rb and $^{41}$K), observation of interspecies interactions, as well as the production of $^{39}$K ultracold gases. We have further achieved the first space-borne demonstration of simultaneous atom interferometry with two atomic species ($^{87}$Rb and $^{41}$K). These results are an important step towards quantum tests of UFF in space, and will allow scientists to investigate aspects of few-body physics, quantum chemistry, and fundamental physics in novel regimes without the perturbing asymmetry of gravity

Expedition 381 Summary

The primary objective of International Ocean Discovery Program Expedition 381 was to retrieve a record of early continental rifting and basin evolution from the Corinth rift, central Greece. Continental rifting is fundamental for the formation of ocean basins, and active rift zones are dynamic regions of high geohazard potential. However, the detailed spatial and temporal evolution of a complete rift system needed to understand rift development from the fault to plate scale is poorly resolved. In the active Corinth rift, deformation rates are high, the recent synrift succession is preserved and complete offshore, and earlier rift phases are preserved onshore. Additionally, a dense seismic database provides high-resolution imaging of the fault network and seismic stratigraphy around the basin. As the basin has subsided, its depositional environment has been affected by fluctuating global sea level and its absolute position relative to sea level, and the basin sediments record this changing environment through time. In Corinth, we can therefore achieve an unprecedented precision of timing and spatial complexity of rift-fault system development, rift-controlled drainage system evolution, and basin fill in the first few million years of rift history. The following are the expedition themes: High-resolution fault slip and rift evolution history, Surface processes in active rifts, High-resolution late Quaternary Eastern Mediterranean paleoclimate and paleoenvironment of a developing rift basin, and Geohazard assessment in an active rift. These objectives were and will be accomplished as a result of successful drilling, coring, and logging at three sites in the Gulf of Corinth, which collectively yielded 1645 m of recovered core over a 1905 m cored interval. Together, these cores provide (1) a long rift history (Sites M0078 and M0080), (2) a high-resolution record of the most recent phase of rifting (Site M0079), and (3) the spatial variation of rift evolution (comparison of sites in the central and eastern rift). The sediments contain a rich and complex record of changing sedimentation, sediment and pore water geochemistry, and environmental conditions from micropaleontological assemblages. The preliminary chronology developed by shipboard analyses will be refined and improved during postexpedition research, providing a high-resolution chronostratigraphy down to the orbital timescale for a range of tectonic, sedimentological, and paleoenvironmental studies. This chronology will provide absolute timing of key rift events, rates of fault movement, rift extension and subsidence, and the spatial variations of these parameters. The core data will also allow us to investigate the relative roles of and feedbacks between tectonics, climate, and eustasy in sediment flux, basin evolution, and basin environment. Finally, the Corinth rift boreholes will provide the first long Quaternary record of Mediterranean-type climate in the region. The potential range of scientific applications for this unique data set is very large, encompassing tectonics, sedimentary processes, paleoenvironment, paleoclimate, paleoecology, geochemistry, and geohazards

Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium

Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan). The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (< 2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer. Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52). These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation