Effects of Eph/ephrin signalling and human Alzheimer's disease-associated EphA1 on Drosophila behaviour and neurophysiology.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease placing a great burden on people living with it, carers and society. Yet, the underlying patho-mechanisms remain unknown and treatments limited. To better understand the molecular changes associated with AD, genome-wide association studies (GWAS) have identified hundreds of candidate genes linked to the disease, like the receptor tyrosine kinase EphA1. However, demonstration of whether and how these genes cause pathology is largely lacking. Here, utilising fly genetics, we generated the first Drosophila model of human wild-type and P460L mutant EphA1 and tested the effects of Eph/ephrin signalling on AD-relevant behaviour and neurophysiology. We show that EphA1 mis-expression did not cause neurodegeneration, shorten lifespan or affect memory but flies mis-expressing the wild-type or mutant receptor were hyper-aroused, had reduced sleep, a stronger circadian rhythm and increased clock neuron activity and excitability. Over-expression of endogenous fly Eph and RNAi-mediated knock-down of Eph and its ligand ephrin affected sleep architecture and neurophysiology. Eph over-expression led to stronger circadian morning anticipation while ephrin knock-down impaired memory. A dominant negative form of the GTPase Rho1, a potential intracellular effector of Eph, led to hyper-aroused flies, memory impairment, less anticipatory behaviour and neurophysiological changes. Our results demonstrate a role of Eph/ephrin signalling in a range of behaviours affected in AD. This presents a starting point for studies into the underlying mechanisms of AD including interactions with other AD-associated genes, like Rho1, Ankyrin, Tau and APP with the potential to identify new targets for treatment.

From coseismic offsets to fault-block mountains.

In the Basin and Range extensional province of the western United States, coseismic offsets, under the influence of gravity, display predominantly subsidence of the basin side (fault hanging wall), with comparatively little or no uplift of the mountainside (fault footwall). A few decades later, geodetic measurements [GPS and interferometric synthetic aperture radar (InSAR)] show broad (∼100 km) aseismic uplift symmetrically spanning the fault zone. Finally, after millions of years and hundreds of fault offsets, the mountain blocks display large uplift and tilting over a breadth of only about 10 km. These sparse but robust observations pose a problem in that the coesismic uplifts of the footwall are small and inadequate to raise the mountain blocks. To address this paradox we develop finite-element models subjected to extensional and gravitational forces to study time-varying deformation associated with normal faulting. Stretching the model under gravity demonstrates that asymmetric slip via collapse of the hanging wall is a natural consequence of coseismic deformation. Focused flow in the upper mantle imposed by deformation of the lower crust localizes uplift, which is predicted to take place within one to two decades after each large earthquake. Thus, the best-preserved topographic signature of earthquakes is expected to occur early in the postseismic period.

Stress changes from the 2008 Wenchuan earthquake and increased hazard in the Sichuan basin.

On 12 May 2008, the devastating magnitude 7.9 (Wenchuan) earthquake struck the eastern edge of the Tibetan plateau, collapsing buildings and killing thousands in major cities aligned along the western Sichuan basin in China. After such a large-magnitude earthquake, rearrangement of stresses in the crust commonly leads to subsequent damaging earthquakes. The mainshock of the 12 May earthquake ruptured with as much as 9 m of slip along the boundary between the Longmen Shan and Sichuan basin, and demonstrated the complex strike-slip and thrust motion that characterizes the region. The Sichuan basin and surroundings are also crossed by other active strike-slip and thrust faults. Here we present calculations of the coseismic stress changes that resulted from the 12 May event using models of those faults, and show that many indicate significant stress increases. Rapid mapping of such stress changes can help to locate fault sections with relatively higher odds of producing large aftershocks.

Predictors of Positive Outcomes and a Scoring System to Guide Management After Fasciotomy for Chronic Exertional Compartment Syndrome.

Background: Chronic exertional compartment syndrome (CECS) of the lower limb usually responds well to fasciotomy in patients with failed nonoperative treatment. Careful history taking and compartment pressure testing are both required to accurately diagnose CECS. Purposes: To evaluate patients with CECS after fasciotomy to establish predictive criteria of positive outcomes and to develop a scoring system to aid clinicians in their management of such patients. Study Design: Case-control study; Level of evidence, 3. Methods: We reviewed data from 28 patients who underwent fasciotomy between 2017 and 2019. All patients had undergone preoperative dynamic intracompartmental pressure (ICP) monitoring. For each patient, subjective preoperative and postoperative pain scores were gained via a questionnaire. The point biserial and Pearson correlation coefficients were used to calculate the association between multiple diagnostic criteria and a reduction in visual analog scale (VAS) pain scores after fasciotomy. Results: A reduction in VAS pain scores was strongly correlated with a peak ICP >40 mm Hg (r = 0.71; P = .0007) and an area under the receiver operating characteristic curve for an intraexercise ICP >22,000 mm Hg·s2 (r = 0.76; P = .0002). A moderate correlation was found between a history of CECS pain (r = 0.61; P = .005), a duration of symptoms of <30 minutes after stopping exercise (r = 0.60; P = .006), and a gradient in the intraexercise ICP >10 mm Hg (r = 0.60; P = .006). When combined into an objective, weighted scoring system (2 points for factors with r > 0.7; 1 point for r = 0.5-0.7), a score of ≥4 points (of 7) had a strong correlation (r = 0.85; P < .00001) with postoperative improvement in the VAS pain score. Linear regression of this score demonstrated a good fit (R 2 = 0.61; P < .0001), indicating a degree of predictive power. Conclusion: We identified diagnostic criteria in the history and examination of patients with CECS that can be used to help predict positive outcomes after fasciotomy. We propose a scoring system to aid clinicians in their management of such patients. We recommend taking these results forward in prospective trials to test the efficacy of predictive scoring.

DYRK1a Inhibitor Mediated Rescue of Drosophila Models of Alzheimer's Disease-Down Syndrome Phenotypes.

Alzheimer's disease (AD) is the most common neurodegenerative disease which is becoming increasingly prevalent due to ageing populations resulting in huge social, economic, and health costs to the community. Despite the pathological processing of genes such as Amyloid Precursor Protein (APP) into Amyloid-ß and Microtubule Associated Protein Tau (MAPT) gene, into hyperphosphorylated Tau tangles being known for decades, there remains no treatments to halt disease progression. One population with increased risk of AD are people with Down syndrome (DS), who have a 90% lifetime incidence of AD, due to trisomy of human chromosome 21 (HSA21) resulting in three copies of APP and other AD-associated genes, such as DYRK1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) overexpression. This suggests that blocking DYRK1A might have therapeutic potential. However, it is still not clear to what extent DYRK1A overexpression by itself leads to AD-like phenotypes and how these compare to Tau and Amyloid-ß mediated pathology. Likewise, it is still not known how effective a DYRK1A antagonist may be at preventing or improving any Tau, Amyloid-ß and DYRK1a mediated phenotype. To address these outstanding questions, we characterised Drosophila models with targeted overexpression of human Tau, human Amyloid-ß or the fly orthologue of DYRK1A, called minibrain (mnb). We found targeted overexpression of these AD-associated genes caused degeneration of photoreceptor neurons, shortened lifespan, as well as causing loss of locomotor performance, sleep, and memory. Treatment with the experimental DYRK1A inhibitor PST-001 decreased pathological phosphorylation of human Tau [at serine (S) 262]. PST-001 reduced degeneration caused by human Tau, Amyloid-ß or mnb lengthening lifespan as well as improving locomotion, sleep and memory loss caused by expression of these AD and DS genes. This demonstrated PST-001 effectiveness as a potential new therapeutic targeting AD and DS pathology.

DYRK1A antagonists rescue degeneration and behavioural deficits of in vivo models based on amyloid-ß, Tau and DYRK1A neurotoxicity.

Alzheimer's disease (AD) involves pathological processing of amyloid precursor protein (APP) into amyloid-ß and microtubule associated protein Tau (MAPT) into hyperphosphorylated Tau tangles leading to neurodegeneration. Only 5% of AD cases are familial making it difficult to predict who will develop the disease thereby hindering our ability to treat the causes of the disease. A large population who almost certainly will, are those with Down syndrome (DS), who have a 90% lifetime incidence of AD. DS is caused by trisomy of chromosome 21 resulting in three copies of APP and other AD-associated genes, like dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) overexpression. This implies that DYRK1a inhibitors may have therapeutic potential for DS and AD, however It is not clear how overexpression of each of these genes contributes to the pathology of each disease as well as how effective a DYRK1A inhibitor would be at suppressing any of these. To address this knowledge gap, we used Drosophila models with human Tau, human amyloid-ß or fly DYRK1A (minibrain (mnb)) neuronal overexpression resulting in photoreceptor neuron degeneration, premature death, decreased locomotion, sleep and memory loss. DYRK1A small molecule Type 1 kinase inhibitors (DYR219 and DYR533) were effective at suppressing these disease relevant phenotypes confirming their therapeutic potential.

Identification of a regulatory autophosphorylation site in the serine-threonine kinase RIP2.

Receptor-interacting protein 2 (RIP2) is a serine-threonine kinase that mediates signaling for many receptors of the innate and adaptive immune systems. Toll like receptors (TLR) are an important component of the innate immune response. Stimulation of RIP2-deficient cells with ligands for TLR 2, 3 and 4 results in impaired cytokine production and decreased activation of NF-kB and MAP kinases compared to wild-type cells. Stimulation of TLR 4 with its ligand lipopolysaccaride (LPS) leads to the activation of RIP2 kinase activity and its autophosphorylation. Here we identify serine residue 176 as a site of autophosphorylation using a combination of mass spectrometry and mutational analysis. Mutation of S176 to alanine not only abolishes autophosphorylation of RIP2 but also significantly decreases its catalytic activity. A phospho-specific anti-S176 antibody detects wild-type RIP2 but not kinase-dead RIP2 or the RIP2 S176A mutant. Endogenous RIP2 in THP-1 cells and mouse bone marrow derived macrophages can be detected by the phospho-RIP2 (S176) antibody only after stimulation with LPS suggesting that the antibody recognizes activated RIP2. In summary, our results indicate that S176 is a regulatory autophosphorylation site for RIP2 and that S176 phosphorylation can be used to monitor the activation state of RIP2.

Nucleation speed limit on remote fluid-induced earthquakes.

Earthquakes triggered by other remote seismic events are explained as a response to long-traveling seismic waves that temporarily stress the crust. However, delays of hours or days after seismic waves pass through are reported by several studies, which are difficult to reconcile with the transient stresses imparted by seismic waves. We show that these delays are proportional to magnitude and that nucleation times are best fit to a fluid diffusion process if the governing rupture process involves unlocking a magnitude-dependent critical nucleation zone. It is well established that distant earthquakes can strongly affect the pressure and distribution of crustal pore fluids. Earth's crust contains hydraulically isolated, pressurized compartments in which fluids are contained within low-permeability walls. We know that strong shaking induced by seismic waves from large earthquakes can change the permeability of rocks. Thus, the boundary of a pressurized compartment may see its permeability rise. Previously confined, overpressurized pore fluids may then diffuse away, infiltrate faults, decrease their strength, and induce earthquakes. Magnitude-dependent delays and critical nucleation zone conclusions can also be applied to human-induced earthquakes.

Missing link between the Hayward and Rodgers Creek faults.

The next major earthquake to strike the ~7 million residents of the San Francisco Bay Area will most likely result from rupture of the Hayward or Rodgers Creek faults. Until now, the relationship between these two faults beneath San Pablo Bay has been a mystery. Detailed subsurface imaging provides definitive evidence of active faulting along the Hayward fault as it traverses San Pablo Bay and bends ~10° to the right toward the Rodgers Creek fault. Integrated geophysical interpretation and kinematic modeling show that the Hayward and Rodgers Creek faults are directly connected at the surface-a geometric relationship that has significant implications for earthquake dynamics and seismic hazard. A direct link enables simultaneous rupture of the Hayward and Rodgers Creek faults, a scenario that could result in a major earthquake (M = 7.4) that would cause extensive damage and loss of life with global economic impact.

A new probabilistic seismic hazard assessment for greater Tokyo.

Tokyo and its outlying cities are home to one-quarter of Japan's 127 million people. Highly destructive earthquakes struck the capital in 1703, 1855 and 1923, the last of which took 105,000 lives. Fuelled by greater Tokyo's rich seismological record, but challenged by its magnificent complexity, our joint Japanese-US group carried out a new study of the capital's earthquake hazards. We used the prehistoric record of great earthquakes preserved by uplifted marine terraces and tsunami deposits (17 M approximately 8 shocks in the past 7000 years), a newly digitized dataset of historical shaking (10000 observations in the past 400 years), the dense modern seismic network (300,000 earthquakes in the past 30 years), and Japan's GeoNet array (150 GPS vectors in the past 10 years) to reinterpret the tectonic structure, identify active faults and their slip rates and estimate their earthquake frequency. We propose that a dislodged fragment of the Pacific plate is jammed between the Pacific, Philippine Sea and Eurasian plates beneath the Kanto plain on which Tokyo sits. We suggest that the Kanto fragment controls much of Tokyo's seismic behaviour for large earthquakes, including the damaging 1855 M approximately 7.3 Ansei-Edo shock. On the basis of the frequency of earthquakes beneath greater Tokyo, events with magnitude and location similar to the M approximately 7.3 Ansei-Edo event have a ca 20% likelihood in an average 30 year period. In contrast, our renewal (time-dependent) probability for the great M > or = 7.9 plate boundary shocks such as struck in 1923 and 1703 is 0.5% for the next 30 years, with a time-averaged 30 year probability of ca 10%. The resulting net likelihood for severe shaking (ca 0.9 g peak ground acceleration (PGA)) in Tokyo, Kawasaki and Yokohama for the next 30 years is ca 30%. The long historical record in Kanto also affords a rare opportunity to calculate the probability of shaking in an alternative manner exclusively from intensity observations. This approach permits robust estimates for the spatial distribution of expected shaking, even for sites with few observations. The resulting probability of severe shaking is ca 35% in Tokyo, Kawasaki and Yokohama and ca 10% in Chiba for an average 30 year period, in good agreement with our independent estimate, and thus bolstering our view that Tokyo's hazard looms large. Given 1 trillion US dollars estimates for the cost of an M approximately 7.3 shock beneath Tokyo, our probability implies a 13 billion US dollars annual probable loss.