Event In AD Research Articles

The impact of volcanism on Scandinavian climate and human societies during the Holocene: Insights into the Fimbulwinter eruptions (536/540 AD)

Recent paleoclimatic research has revealed that volcanic events around 536–540 AD caused severe, short-term global cooling. For this same period, archeological research from various regions evidences significant cultural transformation. However, there is still a lack of understanding of how human societies responded and adapted to extreme climate variability and new circumstances. This study focuses on the effects of the 536/540 AD volcanic event in four Scandinavian regions by exploring the shift in demographic and land use intensity before, during, and after this abrupt climate cooling. To achieve this, we performed climate simulations with and without volcanic eruptions using a dynamically downscaled climate model (iLOVECLIM) at a high resolution (0.25° or ~25 km). We integrated the findings with a comprehensive collection of radiocarbon dates from excavated archeological sites across various Scandinavian regions. Our Earth System Model simulates pronounced cooling (maximum ensemble mean −1.1°C), an abrupt reduction in precipitation, and a particularly acute drop in growing degree days (GDD0) after the volcanic event, which can be used to infer likely impacts on agricultural productivity. When compared to the archeological record, we see considerable regional diversity in the societal response to this sudden environmental event. As a result, this study provides a more comprehensive insight into the demographic chronology of Scandinavia and a deeper understanding of the land-use practices its societies depended on during the 536/540 AD event. Our results suggest that this abrupt climate anomaly amplified a social change already in progress.

Self-Supervised Masked Convolutional Transformer Block for Anomaly Detection.

Anomaly detection has recently gained increasing attention in the field of computer vision, likely due to its broad set of applications ranging from product fault detection on industrial production lines and impending event detection in video surveillance to finding lesions in medical scans. Regardless of the domain, anomaly detection is typically framed as a one-class classification task, where the learning is conducted on normal examples only. An entire family of successful anomaly detection methods is based on learning to reconstruct masked normal inputs (e.g. patches, future frames, etc.) and exerting the magnitude of the reconstruction error as an indicator for the abnormality level. Unlike other reconstruction-based methods, we present a novel self-supervised masked convolutional transformer block (SSMCTB) that comprises the reconstruction-based functionality at a core architectural level. The proposed self-supervised block is extremely flexible, enabling information masking at any layer of a neural network and being compatible with a wide range of neural architectures. In this work, we extend our previous self-supervised predictive convolutional attentive block (SSPCAB) with a 3D masked convolutional layer, a transformer for channel-wise attention, as well as a novel self-supervised objective based on Huber loss. Furthermore, we show that our block is applicable to a wider variety of tasks, adding anomaly detection in medical images and thermal videos to the previously considered tasks based on RGB images and surveillance videos. We exhibit the generality and flexibility of SSMCTB by integrating it into multiple state-of-the-art neural models for anomaly detection, bringing forth empirical results that confirm considerable performance improvements on five benchmarks: MVTec AD, BRATS, Avenue, ShanghaiTech, and Thermal Rare Event.

Concordance between APOE genotyping and proteotyping using the novel Lumipulse G Pan‐ApoE and Lumipulse G ApoE4 RUO assays

AbstractBackgroundThe APOE gene has three different alleles that encode for three different ApoE protein isoforms (APOE2, APOE3, and APOE4), resulting in 6 different phenotypes. Nucleic acid amplification test remains the gold standard for APOE genotyping, however quantification of the ApoE proteins using immunoassays could provide another piece of information, related to the expression levels of the proteins. In this regard, ApoE as a protein biomarker can be used in research to determine its value alone or as part of a panel of plasma biomarkers.MethodThe LUMIPULSE G System is a chemiluminescent enzyme immunoassay platform enabling fully automated processing of samples using ready‐to‐use immunoreaction cartridges. Time to result in these single use test cartridges takes about 30 minutes. The analytical performance of the newly developed Lumipulse G Pan‐ApoE and Lumipulse G ApoE4 RUO assays was determined. Parameters analyzed were precision, sensitivity, linearity, prozone and potential impact of interfering substances. Proof of concept of these novel assays was verified with a set of 230 genotyped plasma samples.ResultThe total within‐lab variability of both assays was ≤8% CV confirming high precision of the LUMIPULSE G system. Using low ApoE concentrated plasma samples, the observed LoD and LoQ (@20% CV) was 0.072 µg/mL (Pan‐ApoE) and 0.152 µg/mL (ApoE4). Linearity was shown across the assay range (0 – 100 µg/mL) for both assays. Neither prozone effect nor significant impact (recovery within 100±10%) of commonly tested endogenous substances (bilirubin, haemoglobin, low and high Protein content, and human anti‐mouse antibodies (HAMA)) was observed. Potential interference was observed for triglycerides and rheumatoid factor (RF) with observed recovery within 100±20%. ApoE proteotyping based on the novel assays resulted in a 99.8% concordance with APOE genotyping (1 discordant result). Moreover, applying the ratio ApoE4/Pan‐ApoE with the measurement values of respective assays, classified correctly between hetero‐ and homozygous E4 carrier status.ConclusionThe analytical performance studies demonstrate low variability and high sensitivity enabling measurement of pan‐ApoE and ApoE4 in plasma. Pan‐apoE and apoE4 quantification can offer relevant insights into the assessment of subjects at risk for AD or adverse events following anti‐amyloid treatments and should be studied further.

Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants

The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear. We sought to assess a potential link between HLHa outcomes and HLH-related gene variants. Clinical characteristics of 130 HLHa patients (age≥ 18 years and HScore≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. Atotal of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit. HLHa-associated diseases (ADs) were neoplasia (n= 49 [37.7%]), autoimmune/inflammatory disease (n= 33 [25.4%]), or idiopathic when no AD was identified (n= 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P= .0008; 2-3 vs 0: 29.4 [3.62-3810], P= .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P= .018; 2-3 vs 0: 13.2 [2.91-126.8], P= .0003). HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

Paleoseismological investigation along the back thrust bounding the northern limb of Janauri Anticline, NW Himalaya, India

Regardless of numerous paleoseismological studies along the active front of the Himalayas, it still lacks precision with respect to earthquake recurrence, rupture, slip mechanism, etc. which hinders understanding of the region's seismic hazards. Considering the seismic hazard posed by the previous Himalayan earthquakes, for instance, from Kashmir, Chamba, Kumaun-Garhwal, Nepal, etc., it becomes vital to identify the seismogenic structures and length of rupture that might be affected in the near future. In the present study, the paleoseismological investigation is carried out along the ∼150 km long Back Thrust (BT) of Himalayan Frontal Thrust bounding the northern limb of Janauri Anticline (JA) in northwest frontal Himalaya. By taking advantage of the optically stimulated luminescence (OSL) dating technique, the present study reports three newly identified seismic events along the BT i.e. 535-1269 AD Event I, 1447–1636 AD Event II, and 1660–1929 AD Event III. Our findings at Palahta locality of Punjab state complement, i.e., 1447–1636 AD (Event II), the effectiveness of previously identified more recent earthquake (MRE) at Hajipur, which further suggest the rupture length of ∼97 km along BT. The other results on the timing of seismic events (Event I and Event III) are well thought out and considered here as independent. Such independent events tend to fill an important gap in the database and provide us an opportunity to explore the paleoseismic events in more detail along the seismogenic structures of the Himalayas. Such a well-established database would assist in better seismic hazard estimation and will directly influence the long-term planning for infrastructure development in the regions like the Himalayas.

What is the impact of ongoing statin use on cognitive decline and dementia progression in older adults with mild-moderate Alzheimer disease?

In addition to the clear cardiovascular benefit, there has been renewed interest in the potential of statins in the prevention of cognitive impairment and dementia in older adults. However, whether ongoing statin use can delay cognitive decline or dementia progression in those with established Alzheimer dementia, is unclear. Using data from NILVAD, we analysed the association between ongoing statin use and cognitive decline (Alzheimer Disease Assessment Scale-Cognitive Subsection [ADAS-Cog])/dementia progression (Clinical Dementia Rating Scale [CDR-Sb]/Disability Assessment for Dementia [DAD]) over 18 months in older adults with mild-moderate AD. Additionally, we assessed the association between ongoing statin use and adverse events in mild-moderate AD. Over one-third (34.9%) of 510 older adults with mild-moderate AD (aged: 72.9 years; 61.9% female) used a statin for the 18-month study duration. Statin use was not associated with the rate of cognitive decline (β: -0.67; 95% CI: -1.71, 0.36, p = 0.20) or dementia progression (β: -0.34; 95% CI -0.71, 0.02; p = 0.07 for CDR-Sb/ β: -2.00; -5.70, 1.70; p = 0.29 for DAD). Further, ongoing statin use was not associated with adverse events, serious adverse events, unscheduled GP visits, or unscheduled hospitalisation. Ongoing statin use was not associated with cognitive decline or dementia progression in mild-moderate AD. Similarly, use was not associated with adverse events including abnormal liver function tests or falls. Whilst safe in those with AD, the current results suggest ongoing statin use does not delay cognitive decline or clinical progression in established AD.

An Iron Age Shock Doctrine

In this article, a dataset of burial grounds is considered in relation to the question of a probable demographic crisis in the 6th century AD, as a consequence of the cosmic event in AD 536-7. Although indications of an extensive crisis can be seen in a wide range of sources, it is difficult to make any estimate of the extent of the crisis. Some hypothetical social consequences are, however, discussed and compared to the Black Death in the 14th century AD. For the 6th century crisis, a widespread upheaval and renegotiation of property rights for land that has been abandoned is suggested, together with a possible redefinition of the nature of property rights. After the crisis there seem to be increased possibilities for private ownership of land, which enables the acquisition of large landholdings among a limited number of people. This is related to an increasingly stratified social structure in the Late Iron Age, where an elite is thought to have been able to take advantage of the crisis for their own benefit. It is argued that this is reflected in the Late Iron Age/Vendel Period burial grounds and their locations, as these might have been used to manifestrenewed property rights.

Assessment of the radiation risk at flight altitudes for an extreme solar particle storm of 774 AD

Intense solar activity can lead to an acceleration of solar energetic particles and accordingly increase in the complex radiation field at commercial aviation flight altitudes. We considered here the strongest ever reported event, namely that of 774 AD registered on the basis of cosmogenic-isotope measurements, and computed the ambient dose at aviation altitude(s). Since the spectrum of solar protons during the 774 AD event cannot be directly obtained, as a first step, we derived the spectra of the solar protons during the ground level enhancement (GLE) #5 on 23 February 1956, the strongest event observed by direct measurements, which was subsequently scaled to the size of the 774 AD event and eventually used as input to the corresponding radiation model. The GLE #5 was considered a conservative approach because it revealed the hardest-ever derived energy spectrum. The global map of the ambient dose was computed under realistic data-based reconstruction of the geomagnetic field during the 774 AD epoch, based on paleomagnetic measurements. A realistic approach on the basis of a GLE #45 on 24 October 1989 was also considered, that is by scaling an event with softer spectra and lower particle fluxes compared to the GLE #5. The altitude dependence of the event-integrated dose at altitudes from 30 kft to 50 kft (9.1–15.2 km) was also computed for both scenarios. Our study of the radiation effects during the extreme event of 774 AD gives the necessary basis to be used as a reference to assess the worst-case scenario for a specific threat, that is radiation dose at flight altitudes.

Early accumulation of Aβ and Tau is associated with increase in cortical thickness

AbstractBackgroundThere is no consensus in the field regarding the relationship between AD pathologies (Aβ, and Tau) and neurodegeneration. One reason that may contribute to this disagreement is the definition of cut‐point to categorize participants with or without significant pathologies. This approach overlooks an important early stage of pathological accumulation. In this study, we take advantage of Florbetaben/MK6240 PET scans from 61/21 young (<40) and healthy participants to redefined the cut‐point of Aβ/Tau uptake and investigate their association with cortical thickness as a measurement of neurodegeneration.MethodTo capture the early effect of pathologies, we quantify global pathologies by averaging AD‐related regions uptake; global Aβ: frontal, parietal, temporal, anterior and posterior cingulate, and precuneus, global Tau: fusiform, amygdala, parahippocampal, entorhinal, inferior temporal, middle temporal, and medial temporal lobe (MTL) Tau: entorhinal and parahippocampal. We redefied the cut‐point of AD pathologies using 95% percentile of the fitted normal distribution to the young subject's uptakes. Using newly defined cut‐points (1.01<global Aβ<1.25, 0.72<global Tau<1.15, and 0.66<MTL Tau<1.11), we identified 232 older participant (64.79±3.55, 94 males, 229 HC) from 394 healthy control (HC) and 52 with mild cognitive impairment (MCI). To assess the relationship between AD pathologies and neurodegeneration, we run a multiple regression to model cortical thickness at each vertex in the identified elders with global Aβ, and global Tau controlling for age, gender, and Intracranial volume (ICV).ResultEarly and low accumulation of Aβ and Tau were associated with higher cortical thickness in many regions throughout the cerebral cortex. More interestingly, MTL (where the early Tau deposition occurs) was among the regions showing a positive association with Aβ deposition and cortical thickness.ConclusionThese results, provide preliminary evidence that early and low accumulations of AD pathologies are associated with higher cortical thickness. Our results may shed some light on the discrepancies between the existing studies investigating the same relationship. As it has been recently hypothesized, it suggests that the cascade of events in AD may start much earlier than what had been considered in the field and this early accumulation of Aβ and Tau has completely different consequences on brain structure/function.

Anti-alzheimer’s Disease Potential of Arabian Coffee Versus Date Palm Seed Extract in Male Rats

Abstract Objectives Utilizing the aluminum chloride rat model for AD to compare the influence of moderately caffeinated (Arabian) and decaffeinated (Date palm seed) coffee on cognitive impairment and pathological events in AD. Methods Twenty Adult Albino male rats of Wistar strain (230 ± 20 g) were divided 4 groups: Group 1: Rats received vehicle and termed as Negative control (NC) group. • Group 2: Rats received Aluminum chloride (10 mg/kg bw, i.p) for 3 weeks (Khan et al., 2013b), starting from 6th to 26th day to induce AD. They were left un-treated and termed as AlCl3 group. • Group 3: Rats were treated intraperitoneally with AlCl3 (10 mg/kg bw) + Arabian coffee aqueous extract (240 mg/kg bw/day, p.o) for 2 weeks (Jang et al., 2013), starting from the 27th day and termed as AlCl3 + Arabian coffee group. This dose is nearly equivalent to human consumption of 6 cups of coffee. • Group 4: Treated intraperitoneally with AlCl3 (10 mg/kg bw) + standardized extract of Date Palm seed dried powder (240 mg/kg bw/day, p.o) for 2 weeks, starting from the 27th day and termed as AlCl3 + Date seed extract group. Results AD rats given Arabian or Date palm seed coffee were protected against memory impairment and had lower serum levels of the abnormal protein (amyloidbeta; Aβ1–42), the central pathogenic contributor to AD, and transforming growth factor-beta (TGF-β). Interestingly, Date palm seed (decaffeinated) coffee seems to provide more pronounced protection against AD than Arabian (moderately caffeinated) coffee as evidenced by the greater decrease in serum Aβ levels. These results suggest a surprising therapeutic potential of moderate caffeine intake in Arabian coffee to ameliorate AD through decreasing serum Aβ levels. However, Date palm seed (decaffeinated) coffee, rich in flavonoids, appears to provide a better AD-modifying ability through a direct reduction of Aβ production. Conclusions Consumption of Arabian coffee containing moderate caffeine seems to ameliorate AD-induced cognitive impairment via decreasing Aβ levels. Interestingly, intake of decaffeinated Date seed extract, rich in flavonoids, appears to provide a superior anti-AD potential through a direct reduction of Aβ production. Funding Sources No funding.

Identification of prognostic alternative splicing signature in gastric cancer

BackgroundAberrant alternative splicing (AS) events could be viewed as prognostic indicators in a large number of malignancies. This study aims to identify prognostic AS events, illuminate the function of the splicing variants biomarkers and provide reliable evidence for formulating public health strategies for gastric cancer (GC) surveillance.MethodsRNA-Seq data, clinical information and percent spliced in (PSI) values were available in The cancer genome atlas (TCGA) and TCGA SpliceSeq data portal. A three-step regression method was conducted to identify prognostic AS events and construct multi-AS-based signatures. The associations between prognostic AS events and splicing factors were also investigated.ResultsWe identified a total of 1,318 survival-related AS events in GC, parent genes of which were implicated in numerous oncogenic pathways. The final prognostic signatures stratified by seven types of AS events or not stratified performed well in risk prediction for GC patients. Moreover, five signatures based on AA, AD, AT, ES and RI events function as independent prognostic indicators after multivariate adjustment of other clinical variables. Splicing network also showed marked correlation between the expression of splicing factors and PSI value of AS events in GC patients.ConclusionOur findings provide a landscape of AS events and regulatory network in GC, indicating that AS events might serve as prognostic biomarkers and therapeutic targets for GC.

γ-Secretase in Alzheimer's disease.

Alzheimer’s disease (AD) is caused by synaptic and neuronal loss in the brain. One of the characteristic hallmarks of AD is senile plaques containing amyloid β-peptide (Aβ). Aβ is produced from amyloid precursor protein (APP) by sequential proteolytic cleavages by β-secretase and γ-secretase, and the polymerization of Aβ into amyloid plaques is thought to be a key pathogenic event in AD. Since γ-secretase mediates the final cleavage that liberates Aβ, γ-secretase has been widely studied as a potential drug target for the treatment of AD. γ-Secretase is a transmembrane protein complex containing presenilin, nicastrin, Aph-1, and Pen-2, which are sufficient for γ-secretase activity. γ-Secretase cleaves >140 substrates, including APP and Notch. Previously, γ-secretase inhibitors (GSIs) were shown to cause side effects in clinical trials due to the inhibition of Notch signaling. Therefore, more specific regulation or modulation of γ-secretase is needed. In recent years, γ-secretase modulators (GSMs) have been developed. To modulate γ-secretase and to understand its complex biology, finding the binding sites of GSIs and GSMs on γ-secretase as well as identifying transiently binding γ-secretase modulatory proteins have been of great interest. In this review, decades of findings on γ-secretase in AD are discussed.

Evolution of the magma plumbing system of Miyakejima volcano with periodic recharge of basaltic magmas

Defining the variations in petrological characteristics of erupted magmas within a high-resolution chronostratigraphy provides a necessary framework for monitoring the long-term activity and eruption potential of an active volcano. Here, we investigate the evolution of the magmatic system of Miyakejima volcano, Japan, between the last two caldera-forming eruptions, at ~ 2.3 ka and AD 2000, based on new stratigraphic constraints, radiocarbon ages, and whole-rock geochemical data. The activity of Miyakejima during this interval can be divided into three magmatic periods based on cyclic whole-rock compositional trends. Period 1 spans the interval between ~ 2.3 ka and the 7th century, from the Hatchodaira eruption with caldera collapse to immediately before the Suoana–Kazahaya eruption. Period 2 spans the time period between the seventh century and the fourteenth century, from the Suoana–Kazahaya to the Sonei–bokujyo eruptions. Period 3 covers the period from the two major flank eruptions that occurred in the sixteenth century to the end of the twentieth century until the last caldera-collapse event in AD 2000. The eruption rate decreased from 0.5 km3 per 1000 years in Period 1 to ~ 0.2 km3 per 1000 years in Period 2 and 3. Recharge of primitive basaltic magmas into shallower crustal systems triggered extensive basaltic fissure eruptions at the beginning of each period. Progressively increasing whole-rock SiO2 contents of the hybrid magmas in subsequent eruptions indicates continuous fractional crystallization in small shallow magma chambers which formed at the start of each magmatic period. Intermittent injections of basaltic magma into shallow magma chambers induced magma mixing that caused eruption of hybrid basaltic andesite in each period. We suggest that some basaltic magmas formed isolated magma reservoirs at shallow depth, in which rapid fractionation was able to occur. Rupturing of these isolated magma storage regions filled with gas-rich evolved magma can lead to violent ejection of andesitic magmas, such as for the Suoana–Kazahaya eruption in the seventh century. Our results suggest two main scenarios of eruption for the basaltic magma system at Miyakejima and similar mafic volcanoes in the northern Izu–Bonin arc; (1) eruption of voluminous basaltic lavas after the recharge of primitive basaltic magmas into the shallow magmatic system, and (2) explosive fissure eruption by rupturing of isolated magma bodies filled with gas-rich evolved magmas.Graphical

Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research.

Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research.

Gray matter network properties show distinct associations with CSF p-tau 181 levels and amyloid status in individuals without dementia.

Gray matter networks are altered with amyloid accumulation in the earliest stage of AD, and are associated with decline throughout the AD spectrum. It remains unclear to what extent gray matter network abnormalities are associated with hyperphosphorylated-tau (p-tau). We studied the relationship of cerebrospinal fluid (CSF) p-tau181 with gray matter networks in non-demented participants from the European Prevention of Alzheimer's Dementia (EPAD) cohort, and studied dependencies on amyloid and cognitive status. Gray matter networks were extracted from baseline structural 3D T1w MRI. P-tau181 and abeta were measured with the Roche cobas Elecsys System. We studied the associations of CSF biomarkers levels with several network's graph properties. We further studied whether the relationships of p-tau 181 and network measures were dependent on amyloid status and cognitive stage (CDR). We repeated these analyses for network properties at a regional level, where we averaged local network values across cubes within each of 116 areas as defined by the automated anatomical labeling (AAL) atlas. Amyloid positivity was associated with higher network size and betweenness centrality, and lower gamma, clustering and small-world coefficients. Higher CSF p-tau 181 levels were related to lower betweenness centrality, path length and lambda coefficients (all p < 0.01). Three-way interactions between p-tau181, amyloid status and CDR were found for path length, lambda and clustering (all p < 0.05): Cognitively unimpaired amyloid-negative participants showed lower path length and lambda values with higher CSF p-tau181 levels. Amyloid-positive participants with impaired cognition demonstrated lower clustering coefficients in association to higher CSF p-tau181 levels. Our results suggest that alterations in gray matter network clustering coefficient is an early and specific event in AD.

Tsunamis in the Greek Region: An Overview of Geological and Geomorphological Evidence

The Greek region is known as one of the most seismically and tectonically active areas and it has been struck by some devastating tsunamis, with the most prominent one being the 365 AD event. During the past decade significant research efforts have been made in search of geological and geomorphological evidence of palaeotsunamis along the Greek coasts, primarily through the examination of sediment corings (72% of studies) and secondarily through boulders (i.e., 18%). The published data show that some deposits have been correlated with well-known events such as 365 AD, 1303 AD, the Minoan Santorini Eruption and the 1956 Amorgos earthquake and tsunami, while coastal studies from western Greece have also reported up to five tsunami events, dating as far back as the 6th millennium BC. Although the Ionian Islands, Peloponnese and Crete has been significantly studied, in the Aegean region research efforts are still scarce. Recent events such as the 1956 earthquake and tsunami and the 2020 Samos earthquake and tsunami highlight the need for further studies in this region, to better assess the impact of past events and for improving our knowledge of tsunami history. As Greece is amongst the most seismically active regions globally and has suffered from devastating tsunamis in the past, the identification of tsunami prone areas is essential not only for the scientific community but also for public authorities to design appropriate mitigation measures and prevent tsunami losses in the future.

Amyloid time: Quantifying the onset of abnormal biomarkers and cognitive impairment along the Alzheimer’s disease continuum

AbstractBackgroundQuantifying the temporal progression of key pathophysiological events in Alzheimer’s disease is crucial for staging disease, dementia risk assessment, and informing clinical trials. This work extends a novel algorithm (sampled iterative local linear approximation; SILLA) developed for modeling PET trajectories to: 1) generate a unified CSF and PET amyloid accumulation timeline, and 2) characterize the temporal progression of biomarker and cognitive changes in AD.Method941 participants from the Wisconsin Registry of Alzheimer’s Prevention, Wisconsin Alzheimer’s Disease Research Center, and Statins in Healthy, At‐Risk Adults: Impact on Amyloid and Regional Perfusion studies underwent [C‐11]PiB PET and/or lumbar puncture; and a subset underwent [F‐18]MK‐6240 PET and anatomical MRI using standardized protocols (Table 1). Amyloid burden was quantified from cortical PiB DVR and CSF Aβ42/40. Amyloid Time, quantified as years from CSF Aβ42/40 positivity, was estimated by simultaneously modeling Aβ42/40 and PiB DVR using an extension of the SILLA method in a subset of 248 participants with both measurements. CSF biomarkers measured using the exploratory Roche NeuroToolKit assays, imaging biomarkers, and cognitive impairment (global CDR, CDR SOB, and diagnosis) were plotted as a function of Amyloid Time. Time between key AD events was estimated using LOWESS curves and positivity thresholds for each AD biomarker and CDR scores.ResultFigure 1 depicts biomarker thresholds. Amyloid Time suggested PET Aβ+, CSF T+, PET T+, CDR=0.5, and CDR=1 occurred 4.0, 12.0, 13.8, 17.7, and 22.0 years following Aβ42/40 positivity (Figure 2, Table 2). Heterogeneity was observed in tau levels relative to Amyloid Time for individual cases. Those with worsening CDR generally had high amyloid and at least one T+ biomarker.ConclusionAmyloid Time based on combined CSF and PET amyloid biomarkers and the SILLA algorithm provides a novel way to quantify the duration of amyloid exposure from the earliest pathophysiologic CSF changes to dementia onset in AD within individuals. This enables characterization of the time between key AD events, which could inform prognosis, identify intervention timing for novel therapies, and enable exploration of mechanisms related to resistance and/or resilience.

Paleoseismicity of the western Humps fault on the Emu Plain, North Canterbury, New Zealand

ABSTRACT The 2016 MW 7.8 Kaikōura Earthquake nucleated on The Humps fault, which ruptured across the Emu Plain in North Canterbury. The paleoearthquake history of the fault was poorly constrained prior to the 2016 earthquake. To determine the timing and single-event displacements (SED) of earthquakes on the fault we use Optically Stimulated Luminescence (OSL) and radiocarbon dates of faulted stratigraphy and analysis of faulting (i.e. geometry and slip) at the McLean-1 trench site. At the trench the fault trace trends east–west and primarily accommodated right-lateral strike-slip in 2016 (2 ± 0.2 m strike slip and 0.35 ± 0.05 m vertical slip northside downthrow). The Humps fault is more seismically active than previously thought and accrued slip during at least six surface rupturing paleoearthquakes. The timing of these earthquakes was: 9.8–15.3 ka BP (Event 1), 8.6–11.5 ka BP (Event 2), 8.1–10.9 ka BP (Event 3), 6.0–8.6 ka BP (Event 4), 1840 AD to 4.5 ka (Event 5), and 2016 AD (Event 6). These earthquakes have a mean recurrence interval of 1.8–3.4 kyr and could have recurrence intervals up to ~9 kyr. Kaikōura-type ruptures could occur as frequently as every ∼2 kyr and maybe longer if The Humps fault rupture geometries are not characteristic.

Systematic Analysis of Survival-Associated Alternative Splicing Signatures in Thyroid Carcinoma.

Alternative splicing (AS) is a key mechanism involved in regulating gene expression and is closely related to tumorigenesis. The incidence of thyroid cancer (THCA) has increased during the past decade, and the role of AS in THCA is still unclear. Here, we used TCGA and to generate AS maps in patients with THCA. Univariate analysis revealed 825 AS events related to the survival of THCA. Five prognostic models of AA, AD, AT, ES, and ME events were obtained through lasso and multivariate analyses, and the final prediction model was established by integrating all the AS events in the five prediction models. Kaplan–Meier survival analysis revealed that the overall survival rate of patients in the high-risk group was significantly shorter than that of patients in the low-risk group. The ROC results revealed that the prognostic capabilities of each model at 3, 5, and 8 years were all greater than 0.7, and the final prognostic capabilities of the models were all greater than 0.9. By reviewing other databases and utilizing qPCR, we verified the established THCA gene model. In addition, gene set enrichment analysis showed that abnormal AS events might play key roles in tumor development and progression of THCA by participating in changes in molecular structure, homeostasis of the cell environment and in cell energy. Finally, a splicing correlation network was established to reveal the potential regulatory patterns between the predicted splicing factors and AS event candidates. In summary, AS should be considered an important prognostic indicator of THCA. Our results will help to elucidate the underlying mechanism of AS in the process of THCA tumorigenesis and broaden the prognostic and clinical application of molecular targeted therapy for THCA.

Climate and Social Changes: Reviewing the Equation with Data from the Huacas de Moche Archaeological Complex, Peru

Investigations at the site of Huacas de Moche—also referred to as Huacas del Sol and de la Luna—on the north coast of Peru show a continuous occupational sequence from around AD 100 to 1500. The longest occupation corresponds to the Moche culture from around AD 100 to 850. Based on available archaeological evidence, this article examines the impact of an El Niño-like event in AD 600 on the history of Huacas de Moche. Widely held hypotheses assumed that this kind of climatic event caused the abandonment of the site; however, such explanations do not fit the current data. After almost three decades of research, archaeological evidence indicates that after the El Niño-like phenomenon of AD 600, the Old Temple of Huaca de la Luna was closed down, and the New Temple was built toward the east of the previous one, on the same slope of Cerro Blanco. Furthermore, on the opposite side of the site, the building called Huaca del Sol experienced its last and greatest architectural expansion, becoming a large-scale palace. These new lines of evidence lead us to reassess the effect that the El Niño-like phenomenon of AD 600 had on the development of the Moche culture at the site.