Early Accumulation Research Articles

Changes in peak oxygen consumption in Fabry disease and associations with cardiomyopathy severity

BackgroundFabry disease (FD) causes multiorgan sphingolipid accumulation, with cardiac involvement responsible for the largest burden of morbidity and mortality. Exercise intolerance in FD is prevalent, yet the mechanisms of this...

Age-related loss of large dendritic spines in the precuneus is statistically mediated by proteins which are predicted targets of existing drugs.

Preservation of dendritic spines is a putative mechanism of protection against cognitive impairment despite development of Alzheimer Disease (AD)-related pathologies. Aging, the chief late-onset AD risk factor, is associated with dendritic spine loss in select brain areas. However, no study to our knowledge has observed this effect in precuneus, an area selectively vulnerable to early accumulation of AD-related pathology. We therefore quantified dendritic spine density in precuneus from 98 subjects without evidence of neurocognitive decline, spanning ages 20-96, and found a significant negative correlation between age and large dendritic spine density. In these same subjects, we conducted liquid chromatography-tandem mass spectrometry of >5000 proteins and identified 203 proteins which statistically mediate the effect of age on large dendritic spine density. Using computational pharmacology, we identified ten drugs which are predicted to target these mediators, informing future studies designed to test their effects on age-related dendritic spine loss and cognitive decline.

Early visual modulation and selection predict saccadic timing during visual search: An ERP study.

Saccadic eye movements, a critical aspect of real-world visual behavior, are preceded by an initial accumulation of visual information followed by the selection of a single location to move one's eyes. However, it is currently unclear how each of these stages uniquely affects saccadic timing. In this study, participants searched for a contour integration target while EEG was used to measure posterior cortical activity between search display onset and first saccade initiation. The goal was to determine whether saccade timing could be attributed to differences in early ERP amplitudes, with the P1 reflecting the magnitude of early perceptual information accumulation and the N1 reflecting the strength of selection leading to the saccadic decision. EOG was used to measure saccade timing, and trials were divided into fast, middle, and slow bins. The N1 response was smallest in the slow saccade tertile, relative to both the fast and middle tertiles, suggesting weak selection. In contrast, the P1 response was largest for this same slow saccadic tertile relative to the middle saccadic tertile, suggesting vigorous information accumulation. Therefore, delays in saccadic behavior may occur when the visual system is overwhelmed with visual input, thus increasing the time to reach a saccadic decision. These findings reconcile models of eye movement behavior which often prioritize either the impact of information accrual or selection, rather than regarding both as an integrated whole.

Longitudinal relationships between Aβ and tau to executive function and memory in cognitively normal older adults

The early accumulation of AD pathology such as Aβ and tau in cognitively normal older people is predictive of cognitive decline, but it has been difficult to dissociate the cognitive effects of these two proteins. Early Aβ and tau target distinct brain regions that have different functional roles. Here, we assessed specific longitudinal pathology-cognition associations in seventy-six cognitively normal older adults from the Berkeley Aging Cohort Study who underwent longitudinal PiB PET, FTP PET, and cognitive assessments. Using linear mixed-effects models to estimate longitudinal changes and residual approach to characterizing cognitive domain-specific associations, we found that Aβ accumulation, especially in frontal/parietal regions, was associated with faster decline in executive function, not memory, whereas tau accumulation, especially in left entorhinal/parahippocampal regions, was associated with faster decline in memory, not executive function, supporting an “Aβ-executive function, tau-memory” double-dissociation in cognitively normal older people. These specific relationships between accumulating pathology and domain-specific cognitive decline may be due to the particular vulnerabilities of the frontal-parietal executive network to Aβ and temporal memory network to tau.

Obesity Promotes Marrow-Derived Myeloid Cell Accumulation while Exercise Reduces Proliferative Signaling in Colon Cancer.

Obesity increases colon cancer risk that has been previously linked to marrow-derived myeloid cells. We previously demonstrated that exercise training (EX) prevents colon cancer initiation, potentially through reduced myelopoiesis. However, it remains unknown whether early myeloid cell accumulation and inflammation in the colon precedes carcinogenesis with high-fat diet (HFD)-induced obesity, and if EX can attenuate these effects. We hypothesized that obesity would promote colon carcinogenesis that was preceded by myeloid cell accumulation and inflammation that would be attenuated by EX. C57BL/6 mice were randomized to a HFD or control (CON) diet for 8 weeks. The HFD mice switched to CON diet and all mice were given intraperitoneal injections of azoxymethane (AOM) to induce colon cancer and randomized into EX or sedentary (SED) conditions. HFD mice developed more aberrant crypt foci (ACF), a marker for early carcinogenesis, compared to CON (p < 0.01), and EX developed fewer ACF compared to SED (p < 0.0001). Marrow-derived (p < 0.001) CD206+ macrophages were elevated in HFD compared to CON at study week 16 (p < 0.01). Marrow-derived CD206- macrophages (p < 0.05) and marrow-derived (p < 0.05) CD206+ macrophages were more abundant in HFD compared to CON at study week 42. EX did not alter colon immune cell populations. β-Catenin protein was higher in HFD compared to CON at study week 42 (p < 0.05), and STAT3 protein content was lower at study week 28 with EX compared to SED (p < 0.05). The results suggest that obesity promotes colon ACF formation, potentially through early inflammatory myeloid cell accumulation. Despite attenuating ACF, EX did not alter myeloid cell accumulation in the colon, suggesting that EX inhibits ACF formation through alternative mechanisms which may include reduced β-Catenin and STAT3 signaling.

Dynamic simulation of differential accumulation history of deep marine oil and gas in superimposed basin: A case study of Lower Paleozoic petroleum system of Tahe Oilfield, Tarim Basin, NW China

According to the complex differential accumulation history of deep marine oil and gas in superposition basins, the Lower Paleozoic petroleum system in Tahe Oilfield of Tarim Basin is selected as a typical case, and the process of hydrocarbon generation and expulsion, migration and accumulation, adjustment and transformation of deep oil and gas is restored by means of reservoine-forming dynamics simulation. The thermal evolution history of the Lower Cambrian source rocks in Tahe Oilfield reflects the obvious differences in hydrocarbon generation and expulsion process and intensity in different tectonic zones, which is the main reason controlling the differences in deep oil and gas phases. The complex transport system composed of strike-slip fault and unconformity, etc. controlled early migration and accumulation and late adjustment of deep oil and gas, while the Middle Cambrian gypsum-salt rock in inner carbonate platform prevented vertical migration and accumulation of deep oil and gas, resulting in an obvious “fault-controlled” feature of deep oil and gas, in which the low potential area superimposed by the NE-strike-slip fault zone and deep oil and gas migration was conducive to accumulation, and it is mainly beaded along the strike-slip fault zone in the northeast direction. The dynamic simulation of reservoir formation reveals that the spatio-temporal configuration of “source-fault-fracture-gypsum-preservation” controls the differential accumulation of deep oil and gas in Tahe Oilfield. The Ordovician has experienced the accumulation history of multiple periods of charging, vertical migration and accumulation, and lateral adjustment and transformation, and deep oil and gas have always been in the dynamic equilibrium of migration, accumulation and escape. The statistics of residual oil and gas show that the deep stratum of Tahe Oilfield still has exploration and development potential in the Ordovician Yingshan Formation and Penglaiba Formation, and the Middle and Upper Cambrian ultra-deep stratum has a certain oil and gas resource prospect. This study provides a reference for the dynamic quantitative evaluation of deep oil and gas in the Tarim Basin, and also provides a reference for the study of reservoir formation and evolution in carbonate reservoir of paleo-craton basin.

Difference in trajectories according to early amyloid accumulation in cognitively unimpaired elderly.

Amyloid β (Aβ), a major biomarker of Alzheimer's disease, leads to tau accumulation, neurodegeneration and cognitive decline. Modelling the trajectory of Aβ accumulation in cognitively unimpaired (CU) individuals is crucial, as treatments targeting Aβ are anticipated. The evolution of Aβ levels was investigated to determine whether it could lead to classification into different groups by studying longitudinal Aβ changes in older CU individuals, and differences between the groups were compared. A total of 297 CU participants were included from the Alzheimer's Disease Neuroimaging Initiative database, and these participants underwent apolipoprotein E (APOE) genotyping, neuropsychological testing, brain magnetic resonance imaging, and an average of 3.03 follow-up 18F-florbetapir positron emission tomography scans. Distinct Aβ trajectory patterns were classified using latent class growth analysis, and longitudinal cognitive performances across these patterns were assessed with a linear mixed effects model. The optimal model consisted of three classes, with a high entropy value of 0.947. The classes were designated as follows: class 1, non-accumulation group (n = 197); class 2, late accumulation group (n = 70); and class 3, early accumulation group (n = 30). The late accumulation and early accumulation groups had more APOE ε4 carriers than the non-accumulation group. The longitudinal analysis of cognitive performance revealed that the early accumulation group showed the steepest decline (modified Preclinical Alzheimer's Cognitive Composite with digit symbol substitution [mPACCdigit], p < 0.001; modified Preclinical Alzheimer's Cognitive Composite with trails B [mPACCtrailsB], p < 0.001) and the late accumulation group showed a steeper decline (mPACCdigit, p = 0.014; mPACCtrailsB, p = 0.007) compared to the non-accumulation group. Our study showed the heterogeneity of Aβ accumulation trajectories in CU older individuals. The prognoses for cognitive decline differ according to the Aβ trajectory patterns.

Temporal dynamics of N-hydroxypipecolic acid and salicylic acid pathways in the disease response to powdery mildew in wheat

Wheat (Triticum aestivum) is a major staple crop worldwide, and its yields are significantly threatened by wheat powdery mildew (Blumeria graminis f. sp. tritici). Enhancing disease resistance in wheat is crucial for meeting global food demand. This study investigated the disease response in wheat, focusing on the bioactive small molecules salicylic acid (SA), pipecolic acid (Pip), and N-hydroxypipecolic acid (NHP), to provide new insights for molecular breeding. We found that endogenous levels of SA, Pip, and NHP significantly increased in infected plants, with Pip and NHP levels rising earlier than those of SA. Notably, the rate of increase of NHP was substantially higher than that of SA. The gene expression levels of SARD1 and CBP60g, which are transcription factors for SA, Pip, and NHP biosynthesis, increased significantly during the early stages of infection. We also found that during the later stages of infection, the expression of ALD1, SARD4, and FMO1, which encode enzymes for Pip and NHP biosynthesis, dramatically increased. Additionally, ICS1, which encodes a key enzyme involved in SA biosynthesis, also showed increased expression during the later stages of infection. The temporal changes in ICS1 transcription closely mirrored the behavior of endogenous SA levels, suggesting that the ICS pathway is the primary route for SA biosynthesis in wheat. In conclusion, our results suggest that the early accumulation of Pip and NHP cooperates with SA in the disease response against wheat powdery mildew infection.

Transcriptome and weighted gene co-expression network analyses reveal key genes and pathways involved in early fruit ripening in Citrus sinensis

BackgroundThe fruit ripening period is an important target trait in fruit tree crop breeding programs. Thus, citrus tree breeders seek to develop extreme early ripening cultivars that allow optimization of citrus maturation periods. In this study, we explored the regulatory network involved in fruit ripening in Citrus sinensis using the ‘Newhall’ navel orange variety and its early-ripening mutant, ‘Gannanzao’. This research will provide a basis for further research on important signaling pathways, gene functions and variety breeding of Citrus sinensis related to fruit ripening period.ResultsPhysiological analyses suggested that early fruit ripening in ‘Gannanzao’ is regulated by early accumulation of abscisic acid (ABA), persistently high levels of jasmonic acid (JA), and higher sucrose content in the pericarp. Pericarp samples from ‘Gannanzao’ and ‘Newhall’ navel oranges were sampled for RNA sequencing analysis at 180, 200, and 220 days after flowering; 1430 differentially expressed genes (DEGs) were identified. Functional enrichment analysis indicated that these DEGs were mainly enriched in the plant hormone signal transduction and sugar metabolism pathways, as well as other pathways related to fruit ripening. Important DEGs associated with fruit ripening in ‘Gannanzao’ included genes involved in ABA and JA metabolism and signal transduction, as well as sugar metabolism. Weighted gene co-expression network analysis showed that the deep pink module had the strongest correlations with ABA content, JA content, and early ripening. Based on gene functionality and gene expression analyses of 37 genes in this module, two candidate hub genes and two ethylene response factor 13 (ERF13) genes (Cs_ont_5g000690 and Cs_ont_5g000700) were identified as key genes regulated by ABA and JA signaling. These findings will help to clarify the mechanisms that underlie early citrus fruit ripening and will lead to the development of excellent genetic resources for further breeding of extreme early-ripening varieties.ConclusionsThrough analyses of the ‘Newhall’ navel orange cultivar and its early-ripening mutant ‘Gannanzao’, we identified genes involved in ABA and JA metabolism, signal transduction, and sugar metabolism that were related to fruit ripening. Among these, two ERF13 genes were inferred to be key genes in the regulation of fruit ripening. These findings provide insights into the genetic architecture related to early fruit ripening in C. sinensis.

Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment

Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ. To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline. This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024. Baseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Cross-sectional and longitudinal PET and CSF measures of brain Aβ pathology. This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aβ42/40: β = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aβ42/40: β = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P = .002; Aβ42/40: β = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Results of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.

Unraveling the spatial imprint of hominin and carnivore accumulations in Early Pleistocene African sites

Reconstructions of palimpsest formation and dynamics in Early Pleistocene African archaeological deposits have undergone significant advances thanks to taphonomic research. However, the spatial imprint of different agents implicated in most of these accumulations still needs to be addressed. We hypothesize that different site formation dynamics may yield diverse spatial distributions of archaeological remains, reflecting the intervention of different agents (i.e., hominins, felids, hyaenids) in palimpsests. This study aims to investigate the spatial patterns of archaeological remains in a selected sample of Early Pleistocene accumulations with the goal of understanding and characterizing their spatial dynamics. Building on previous taphonomic interpretations of twelve paradigmatic archaeological deposits from Olduvai Bed I (FLK Zinj 22 A, PTK 22 A, DS 22B, FLK N 1–2 to 5, FLK NN 3, DK 1–3) and Koobi Fora (FxJj50, FxJj20 East and FxJj20 Main), we explore the spatial patterns of remains statistically and use hierarchical clustering on principal components analysis (HCPC) to group the highest-density spots at these sites based on a number of spatial variables. The results of this approach show that despite sharing a similar inhomogeneous pattern, anthropogenic sites and assemblages where carnivores played the main role display fundamentally different spatial features. Both types of spatial distributions also show statistical differences from modern hunter-gatherer campsites. Additional taphonomic particularities and differing formation processes of the analyzed accumulations also appear reflected in the classifications. This promising approach reveals crucial distinctions in spatial imprints related to site formation and agents’ behavior, prompting further exploration of advanced spatial statistical techniques for characterizing archaeological intra-site patterns.

Early oxidative stress and DNA damage in Aβ-burdened hippocampal neurons in an Alzheimer’s-like transgenic rat model

Oxidative stress is a key contributor to AD pathology. However, the earliest role of pre-plaque neuronal oxidative stress, remains elusive. Using laser microdissected hippocampal neurons extracted from McGill-R-Thy1-APP transgenic rats we found that intraneuronal amyloid beta (iAβ)-burdened neurons had increased expression of genes related to oxidative stress and DNA damage responses including Ercc2, Fancc, Sod2, Gsr, and Idh1. DNA damage was further evidenced by increased neuronal levels of XPD (Ercc2) and γH2AX foci, indicative of DNA double stranded breaks (DSBs), and by increased expression of Ercc6, Rad51, and Fen1, and decreased Sirt6 in hippocampal homogenates. We also found increased expression of synaptic plasticity genes (Grin2b (NR2B), CamkIIα, Bdnf, c-fos, and Homer1A) and increased protein levels of TOP2β. Our findings indicate that early accumulation of iAβ, prior to Aβ plaques, is accompanied by incipient oxidative stress and DSBs that may arise directly from oxidative stress or from maladaptive synaptic plasticity.

β-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer’s Disease

Hyperactivity mediated by synaptotoxic β-amyloid (Aβ) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer’s disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aβ peptides before Aβ plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aβ binding anticalin protein (Aβ-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of β-amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aβ-anticalin-dependent depletion of naturally secreted Aβ monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aβ monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.

Retraction: Cell detachment and apoptosis induction of immortalized human prostate epithelial cells are associated with early accumulation of a 45 kDa nuclear isoform of clusterin.

Retraction: Cell detachment and apoptosis induction of immortalized human prostate epithelial cells are associated with early accumulation of a 45 kDa nuclear isoform of clusterin.

Dynamic changes in mRNA nucleocytoplasmic localization in the nitrate response of Arabidopsis roots.

Nitrate is a nutrient and signal that regulates gene expression. The nitrate response has been extensively characterized at the organism, organ, and cell-type-specific levels, but intracellular mRNA dynamics remain unexplored. To characterize nuclear and cytoplasmic transcriptome dynamics in response to nitrate, we performed a time-course expression analysis after nitrate treatment in isolated nuclei, cytoplasm, and whole roots. We identified 402 differentially localized transcripts (DLTs)in response to nitrate treatment. Induced DLT genes showed rapid and transient recruitment of the RNA polymerase II, together with an increase in the mRNA turnover rates. DLTs code for genes involved in metabolic processes, localization, and response to stimulus indicating DLTs include genes with relevant functions for the nitrate response that have not been previously identified. Using single-molecule RNA FISH, we observed early nuclear accumulation of the NITRATE REDUCTASE 1 (NIA1) transcripts in their transcription sites. We found that transcription of NIA1, a gene showing delayed cytoplasmic accumulation, is rapidly and transiently activated; however, its transcripts become unstable when they reach the cytoplasm. Our study reveals the dynamic localization of mRNAs between the nucleus and cytoplasm as an emerging feature in the temporal control of gene expression in response to nitrate treatment in Arabidopsis roots.

An Early Accumulation of Serum Uric Acid Confers More Risk of Heart Failure: A 10-year Prospective Cohort Study.

Evidence on the longitudinal association of serum uric acid (SUA) with the risk of heart failure (HF) was limited and controversial. This study aimed to investigate the associations of cumulative SUA (cumSUA), incorporating its time course of accumulation, with the risk of HF. This prospective study enrolled 54,606 participants from the Kailuan study. The magnitude of SUA accumulation was expressed as cumSUA, exposure duration, and cumulative burden from baseline to the third survey, with cumSUA, calculated by multiplying mean values between consecutive examinations by time intervals between visits, as the primary exposure. During a median follow-up of 10.00 years, 1,260 cases of incident HF occurred. A higher risk of HF was observed in participants with the highest versus the lowest quartile of cumSUA (adjusted hazard ratio [aHR], 1.54; 95% confidence interval [CI], 1.29-1.84), 6-years (6 years) versus 0-year exposure duration (aHR, 1.87; 95% CI, 1.43-2.45), cumulative burden >0 versus =0 (aHR, 1.55; 95 CI, 1.29-1.86), and those with a negative versus positive SUA slope (aHR, 1.12; 95% CI, 1.02-1.25). When cumSUA was incorporated with its time course, those with cumSUA≥median and a negative SUA slope had the highest risk of HF (aHR, 1.55; 95% CI, 1.29-1.86). Incident HF risk was associated with the magnitude and time course of cumSUA accumulation. Early accumulation resulted in a greater risk of HF than later accumulation, indicating the importance of optimal SUA control earlier in life.

Dynamic accumulation of a high-grade gas hydrate system: insights from the trial production gas hydrate reservoir in the Shenhu area, northern South China Sea

The ultimate enrichment level and quantity of gas hydrate resources are influenced by the dynamic process of accumulation and preservation. High-resolution 3-D seismic data, logging while drilling (LWD), pressured coring, and in situ testing were used to characterize the dynamic accumulation and preservation of the trial production high-grade gas hydrate reservoir (HGGHR) in the Shenhu area. Through seismic variance analysis and ant-tracking, we found that newly identified mud diapir-associated faults with three development stages controlled the migration and accumulation of gas hydrate and shifted the base of the gas hydrate stability zone (BGHSZ), resulting in dynamic accumulation and dissociation of gas hydrates. The recognized double bottom simulating reflectors (BSRs) were concluded to have been formed due to the shift of the BGHSZ caused by the variational equilibrium conditions. The interval between the double BSRs was inferred to be a disequilibrium zone where gas recycling occurred, contributing to the coexistence of gas hydrates and free gas and the dynamic formation of the HGGHR. Multiple gliding faults formed within the GHSZ in the late period have altered the HGGHR and control the present thickness and distribution of the gas hydrates and free gas in the hanging wall and footwall. Under the influence of geothermal fluids and the fault system associated with the mud diapir, the HGGHR experienced dynamic accumulation with three stages, including early accumulation, medium-term adjustment, and late alteration and preservation. We conclude that four factors affected the formation, distribution, and occurrence of the HGGHR: the geothermal fluids accompanying the deep mud diapir below the reservoir, the dual supply of thermogenic gas and biogenic gas, the recycling of hydrate gas beneath the BGHSZ, and the post-gas hydrate faults developed within the GHSZ. A geological model illustrating the dynamic formation of the trial production HGGHR was proposed, providing a reference for future exploration of HGGHRs with a great production potential in deepwater settings.

The totipotent 2C-like state safeguards genomic stability of mouse embryonic stem cells.

Mouse embryonic stem cells (mESCs) sporadically transition to a transient totipotent state that resembles blastomeres of the two-cell (2C) embryo stage, which has been proposed to contribute to exceptional genomic stability, one of the key features of mESCs. However, the biological significance of the rare population of 2C-like cells (2CLCs) in ESC cultures remains to be tested. Here we generated an inducible reporter cell system for specific elimination of 2CLCs from the ESC cultures to disrupt the equilibrium between ESCs and 2CLCs. We show that removing 2CLCs from the ESC cultures leads to dramatic accumulation of DNA damage, genomic mutations, and rearrangements, indicating impaired genomic instability. Furthermore, 2CLCs removal results in increased apoptosis and reduced proliferation of mESCs in both serum/LIF and 2i/LIF culture conditions. Unexpectedly, p53 deficiency results in defective response to DNA damage, leading to early accumulation of DNA damage, micronuclei, indicative of genomic instability, cell apoptosis, and reduced self-renewal capacity of ESCs when devoid of 2CLCs in cultures. Together, our data reveal that transition to the privileged 2C-like state is a major component of the intrinsic mechanisms that maintain the exceptional genomic stability of mESCs for long-term self-renewal.

A clathrin mediated endocytosis scaffolding protein, Intersectin 1, changes in an isoform, brain region, and sex specific manner in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary Tau tangles in the brain. We previously identified a set of candidate AD microRNAs (miRNAs) in human cerebrospinal fluid (CSF) and used a target prediction pipeline to identify mRNAs and pathways that could potentially be regulated by the miRNAs. Of these pathways, clathrin mediated endocytosis (CME) was selected for further investigation. CME is altered in multiple brain cell types in AD and is implicated in early cellular phenotypes such as enlarged early endosomes and pathogenic processing of Aβ. However, a comprehensive evaluation of major CME hub proteins in humans with AD across multiple brain regions is lacking. Thus, we used immunoblots to evaluate human post-mortem AD and control (CTL) frontal cortex (FC; AD n = 22, CTL n = 23) and hippocampus (HP; AD n = 34, CTL n = 22) for changes in Intersectin 1 (ITSN1), Phosphatidylinositol Binding Clathrin Assembly Protein gene (PICALM), Clathrin Light Chain (CLT), FCH and Mu Domain Containing Endocytic Adaptor 1 (FCHO1), Adaptor Related Protein Complex 2 (AP2) Subunit Alpha 1 (AP2A1), and Dynamin 2 (DNM2). Of these, we found that in AD, ITSN1-long (ITSN1-L) was decreased in the FC of males and HP of females, while ITSN1-short was increased in the HP of both males and females. We further evaluated ITSN1-L levels in cortex (CTX) and HP of the 5xFAD mouse model of Aβ pathology at different timepoints during aging and disease progression by immunoblot (n = 5-8 per group). At 3 months, female 5xFAD exhibited an increase of ITSN1-L in CTX but a decrease at 6 and 9 months. Additionally, immunofluorescent staining of 5xFAD primary HP neurons showed an increase of ITSN1-L in matured 5xFAD neurons at 21 and 28 days in vitro. Together, our studies show that in AD, isoforms of ITSN1 change in a brain region-and sex-dependent manner. Further, changes in ITSN1-L are transient with levels increasing during early Aβ accumulation and decreasing during later progression. These findings suggest that ITSN1 expression, and consequently CME activity, may change depending on the stage of disease progression.

Patterns of Early Neocortical Amyloid-β Accumulation: A PET Population-Based Study.

The widespread deposition of amyloid-β (Aβ) plaques in late-stage Alzheimer disease is well defined and confirmed by invivo PET. However, there are discrepancies between which regions contribute to the earliest topographic Aβ deposition within the neocortex. Methods: This study investigated Aβ signals in the perithreshold SUV ratio range using Pittsburgh compound B (PiB) PET in a population-based study cross-sectionally and longitudinally. PiB PET scans from 1,088 participants determined the early patterns of PiB loading in the neocortex. Results: Early-stage Aβ loading is seen first in the temporal, cingulate, and occipital regions. Regional early deposition patterns are similar in both apolipoprotein ε4 carriers and noncarriers. Clustering analysis shows groups with different patterns of early amyloid deposition. Conclusion: These findings of initial Aβ deposition patterns may be of significance for diagnostics and understanding the development of Alzheimer disease phenotypes.