bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid suppression of macroscopic homomeric Kv1.2 and heteromeric Kv1.1/1.2 currents by amyloid beta (1‐42) peptide: Implications for Alzheimer’s disease
Authors: Jamshidi Dina , Watkins Joshua , DeBoeuf Kristi , Farley Joseph
Published: June 2023

Background

The roles of Aβ in the pathogenesis of Alzheimer ’s disease (AD) include disruption of 1) Ca2+ homeostasis, 2) synaptic communication and function, and 3) synaptic plasticity mechanisms thought to be critical for learning and memory. Exactly how these abnormalities arise is incompletely understood. Our lab has focused on the potential involvement of voltage‐gated potassium channels (VGKCs) in several of these processes. VGKCs are activated during an action potential and regulate Ca2+ influx, and inhibition of VGKCs can lead to synapto‐ and neuro‐toxicity. In the nervous system, members of the Kv1.x family can be expressed as homomers or select heteromers; e.g., Kv1.1 is often co‐expressed with Kv1.2. Studies in our lab have shown that Aβ peptides suppress VGKC activity, particularly Kv1.1. Here we asked if Aβ suppression is specific to Kv1.1 homomers, or if it affects other members of the Kv1.x family (e.g., Kv1.2) and/or heteromers also?

Method

Stage V/VI Xenopus laevis oocytes were acquired from Ecocyte Bioscience (Austin, TX) and injected with Kv1.2 cRNA for homomeric expression. Heteromeric expression was evaluated by coinjection of Kv1.1 and 1.2 cRNA. The effects of bath application (1 μM) of Aβ(1‐42) on macroscopic currents from homomeric Kv1.2 and 1.1/1.2 heteromeric channels were assessed using two‐electrode voltage clamp (TEVC). DMSO was used as a control.

Result

As seen for homomeric Kv1.1 channels, Aβ suppressed homomeric Kv1.2 channels by ∼50% in 30 min. About 50% of this suppression was dependent on intracellular Ca2+. Aβ(1‐42) suppressed macroscopic heteromeric Kv1.1/1.2 channels by ∼41% in 30 min. The suppression was independent of changes in activation‐deactivation kinetics or voltage dependency.

Conclusion

Heterologously expressed homomeric Kv1.2 and heteromeric Kv1.1/1.2 channels were both suppressed by Aβ(1‐42), similar to Kv1.1 homomers. Suppression of homomeric and heteromeric Kv1.x channels could potentially lead to larger and longer action potentials, resulting in a greater influx of Ca2+ into presynaptic terminals of excitatory neurons, and depolarization of dendritic spines. Both could contribute to synapto‐ and neuro‐toxicity via increased glutamate release and depolarization of NMDA receptors.
The reliability and validity of the snellen memory test for point‐of‐care detection of Alzheimer’s risk in cognitively unimpaired older adults
Authors: Gosselin Emma J , Thompson Louisa I , Sinoff Stuart , Strenger Jennifer , Snyder Peter J , Maruff Paul , Alber Jessica
Published: June 2023

Background

Episodic memory decline is one of the earliest cognitive indicators in Alzheimer’s disease (AD) with impairment in memory in older adults an important indicator of incipient AD. Optometry has potential for population based, point‐of‐care screening as retinal biomarkers can detect both symptomatic and preclinical AD. Here, we aimed to develop and optimize a test of episodic memory for use in clinical optometry/ophthalmology settings alongside retinal imaging methods to detect both preclinical and early symptomatic AD.

Method

30 cognitively normal (CN) older adults (55‐81 years; 68.5±7) from the Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS) completed the Snellen Memory Test (SMT). Participants completed a a Snellen Eye Chart for three learning trials of 10 seconds exposures, followed by immediate free recall. After a 20‐minute delay, participants completed delayed free recall in which they were asked to recall as many of the letters as they had been shown. This was followed by a recognition test in which participants viewed a mock chart identifying the correct letters and if they were in the correct location as the original chart.

Result

An intraclass correlation coefficient was calculated to determine the inter‐rater reliability among three raters for 10 randomly selected administrations. Overall results indicated good reliability with a mean coefficient of 0.87 (95% CI: 0.71‐1.03). Convergent and divergent validity for the 30 participants was assessed by comparing SMT performance to RBANS indices and the Free and Cued Selective Reminding Test (FCSRT). The SMT significantly correlated with the RBANS Immediate Memory Index (r = 0.38‐0.52), Language Index (r = 0.39‐0.51), and Attention Index (r = 0.39‐0.46) as well as with selective reminding trial 1 and 2 (r = 0.45‐0.78), and free and cued recall for trial 3 (r = 0.45‐0.47).

Conclusion

The SMT has potential as an episodic memory test that could be used for point of care detection of preclinical AD. Future work will continue to validate the SMT against reference standard neuropsychological assessments of episodic memory and against AD retinal imaging biomarkers.
Day‐to‐day sleep and circadian variability in association with Alzheimer’s Disease biomarkers
Authors: Baril Andree‐Ann , Picard Cynthia , Labonté Anne , Sanchez Erlan , Duclos Catherine , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Breitner John C.S. , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: June 2023

Background

Increasing evidence shows that Alzheimer’s Disease (AD) pathology, i.e., the Aß peptide, tau tangles and the APOEε4 allele, have all been associated with disrupted sleep and change in circadian rhythms. However, objective sleep measurements are often assessed over a single night. Measures of day‐to‐day variability might reveal unstable sleep and circadian rhythms that may reflect neurodegenerative processes. We sought to evaluate the association between AD biomarkers and sleep and circadian variability measured over a week of actigraphy.

Method

203 dementia‐free participants (age: 68.5±5.4 years, 151 women) from the PREVENT‐AD cohort with known APOEε4 carrier status were tested with a week of actigraphy. Overlapping subsamples were tested for determination of cerebrospinal fluid (CSF) Aß1‐42, total t‐tau and p(181)‐tau (n = 100); CSF apoE protein (n = 69); and plasma Aß1‐42 (n = 144). Day‐to‐day variability in actigraphy circadian and sleep measures were assessed using the standard deviation of individual results. Day‐to‐day variability was compared between APOEε4 carriers were compared to non‐carriers using t‐tests. Linear regressions were performed between day‐to‐day variability with CSF and plasma, adjusted for age, sex, and time interval between measurements. An interaction term for APOEε4 carrier status was additionally tested in regression models.

Result

APOEε4 carriers did not differ meaningfully from non‐carriers regarding sleep and circadian variability. Lower CSF Aß1‐42 was associated with higher day‐to‐day variability of time of morning awakening and nighttime sleep duration (ß = ‐0.263, p = 0.009; b = ‐0.206, p = 0.041). Higher plasma Aß1‐42 was also associated with higher day‐to‐day variability for time in bed, activity counts, sleep onset latency, sleep efficiency, and nighttime sleep duration (ß = 0.160 to 0.242; p = 0.010 to 0.002). Lower CSF apoE protein was associated with increased day‐to‐day variability for time of morning awakening, time in bed, activity counts, and nighttime sleep duration (ß = ‐0.243 to ‐0.420; p = 0.042 to <0.001). Higher CSF t‐tau, and a trend for p(181)‐tau were associated with time of morning awakening day‐to‐day variability inε4 carriers only (interaction p<0.001;ß = 0.330, p = 0.047; b = 0.281, p = 0.094).

Conclusion

Sleep and circadian variability are associated with biomarkers of AD pathology and apoE metabolism. These results may suggest that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep and circadian function.
Transcriptomic profiling of brain amyloidosis and Alzheimer’s disease phenotypes identifies novel gene targets from peripheral blood gene expression data
Authors: Sanjay Apoorva Bharthur , Svaldi Diana , Logan Paige E. , Stage Eddie , Apostolova Liana G.
Published: June 2023

Background

In an effort towards pre‐symptomatic risk assessment, precision medicine and biomarker development in AD, we evaluated the efficacy of characterizing and clustering peripheral blood transcriptomic data with respect to brain amyloidosis.

Method

356 ADNI participants with blood gene expression, Florbetapir SUVR, neurodegeneration measures and CSF measures (CN = 120, EMCI = 130, LMCI = 72 and AD = 34) were identified (Table‐1). Differential expressed genes from ∼50,000 transcripts (p<0.001) were identified. Pairwise euclidean distance between genes was used to construct a gene‐gene distance matrix followed by K‐means clustering (Figure‐1). Gene enrichment analysis was performed on each cluster to identify biological processes associated with the cluster. “Eigengene”; a data vector representing the whole cluster was obtained for each cluster using Principal Component Analyses. The top driver genes were identified from each cluster. We used the tool MAGMA (Multi‐marker Analysis of GenoMic Annotation) to analyze variants in the driver genes. Voxel‐wise multiple regression in SPM12 with age and sex as covariates was used to visualize the pattern of association of driver gene expression with brain amyloidosis. The association of the transcripts identified through our analyses to amyloid SUVR, and disease diagnosis were validated in the external ImaGene(n = 160) dataset.

Result

We identified five clusters with distinct biological processes highly relevant in AD. All five clusters were significantly associated with Florbetapir SUVR and CSF Abeta measures (p<0.05) (Figure‐2). 28 driver genes were identified. Six driver genes (BAIAP3, E2F2, PSMF1, SMOX, UBE20 and RNF11) had negative association with amyloidosis in the lateral temporal, lateral parietal and temporo‐ and parieto‐occipital areas, in addition to regions of the frontal lobe (Figure‐3). One of the driver genes, KANK2, and overall, 29 of the differentially expressed genes had SNPs significantly associated with AD and MCI phenotype (Table‐2). The top driver genes showed similar correlation to amyloid SUVR in the ImaGene dataset (Figure‐4B). A logistic regression model with 28 driver genes, and age and sex as covariates predicted amnestic MCI diagnosis in the external dataset with an AUC of 0.82(Figure‐4A).

Conclusion

Using a data driven approach we identified novel gene targets from peripheral blood which directly correlate to amyloid‐related pathogenesis and AD phenotype
Phenoconversion and disease progression observed in mutation carriers of familial Frontotemporal Lobar Degeneration in the ALLFTD Consortium
Authors: Heuer Hilary W. , Clark Annie L , Brushaber Danielle , Forsberg Leah K. , Miyagawa Toji , Staffaroni Adam M. , Huey Edward D. , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. , Investigators ALLFTD
Published: June 2023

Background

The ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study is designed to characterize both sporadic and familial FTLD (f‐FTLD) through annual detailed clinical, neuropsychological, biomarker, and neuroimaging assessments to capture disease onset and trajectory in preparation for therapeutic trails in FTLD. Transitions from asymptomatic to mild disease, or from mild to overt, may reveal critical windows for intervention.

Method

169 f‐FTLD participants carrying mutations in the main FTLD‐associated genes (79 C9orf72; 37 GRN; 53 MAPT) with at least two clinical assessments were included for analysis of phenoconversion from asymptomatic or mild disease. [CDRÒ + NACC FTLD global scores (Miyagawa et al, 2020) were used to define baseline status at first visit: “asymptomatic” = 0 and “mild” = 0.5. Conversion was defined as “partial” (asymptomatic to mild), “definite” (asymptomatic to overt [CDRÒ + NACC FTLD > = 1) and “mild to overt” (0.5 to > = 1).

Result

Definite conversion occurred most often in MAPT mutation carriers, with 5/43 asymptomatic carriers transitioning through mild to overt across multiple visits. Definite conversion was also seen in 2/65 C9orf72 expansion carriers and 1/30 GRN mutation carriers. All definite converters were assessed as mild (CDRÒ + NACC FTLD = 0.5) for at least one intermediate visit; definite conversion was observed from 2‐4 years from initial assessment. Partial conversions also occurred in all three genetic groups (MAPT: 6; C9orf72: 5; GRN: 5). Further conversion is expected to be observed in these participants in additional follow‐up visits. C9orf72 expansion carriers were less likely to progress from a baseline of mild to overt (3/14) than GRN carriers (4/6) or MAPT (7/10).

Conclusion

Longitudinal assessment through natural history studies can capture early phenoconversion in carriers of FTLD‐associated genetic mutations; corresponding imaging, cognitive, and biomarker profiles captured may provide insights into disease mechanisms and trajectories.
Association between beta amyloid plaque deposition and neuronal activity measured by Resting‐state fMRI in Alzheimer’s Disease and mild cognitive impairment
Authors: Haddad Seyyed M. H. , Soddu Andrea , Menon Ravi S. , Bartha Robert
Published: June 2023

Background

Despite the important role of amyloid‐beta protein (Aβ) in the initiation and progression of Alzheimer’s Disease (AD), the precise mechanism by which Aβ disrupts neuronal activity (NA) and structure during disease development, and whether this protein is an appropriate therapeutic target is still controversial. Recently, we introduced several novel NA metrics (Kazemeifar, PLoS One 2017; Haddad, ISMRM 2019) based on specific spatiotemporal features of the resting‐state fMRI (rs‐fMRI) signal. These NA metrics are significantly lower in AD and mild cognitive impairment (MCI) compared to normal elderly controls. Here, we examine whether there is an association between resting‐state fMRI NA levels and Aβ deposition in grey matter (GM) measured by PET in AD and MCI.

Method

[18F]florbetapir Aβ PET images and rs‐fMRI data (TR = 3s, 197 volumes) in 9 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, 3 early MCI (EMCI), 3 MCI, and 3 AD, aged 77 ± 7 years, 3 females) were included. The rs‐fMRI data was pre‐processed and decomposed into independent components (ICs) using IC analysis. The ICs associated with neuronal activity were identified using a support vector machine classifier (Demertzi, Cortex 2014). NA was quantified in each voxel using the magnitude of the neuronal ICs in the rs‐fMRI signal. This magnitude was calculated based on similarity (cross‐covariance) between each neuronal IC and rs‐fMRI signal (Haddad, ISMRM 2019). In each subject, the pre‐processed PET images (Jagust, Alzheimers. Dement. 2015) were registered to the T1‐weighted image to which the NA maps were already registered. GM voxelwise correlation was then conducted between the NA and [18F]florbetapir uptake maps in each subject.

Result

The NA and [18F]florbetapir uptake maps in one EMCI subject (Figure 1) and related scatter plot (Figure 2) show the correlation between NA and [18F]florbetapir uptake in GM. In all subjects studied, NA and [18F]florbetapir uptake were significantly negatively correlated (r = ‐0.25 ± 0.14) (Table 1).

Conclusion

The negative correlation between NA and [18F]florbetapir uptake in this preliminary study indicates that Aβ deposition contributes to decreased neuronal activity in AD and MCI measured by rs‐fMRI. Future studies should determine the susceptibility of various brain regions to Aβ accumulation.
Abnormal gamma frequency phase‐amplitude coupling associated with network hyperexcitability in Alzheimer’s Disease
Authors: Prabhu Pooja , Ranasinghe Kamalini G , Morise Hirofumi , Kudo Kiwamu , Hinkley Leighton B , Lerner Hannah M , Mizuiri Danielle , Licata Abigail , Kotegar Karunakar A , Findlay Anne , Miller Bruce L , Gorno‐Tempini Marilu , Kramer Joel H. , Rankin Katherine P , Garcia Paul , Kirsch Heidi , Houde John F , Vossel Keith , Nagarajan Srikantan S
Published: June 2023

Background

Alzheimer’s disease (AD) carries an increased risk of seizures and subclinical epileptiform activity (Vossel et al. 2016). Network hyperexcitability which is the underlying phenomenon of epileptic manifestations is thought to contribute to AD pathophysiological processes. Recently we demonstrated that greater degree of neural synchronization deficits within 2‐8Hz range of frequency oscillations are sensitive indicators of network hyperexcitability (Ranasinghe et al. 2021). Here, we sought to examine the high frequency gamma band deficits associated with network hyperexcitability in AD patients.

Methods

Specifically, we quantified Phase Amplitude Coupling (PAC) between the amplitude of gamma oscillations (30‐40Hz); with the phase of 2‐8Hz oscillations) (Figure 1). We used 60s resting‐state magnetoencephalography (MEG) recordings from 48 AD patients (n = 22, with subclinical epileptiform activity, AD‐EPI+; n = 28 without subclinical epileptiform activity, AD‐EPI‐), and 35 age‐matched controls. We computed PAC for each of 68 cortical regions (Desikan et al. 2006) on source‐space reconstructed MEG signal using the mean vector length (Canolty et al. 2006).

Results

Permutation cluster test was performed for statistical comparisons between AD patients vs. age matched controls, and AD‐EPI+ vs. AD‐EPI‐. Patients with AD showed significantly higher theta (4‐8 Hz)‐gamma coupling in the left parahippocampal and right caudal‐middle frontal regions. Importantly, this increased left parahippocampal theta‐gamma coupling was significantly higher in AD‐EPI+ patients than in AD‐EPI‐. AD‐EPI+ also showed higher alpha (8‐12Hz)‐gamma coupling in the right parahippocampal region compared to AD‐EPI‐ (Figure 2).

Conclusion

These results not only identify gamma band coupling deficits specifically localized to medial temporal regions which are the earliest affected regions in AD pathophysiology but also delineate the associated vulnerabilities of network hyperexcitability in AD.
Amyloid accumulation in the medial temporal area starts in the mild cognitive impairment stage of Alzheimer’s disease in [18F]flutemetamol positron emission tomography
Authors: Imabayashi Etsuko , Ishii Kenji , Toyohara Jun , Kojima Narumi , Tago Tetsuro , Sakata Muneyuki , Wagatsuma Kei , Ishibashi Kenji , Tokumaru Aya M. , Kim Hunkyung
Published: June 2023

Background

This study was aimed to evaluate the hierarchical accumulation of amyloid in the Alzheimer’s brain according to clinical stage using [18F]flutemetamol positron emission tomography.

Method

This was a prospective, single‐cohort study of volunteers who lived independently in Itabashi‐ku (Tokyo, Japan). One hundred thirty‐six participants (female/male = 96/40, mean age/standard deviation = 79.2/4.0 years) were recruited. Two subjects, one with meningeal thickening and another with sequelae in the brain, and 17 visually amyloid‐negative MCI subjects who possibly had neurodegenerative disease other than Alzheimer’s disease were excluded from the further analysis. We applied voxel‐based regression slope analysis using composite voxel of interest values calculated with Cortex ID Suite (GE Healthcare) and [18F]flutemetamol positron emission tomography images in three groups: 70 amyloid‐negative cognitively normal (CN) participants, 29 amyloid‐positive cognitively normal (PreC) participants, and 18 amyloid‐positive MCI (MCI+) participants. Statistical Parametric Mapping 12 software was used for analysis.

Result

Compared with the CN group, the PreC group showed accelerated amyloid accumulation in a wide area, except for the medial temporal lobe, paracentral sulcus, and medial occipital lobe. In amyloid‐positive subjects, amyloid accumulation was quicker in the paracentral sulcus, occipital cortex, and left medial temporal lobe in the MCI+ group than in the PreC group. Additional voxel of interest analyses were applied to the statistically significant areas. In the right posterior cingulate area, there was no significant difference between the PreC and MCI+ groups; however, the PreC and MCI+ groups showed a significantly quicker amyloid accumulation than the CN group. In contrast, in the left medial temporal area, the increase of amyloid accumulation was greater only in the MCI+ group compared to the PreC and CN groups.

Conclusion

In amyloid‐positive subjects, amyloid accumulation in the left medial temporal lobe did not increase in the preclinical stage. In the medial temporal and occipital lobes, which are relatively spared from amyloid accumulation, it is considered to start late in the MCI stage and not in the preclinical stage. Further study of volume and other biomarkers is requreid to evaluate the regional pathophysiological variability of AD.
Increased white matter hyperintensity burden on MRI in autosomal dominant familial compared to young onset sporadic Alzheimer’s disease.
Authors: Accorroni Alice , Fraser Maggie R , Walsh Phoebe , O'Connor Antoinette , Cardoso M Jorge , Fox Nick C , Sudre Carole H , Ryan Natalie S
Published: June 2023

Background

White matter hyperintensities (WMH) on MRI may be observed in familial and sporadic AD. However, studies comparing WMH burden between these two groups are lacking. We conducted this study to evaluate the load and distribution of WMH in individuals with autosomal dominant familial Alzheimer’s disease (FAD) and young onset sporadic AD (SAD), their relationship to grey matter volumes and to neuropsychological test scores (NPT).

Method

In this cross‐sectional study, we evaluated global and local differences in WMH severity on MRI in 19 individuals with symptomatic FAD due to Presenilin 1 mutations, 20 individuals with young onset SAD and 19 healthy control subjects, controlling for age, cerebrovascular risk (CVR) and APOEε4 carrier status. Relationships between WMH, grey matter (GM) volumes and NPT were also investigated.

Result

The FAD group had higher WMH load in all the areas considered apart from juxta‐cortical and periventricular layers when compared to the SAD group. The two groups were well matched for disease duration and severity of cognitive impairment as assessed by the MMSE. APOEε4 genotype and cardiovascular risk factors acted as negative confounders in the identified differences in WMH volumes. There was no association between WMH and GM volumes or NPT in either AD group.

Conclusion

Despite their young age and minimal CVR, the FAD group in this study had a higher load of WMH compared to the SAD group, suggesting that WMH may reflect aspects of AD pathology that are particularly prominent in FAD. Our analysis suggests that APOEε4 genotype and cardiovascular risk factors may have a greater influence on WMH burden in SAD than in FAD. Furthermore, we did not identify a correlation between WMH load and GM volumes in either group, suggesting that WMH are not merely correlates of GM pathology in AD but may represent independent features of the disease.
Degradation of Oligomer Tau by Autophagy
Authors: Imai Miku , Hamano Tadanori , Sasaki Hirohito
Published: June 2023

Background

The specific pathological findings in Alzheimer’s disease (AD) brain are senile plaques composed of amyloid‐β protein (Aβ) and neurofibrillary tangles (NFTs) composed of highly phosphorylated tau protein. It has been suggested that autophagy may play an important role in the degradation of tau proteins. In this study, we investigated whether autophagy is involved in the degradation of oligomeric tau by immunohistochemistry using autopsied AD brains.

Method

Frozen brains were homogenized to produce lysates, and Western blotting (WB) was performed using anti‐LC3 antibody, a marker of autophagy. The parietal lobes of the same autopsy brains were used for immunohistochemical analysis using anti‐LC3, anti‐P62, anti‐oligomeric tau antibody (TOC‐1) and anti‐phosphorylated tau antibody (PHF‐1).

Result

In the WB of the temporal lobe, LC3‐II was generally increased in AD brains compared to controls. In addition, immunostaining showed that oligomeric tau (TOC1) and LC3 coexisted in AD brains. In AD and control brains, phosphorylated tau, which stained faintly, was found to coexist with LC3, but LC3 was not found in the cytoplasm of neurons with serious phosphorylated tau (PHF‐1) deposition. However, the coexistence of highly phosphorylated tau and p62 was remarkable. No LC3 or P62 staining was observed in the neuropil thread.

Conclusion

These results suggest that oligomeric tau is degraded by autophagy and phosphorylated tau is also degraded by autophagy, but autophagy may no longer function when the degree of phosphorylated tau deposition is serious.
Brain regional alternative splicing and clinical traits in Alzheimer’s disease
Authors: Kim Sara , Han Seonggyun , Nho Kwangsik , LEE YOUNGHEE , Koh Insong
Published: June 2023

Background

Alzheimer’s disease (AD) is one of the most complex diseases and is characterized by neuropathological features, including accumulation of beta‐amyloid plaques and tau neurofibrillary tangles. These neuropathological features exhibit heterogeneity across brain regions in different patients, leading to different symptoms. Dysregulation of alternative splicing (AS) has been observed to contribute to neuropathological features in AD; however, their molecular mechanisms via AS remain unclear. Therefore, we aimed to systemically investigate the impact of AS (i.e., exon skipping) on AD‐related neuropathological features (i.e., Braak stage and plaque density) and the functional connections of alternately spliced genes across multiple brain regions in AD patients.

Method

We analyzed RNA‐seq data generated by the MSBB project representing two brain regions: the frontal region (frontal pole; FP, n = 175, inferior frontal gyrus; IF, n = 87) and the temporal (parahippocampal gyrus; PH, n = 93 and superior temporal gyrus; ST, n = 101). The data were mapped to the hg19 reference genome with the STAR aligner and exon skipping rates were estimated as percent spliced in (PSI) by rMATs. Then, we performed a linear regression to evaluate clinical or pathogenic associations between exon PSI levels and the Braak stage and plaque density mean for each brain region, considering sex as a covariate.

Result

We identified 192 and 158 exon skipping (ES) associated with Braak stages in the frontal and temporal regions, respectively. In addition, 863 and 845 events were associated with plaque density. Notably, while the two regions shared only 20% (60 events) of Braak‐associated ES, they coincided in 90% (808 events) of plaque‐associated ES. Enrichment analysis of functional annotations found that frontal‐specific ES associated with Braak stage was enriched in interleukin signaling and the neurodegenerative‐related CDK5 pathway, while temporal‐specific ES was enriched in lipoprotein clearance functional pathways. For plaque density‐associated ES shared between regions, the most significantly enriched pathway was Notch4 signaling, represented for example by SOD2, in which skipping of the functional domain‐encoding exon 4 was associated with plaque mean in both regions.

Conclusion

This study provides a landscape of brain region‐dependent AS events and of AD risk genes that contribute to neuropathological features in AD patients.
Rapid and economic method to measure chocolate viscosity
Authors: Monteiro Luciana , Cooney Joseph , Martini Silvana
Published: June 2023

The objective of this research was to use simple and economic techniques to measure chocolate viscosity and compare the values with the ones obtained using a rheometer. Two techniques were used: (a) Zahn cup number 5, and (b) ring/spread test using a ring and a template with concentric circles (ring method). Seven chocolates with a wide range of viscosities were used: (a) three 70% dark chocolates; (b) 70% dark chocolate with 1% lecithin added; (c) 70% dark chocolate with 10% cocoa butter added; (d) a Swiss‐style milk chocolate; (e) a 50% milk chocolate. Results from this research showed that the viscosity obtained using the Zahn cups was positively correlated with the Casson plastic viscosity (r = 0.897; p = 0.016) while the values obtained using the ring/spread method were negatively correlated with the Casson yield stress (r = −0.916; p = 0.004) and the Casson plastic viscosity (r = −0.897; p = 0.007). These results are helpful for small producers of chocolate that need to quantify the viscosity of their product using simple and economic techniques.
A DFT mechanistic study on the N‐acyloxyamine‐initiated controlled degradation of polypropylene
Authors: Yu Fang , Ma Tian , Liang Wenbin , Lei Ming
Published: June 2023

N‐acyloxyamine is an excellent radical initiator for the controlled degradation of polypropylene (PP). Irgatec CR 76 (CR‐76) is one of the most important N‐acyloxyamines for the controlled degradation processes. The experiments show that 2 wt% CR‐76 caused a degradation and lowering of Mw to over 50% and of Mn in 10%–15%. The density functional theory (DFT) calculated results indicate that the NO bond cleavage of enol‐CR‐76 is the easiest to generate nitrogen (N˙) and ˙CH2COO radicals. In the controlled degradation process of PP, compared with the generated nitrogen (N˙), nitroxyl (NO˙), and nitrogen peroxide (NOO˙) radicals, the produced small molecule radicals such as CH3COO˙, (CH3)2CH˙, and (CH3)2CHCH2˙ radicals show better activity in the hydrogen abstraction process of PP. In addition, the NO˙, NOO˙, and ROO˙ (R = (CH3)2CH) radicals were proposed to be of importance in the radical coupling and β‐scission of PP˙ radical after the hydrogen abstraction in the controlled degradation of PP. This provide new insights into the controlled degradation of PP. Furthermore, thereby some theoretical guidance could be provided into the design of new N‐acyloxyamine radical initiator for the controlled degradation of polymers.
Thermal‐Responsive Liquid Crystal Elastomer Foam‐based Compressible and Omnidirectional Gripper
Authors: Zhang Xinyuhang , Liao Wei , Wang Yunpeng , Yang Zhongqiang
Published: June 2023

Liquid crystal elastomers (LCEs) are considered to be a promising material for the fabrication of soft grippers because of their large and reversible deformations, an LCE gripper with suitable compressibility and omnidirectionality has not yet been developed. To overcome these obstacles, this study utilizes salt template method to fabricate a rod‐like LCE foam as gripper. The thickness of the compressible foam can be reduced by up to 77%, temporarily maintaining the deformation and enabling the gripper to pass through slits. The foam was aligned along the long axis and the length of the foam exhibits reversible thermal responsiveness and contract up to 57% along its alignment. Additionally, when the foam approaches a heat source, the generated temperature gradient results in a contraction gradient owing to the low thermal conductivity of the LCE foam. This in turn causes the foam to reversibly bend with a bending angle up to 93° and follow the movement of a heat source omnidirectionally. The developed gripper successfully grasps, moves, and releases hot objects in a cold and safe place, demonstrating its potential for emergency disposal. Thus, LCE foams can be considered suitable materials for novel gripper design and construction.
Mureneinwirkungen auf Massivbrückenüberbauten
Authors: Friedl Caroline , Wernhart Susanna , Scheidl Christian , Proske Dirk
Published: June 2023

Brückenbauwerke im alpinen Raum unterliegen verschiedenen Naturgefahren. Dazu zählen auch Muren. Murenereignisse führen nachweisbar auch zur Zerstörung von Brücken. Um Brücken für solche Einwirkungen zu bemessen, sind Angaben zur Anprallkraft von Muren notwendig. Für Murenanpralle gegen Pfeiler liegen umfangreiche, sowohl miniaturisierte als auch Realgrößenversuche vor. Für Brückenüberbauten sind bisher keine solchen Versuche bekannt. In diesem Beitrag werden miniaturisierte Murenanprallversuche an Massivbrückenquerschnitten vorgestellt. Basierend auf den Versuchsergebnissen werden Empfehlungen für die Bemessung von Massivbrücken in exponierten Lagen gegeben.
Video game addiction in psychiatric adolescent population: A hospital‐based study on the role of individualism from South China
Authors: Zhou Rui , Xiao Xing‐Yu , Huang Wen‐Jun , Wang Fei , Shen Xiao‐Qing , Jia Fu‐Jun , Hou Cai‐Lan
Published: June 2023

Background

For decades, video game‐related behaviors have been investigated in different psychologic research, much of whose attention has been paid to video game addiction (VGA), while the differences between VGA and social media addiction (SMA) should have deserved more attention. In addition to detecting common risk factors of VGA, one core question is whether social inclination (individualism or collectivism) matters.

Object

The objectives of this study were to clarify the prevalence of VGA and SMA,, identify the influencing factors of VGA, and clarify the relationships between VGA and adolescents’ individualism–collectivism inclination.

Method

The survey was conducted among 110 adolescent psychiatric patients. For each interviewee, psychological scales were filled face to face. Path analysis was used to examine the causation structure of the childhood trauma‐related symptoms.

Result

The prevalence of VGA was 40.9% (45 out of 110), and it was 41.8% for SMA (46 out of 110); childhood trauma, social media addiction, the individualistic inclination, and the rate of homosexuality were observed to be independent indicators for video game addiction (r2 = 0.46).

Conclusion

Psychological counseling on patients’ internet‐related behaviors may focus on the individualistic personality and possible childhood trauma, which are two important risk factors of video game addiction. It is recommended to distinguish between video game addiction and social addiction in clinical practice.
Risk factors of postoperative bile leakage after liver resection: A systematic review and meta‐analysis
Authors: Xue Shuai , Wang Haichuan , Chen Xiangzheng , Zeng Yong
Published: June 2023

Objective

Postoperative bile leakage (POBL) is one of the most common complications after liver resection. However, current studies on the risk factors for POBL and their impacts on surgical outcomes need to be more consistent. This study aims to conduct a meta‐analysis to analyze the risk factors for POBL after hepatectomy.

Methods

We incorporated all eligible studies from Embase, PubMed, and the Web of Science database (until July 2022) into this study. RevMan and STATA software were used to analyze the extracted data.

Results

A total of 39 studies, including 43,824 patients, were included in this meta‐analysis. We found that gender, partial hepatectomy, repeat of hepatectomy, extended hepatectomy, abdominal drain, diabetes, Child≥B, solitary tumor, and chemotherapy are the factors of grade B and C POBL. Some recognized risk factors were considered potential risk factors for grade B and C bile leakage because no subgroup analysis was performed, like HCC, cholangiocarcinoma, major resection, posterior sectionectomy, bi‐segmentectomy, S4 involved, S8 involved, central hepatectomy, and bile duct resection/reconstruction. Meanwhile, cirrhosis, benign diseases, left hepatectomy, and Segment 1 resection were not significant for grade B and C bile leakage. The influence of lateral sectionectomy, anterior sectionectomy, S1 involved, S3 involved, high‐risk procedure, laparoscope, and blood loss>1000 mL on POBL of ISGLS needs further research. Meanwhile, POBL significantly influenced overall survival (OS) after liver resection.

Conclusions

We identified several risk factors for POBL after hepatectomy, which could prompt the clinician to decrease POBL rates and make more beneficial decisions for patients who underwent the hepatectomy.
Construction of refined staging classification systems integrating FIGO/T‐categories and corpus uterine invasion for non‐metastatic cervical cancer
Authors: Huang Xiao‐Dan , Chen Kai , Shi Liu , Luo Ying‐Shan , Ou‐Yang Yi , Li Jun‐Yun , Huo Lan‐Qing , Huang Lin , Chen Fo‐Ping , Cao Xin‐Ping
Published: June 2023

Background

To investigate the prognostic value of corpus uterine invasion (CUI) in cervical cancer (CC), and determine the necessity to incorporate it for staging.

Methods

A total of 809 cases of biopsy‐proven, non‐metastatic CC were identified from an academic cancer center. Recursive partitioning analysis (RPA) method was used to develop the refined staging systems with respect to overall survival (OS). Internal validation was performed by using calibration curve with 1000 bootstrap resampling. Performances of the RPA‐refined stages were compared against the conventional FIGO 2018 and 9th edition TNM‐stage classifications by the receiver operating characteristic curve (ROC) and decision curve analysis (DCA).

Results

We identified that CUI was independently prognostic for death and relapse in our cohort. RPA modeling using a two‐tiered stratification by CUI (positive and negative) and FIGO/T‐categories divided CC into three risk groupings (FIGO I′‐III'/T1′‐3′), with 5‐year OS of 90.8%, 82.1%, and 68.5% for proposed FIGO stage I′–III', respectively (p ≤ 0.003 for all pairwise comparisons), and 89.7%, 78.8%, and 68.0% for proposed T1′‐3′, respectively (p < 0.001 for all pairwise comparisons). The RPA‐refined staging systems were well validated with RPA‐predicted OS rates showed optimal agreement with actual observed survivals. Additionally, the RPA‐refined stages outperformed the conventional FIGO/TNM‐stage with significantly higher accuracy of survival prediction (AUC: RPA‐FIGO vs. FIGO, 0.663 [95% CI 0.629–0.695] vs. 0.638 [0.604–0.671], p = 0.047; RPA‐T vs. T, 0.661 [0.627–0.694] vs. 0.627 [0.592–0.660], p = 0.036).

Conclusion

CUI affects the survival outcomes in patients with CC. Disease extended to corpus uterine should be classified as stage III/T3.
Treatment outcome comparisons of first‐line targeted therapy in patients with KRAS wild‐type metastatic colorectal cancer: A nationwide database study
Authors: Liang Yi‐Hsin , Chen Kuo‐Hsing , Shao Yu‐Yun
Published: June 2023

Background

The first‐line systemic therapy for metastatic colorectal cancer (mCRC) is a combination of one targeted therapy agent and a chemotherapy doublet. Whether bevacizumab or anti‐epidermal growth factor receptor (anti‐EGFR) monoclonal antibody (mAb) is the more effective addition to a chemotherapy doublet as the first‐line treatment for inoperable KRAS wild‐type mCRC remains controversial in prior clinical trials. Moreover, the association between the sidedness of primary tumors and the efficacy of anti‐EGFR mAb needs to be addressed.

Methods

We established a cohort of patients with KRAS wild‐type mCRC who were treated with first‐line targeted therapy plus doublet chemotherapy between 2013 and 2018 using Taiwan's National Health Insurance Research Database. Secondary surgery was defined as either resection of primary tumors, liver metastases, lung metastases, or radiofrequency ablation.

Results

A total of 6482 patients were included; bevacizumab and anti‐EGFR mAb were the first‐line targeted therapies in 3334 (51.4%) and 3148 (48.6%) patients, respectively. Compared with those who received bevacizumab, patients who received anti‐EGFR mAb exhibited significantly longer overall survival (OS; median, 23.1 vs. 20.2 months, p = 0.012) and time to treatment failure (TTF; median, 11.3 vs. 10 months, p < 0.001). Among left‐sided primary tumors, the OS and TTF benefits of anti‐EGFR mAb remained. Among right‐sided primary tumors, the OS and TTF were similar regardless of the type of targeted therapy. In multivariate analyses, first‐line anti‐EGFR mAb therapy remained an independent predictor of longer OS and TTF for left‐sided primary tumors. Patients who received anti‐EGFR mAb were more likely to receive secondary surgery (29.6% vs. 22.6%, p < 0.0001) than patients who received bevacizumab.

Conclusion

For patients who received first‐line doublet chemotherapy for KRAS wild‐type mCRC, adding anti‐EGFR mAb was associated with significantly longer OS and TTF, especially for left‐sided primary tumors.
Synthesis of S‐Adenosyl‐L‐Methionine Analogs with Extended Transferable Groups for Methyltransferase‐Directed Labeling of DNA and RNA
Authors: Malikėnas Martynas , Masevičius Viktoras , Klimašauskas Saulius
Published: June 2023

S‐Adenosyl‐L‐methionine (AdoMet) is a ubiquitous methyl donor for a variety of biological methylation reactions catalyzed by methyltransferases (MTases). AdoMet analogs with extended propargylic chains replacing the sulfonium‐bound methyl group can serve as surrogate cofactors for many DNA and RNA MTases, enabling covalent derivatization and subsequent labeling of their cognate target sites in DNA or RNA. Although AdoMet analogs with saturated aliphatic chains are less popular than propargylic ones, they can be useful for dedicated studies that require certain chemical derivatization. Here we describe synthetic procedures for the preparation of two AdoMet analogs, one with a transferable 6‐azidohex‐2‐ynyl group (carrying an activating C≡C triple bond and a terminal azide functionality), and the other one with a transferable ethyl‐2,2,2‐d3 group (an isotope‐labeled aliphatic moiety). Our synthetic approach is based on direct chemoselective alkylation of S‐adenosyl‐L‐homocysteine at sulfur with a corresponding nosylate or triflate, respectively, under acidic conditions. We also describe synthetic routes to 6‐azidohex‐2‐yn‐1‐ol and conversion of the alcohols to corresponding nosylate and triflate alkylators. Using these protocols, the synthetic AdoMet analogs can be prepared within 1 to 2 weeks. © 2023 Wiley Periodicals LLC.

Basic Protocol 1: Synthesis of 6‐azidohex‐2‐yn‐1‐ol

Basic Protocol 2: Synthesis of 4‐nitrobenzenesulfonate

Basic Protocol 3: Synthesis of trifluoromethanesulfonates

Basic Protocol 4: S‐Alkylation of AdoHcy with sulfonates

Basic Protocol 5: Purification and characterization of AdoMet analogs
Comparative Study of the Crystal Structure and Simulated 3D Structure of the Hsp90N‐Inhibitor Complex
Authors: Qin Wei , Li Jie , Wang Ming‐Chan , Li Xin‐Yu , Li Peng‐Quan , Zhao Dong , Chu Hai‐Qing , Fu Jia , He Chun‐Xia , Li Hui‐Jin , Xing Lu , Zhou Xin , Zhang Ye , Sun Fang‐Yun , Cao Hui‐Ling
Published: June 2023

The crystal structure of a target‐ligand plays an indispensable role in rational drug design, structural optimization, and understanding the molecular interaction mechanism. For drug targets without crystal structures, the simulated 3D structure will provide an alternative important reference. However, the credibility of the simulated structure and its difference from the real crystal structure deserve deep consideration. The complex crystal structures of the target Hsp90N and its four small molecular inhibitors has previously been successfully determined. Herein, computer‐aided molecular docking technology is applied to predict complex 3D structures, and the comparison between the simulated 3D structures and crystal structures is analyzed. Compared with the complex crystal structures, the simulated 3D structures of the four groups have higher consistency with the main chains, whereas the branch chains, binding modes of inhibitors, and molecular interactions are different in detail. Thus, the simulated 3D complex structure can provide useful information to guide drug design and structural optimization of inhibitors when the crystal structure is missing, but it cannot replace the crystal structure and should be used with caution.
DNA methylation in small cell lung cancer
Authors: Zhu Xianmin , Gao Yuehua , Feng Yimiao , Zheng Jie , Dong Yixiao , Zhang Peng , Zhu Yuming , Fan Guoping
Published: June 2023

Small cell lung cancer (SCLC) originates from pulmonary neuroendocrine cells and accounts for approximately 15% of lung cancer incidents. Patients with SCLC have a very low survival rate due to fast progression and early metastasis. Despite the recent approval of immune checkpoint blockade for treatment of SCLC by US FDA, conventional platinum chemotherapy remains the first‐line treatment which always develops quick drug resistance. To define targets for diagnosis and treatment, SCLC has been categorized by different molecular markers. The most popular markers include genomic mutations in tumour suppressor genes such as TP53 and RB1 and expression of lineage‐specific transcription factors (TFs), that is ASCL1, NEUROD1, POU2F3 and YAP1. As DNA methylation is an important hallmark of cancer, efforts were made to investigate the mechanisms of DNA methylation involved in SCLC progression. Indeed, SCLC has distinct pattern of DNA methylation due to its different features compared to non‐SCLC and other tumours. In this review, we summarized the mechanisms of DNA methylation in SCLC which are associated with lineage‐specific TFs, cell proliferation, anti‐apoptosis, drug resistance, immune evasion and metastasis. We foresaw the challenges of applying DNA methylation in clinical diagnosis and treatment and discussed new approaches and technologies to overcome them. Combined with other gene regulatory information such as transcription and histone modification, DNA methylation/hydroxymethylation in SCLC will be resolved at single‐cell resolution to dissect the tumour microenvironment. The huge multiomics data will be processed and integrated with clinical data such as clinical images and pathological histochemistry by artificial intelligence and cloud computing. Circulating cell‐free DNA methylation will greatly enhance early diagnosis and prognosis prediction. New organoid and organ chip models will break through the obstacles of sampling limitation, faithfully simulate the physiology of human tissues and enable examining spatiotemporal DNA methylation during SCLC progression.
The utility of coded very high frequency telemetry for monitoring reintroduced mammal populations
Authors: Frick Chloe H. , Hole Donell , Sandow Derek , Olds Liberty G. M. , Ostendorf Bertram , Taggart David , Roshier David
Published: June 2023

Very high frequency (VHF) radio tracking technology deployed on terrestrial vertebrates has been well utilized in ecology without much evolution since the 1960s. With the advent of multi‐species rewilding projects, and the new field of reintroduction biology, there has been an increase in requirements for telemetry systems to monitor survival and mortality for many animals simultaneously. Common, pulsed VHF can only monitor one individual on each radio frequency, and the number of individuals monitored is constrained by the amount of time spent on each frequency to facilitate a detection and the number of receivers. Coded VHF largely removes these constraints by using a digital code that can simultaneously monitor up to 512 individuals on a single frequency. Incorporated into an autonomous monitoring system, the coded VHF system also greatly reduces time in the field to confirm the status of individuals. Here we demonstrate the utility of coded VHF technologies applied to monitoring a reintroduced population of brush‐tailed bettong (Bettongia penicillata) on the Southern Yorke Peninsula in southern Australia. A system of autonomous monitoring towers was able to monitor 28 different individuals simultaneously without having to change frequency on any of the towers. During a single 24‐h period, one individual was recorded 24,078 times. Key benefits of the high detection rate and autonomous recording are, a timely response to mortalities or a predation event, the detection of nocturnal, cryptic, or burrowing species whenever they are active, and the reduced need for personnel to be in the field.