bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential protein expression identified by digital spatial profiling (DSP) in the hippocampi of resilient individuals
Authors: Walker Jamie M. , Dehkordi Shiva Kazempour , Richardson Timothy , Zare Habil , Orr Miranda E.
Published: December 2020

Background

An intriguing group of individuals, termed “resilient”, demonstrate neuropathologic changes consistent with Alzheimer disease (AD), yet display no cognitive impairment. Studies have reported less neuronal loss overall, less gliosis, and fewer comorbidities (such as cerebrovascular disease) in these individuals. We sought to analyze protein expression in and around normal and neurofibrillary tangle (NFT)‐bearing neurons in these individuals as compared to those with cognitive decline.

Method

Utilizing Nanostring’s GeoMx™ Digital Spatial Profiling (DSP) technology, we compared individuals with AD neuropathologic change and dementia (n = 6) to individuals with AD neuropathologic change and no dementia (n = 8). The DSP panel allowed for spatial analysis of the level of expression of 89 different proteins in multiple regions of interest on formalin‐fixed paraffin embedded sections. We analyzed hippocampal sections, with our regions of interest (ROIs) being NFT‐bearing neurons, non‐NFT‐bearing neurons, and their immediate neuronal microenvironments (50 μm diameter surrounding the neuronal cell body) (Figure 1).

Result

Analyses identified 11 proteins having differential expression in tangle‐bearing neurons when comparing resilient to demented individuals. These included IDH1, GFAP, CD68, IDE, SYP and Histone H3. In addition, IDH1, CD68 and SYP were differentially expressed in the environment of normal and tangle‐bearing neurons when comparing resilient to demented individuals. IDH1 displayed significantly lower expression in the resilient individuals. It is thought that IDH1 is upregulated under energetic and oxidative stress. Similarly, PINK1 (which is upregulated in response to mitochondrial dysfunction and oxidative stress) displayed lower expression in the environment of normal and tangle‐bearing neurons in the resilient. Therefore, we hypothesize that there is less energetic and oxidative stress in the resilient individuals. Synaptophysin (SYP) is increased in the resilient, which likely indicates better maintenance of neuronal synapses and synaptic connections. Furthermore, neurofilament light chain (NEFL) and ubiquitin c‐terminal hydrolase (Park5) expression were higher in the resilient compared to the demented in the environment of NFTs. These differences all suggest healthier intact axons, dendrites and synapses in the resilient.

Conclusion

In conclusion, resilient individuals display protein expression patterns suggestive of an environment containing less energetic and oxidative stress, which in turn results in maintenance of neurons and their synaptic connections.
Effects of omega‐3 fatty acids on cerebral white matter hyperintensities and medial temporal lobe atrophy in older non‐demented adults: A 3‐year randomized‐controlled phase 2 trial
Authors: Bowman Gene L , Silbert Lisa C , Dodge Hiroko H , Hagen Kirsten , David Jason C , Murchison Charles F , Lahna David , Kaye Jeffrey , Quinn Joseph F , Shinto Lynne
Published: December 2020

Background

The n‐3 PUFA may modulate risk for age‐related cognitive impairment through vascular mechanisms. MRI derived cerebral white matter hyperintensities (WMH) presumptively reflect small vessel disease and their accumulation increases risk for age‐related cognitive decline and dementia. Blood n‐3 PUFA are consistently associated with reduced WMH and stroke. The primary aim here was to evaluate n‐3 PUFA supplementation on WMH accumulation over 3 years in an older population with evidence of WMH and absence of n‐3 PUFA supplementation.

Methods

The study was a double‐blind, placebo‐controlled trial, with participants randomized to a daily dose of fish oil (1650 mg combined eicosapentaenoic acid‐EPA and docosahexaenoic acid‐DHA) or placebo oil (soybean) for a 3‐year intervention. Main inclusion criteria were: non‐demented (MMSE > 24), age > 74 years, WMH volume > 5.0 cc, and plasma n‐3 PUFA (EPA+DHA) < 110 umol/L (or < 5.5 percent of total fatty acids). The primary endpoint was 3‐year change in total WMH volume. Secondary endpoints include changes in regional brain volumes and white matter integrity. Exploratory endpoints include measures of cerebral blood flow, domain‐specific and global cognitive measures with subgroup analyses by APOE4 genotype. A linear mixed‐effects model was used to assess the outcomes.

Results

102 subjects were enrolled (mean age 81±4.4, MMSE 27.8±1.7; 60% female, 27.5% APOE4 positive) and a total of 78 participants completed the trial. Supplementation had no beneficial effect on rate of WMH progression, which increased by a mean of 1.07 cc per year in the n‐3 PUFA group vs 1.12 cc per year in the placebo group (p = 0.30 for time*trial arm interaction). Three‐year changes in executive cognitive function z‐scores were not different between treatment groups (p = 0.24). No differences in adverse events between groups were observed .

Conclusion

N‐3 PUFA compared with placebo, failed to slow 3‐year WMH accumulation and executive function decline in older non‐demented adults presenting with evidence of WMH. N‐3 PUFA at the 1.65‐gram dose appears safe in older adults over 3‐years. Additional MRI and cognitive outcomes with detailed safety profiles are planned for presentation.
Reduced [18F]flortaucipir retention in white matter hyperintensities compared to normal‐appearing white matter
Authors: Moscoso Alexis , Whitman A.J. , Baker Suzanne L. , La Joie Renaud , Pascoal Tharick A. , Rosa‐Neto Pedro , Rabinovici Gil D. , Jagust William J. , Grothe Michel , Schöll Michael
Published: December 2020

Background

Recent research has suggested that the use of white matter (WM) reference regions for longitudinal tau PET imaging might result in more stable estimates of tau accumulation. However, tau tracers display affinity for the β‐sheet structure formed by proteins such as the myelin basic protein, a major component of axons, and thus WM lesions might influence tau tracer retention in the WM. Here, we explored whether [18F]flortaucipir shows reduced retention in WM lesions, assessed as WM hyperintensities (WMH), and further studied how [18F]flortaucipir retention in WM changes over time.

Method

We included data from 678 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had undergone a baseline [18F]flortaucipir‐PET as well as T1 and FLAIR MRI scanning. WMH were automatically delineated in the FLAIR images using the Lesion Segmentation Toolbox in SPM12. To avoid partial volume effects, we eroded the WM and WMH masks so that all voxels within a distance of 3 mm from any non‐WM voxel were removed. The inferior portion of the cerebellar gray matter was used as the reference region to derive Standardized Uptake Value Ratios (SUVR). SUVR in WMH and normal‐appearing WM (NAWM) were compared using paired t‐tests. Among participants with at least one‐follow up [18F]flortaucipir scan (N=217, mean follow‐up time 1.5 years), longitudinal SUVR changes in the WM were estimated using Linear Mixed Models.

Result

Older age was associated with lower SUVR in both NAWM (r=‐0.10, p=0.007) and WMH (r=‐0.21, p<0.001) but not with [18F]flortaucipir retention in the medial temporal cortex after adjusting for amyloid‐β (Aβ) status and diagnosis (r=‐0.04, p=0.36, Meltzer‐corrected for partial volume effects). Compared to NAWM, WMH areas displayed significantly reduced SUVR independently of cognitive impairment and Aβ status (p<0.001, Figure 1). Longitudinal analyses revealed that SUVR in the WM decreased over time (‐0.009 SUVR/year, p=0.003), while medial temporal SUVR increased (0.009 SUVR/year, p=0.03).

Conclusion

Low [18F]flortaucipir retention in the WM is associated with advancing age and presence of WM lesions, supporting the hypothesis that [18F]flortaucipir retention in the WM might reflect its myelin content. These findings do not support the use of WM reference regions for [18F]flortaucipir PET imaging.
LatAm‐FINGERS (Latin America)
Authors: Crivelli Lucia
Published: December 2020

Background

LatAm‐FINGERS is a Latin American initiative to develop a multicenter, randomized controlled trial for the prevention of cognitive deterioration and dementia and to share, compare and harmonize the data. LatAm‐FINGERS gathers Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, Mexico, Paraguay, Peru, Puerto Rico, and Uruguay.

Method

1,400 subjects (100 older adults from each country) at a high risk of cognitive deterioration due to sedentary lifestyle, poor diet, and a suboptimal metabolic‐cardiovascular profile will be randomly assigned to a Systematic Lifestyle Intervention (SLI) or a Flexible Lifestyle intervention (FLI). The SLI group will receive dietary counseling, intensive physical exercise, cognitive training and control of cardiovascular risk factors. The FLI group will receive regular health advice. Participants will be evaluated every six months. Baseline assessment will include clinical and neuropsychological assessment, APOE genotyping, and MRI. Aims: 1. A) To evaluate the feasibility of the FINGER multi‐domain lifestyle intervention in Latin America B) To evaluate the efficacy of the intervention, primarily on a global cognitive composite score ‐Preclinical Alzheimer Cognitive Composite (PACC)‐ and on specific cognitive domains: episodic memory, executive function, and processing speed. Efficacy variables were selected in order to be harmonized with the original FINGER project and with the ongoing U.S. POINTER protocol. See table 1. Data Sharing: Data collected in each center will be housed in REDCap (Research Electronic Data Capture) at the University of São Paulo Medical School and backup will be stored on a cloud. The data sharing will be managed jointly by the LatAm FINGERS steering committee (SC). Reputable investigators will be welcomed to apply two years after the study is completed. Requests for data will be reviewed by two members from the LatAm FINGERS SC and the decision to grant access to data will be based on scientific merit. The LatAm FINGERS will request the Data Transfer Agreement. Status and Timeline: Protocol design has been completed, application for Alzheimer's Association funding has been submitted and review and response are pending. Recruitment of subjects is expected to begin in June 2020. Preliminary data release is expected by Dec. 2020.
The pattern of performance on sensitive tests of four cognitive domains differentiates groups with progressive cognitive decline in Alzheimer's disease
Authors: Maljkovic Vera , Battioui Chakib
Published: December 2020

Background

A screening challenge for Alzheimer’s disease (AD) is a paucity of tests sensitive to the different stages of the disease continuum. Progression of clinical disease suggests that multiple tests, sensitive to individual stages of disease development, may better define the range of cognitive abilities and predict the next cognitive domain to decline.

Method

78 healthy controls and 29 clinically diagnosed cognitively impaired participants (23 Mild Cognitive Impairment, MCI, 6 mild Alzheimer’s dementia, mildAD) ages 60‐76, self‐administered at home 9 CANTAB tasks on a provided iPad (Maljkovic et al, AAIC 2019). Four tasks were selected for further analysis: spatial working memory (SWM), paired‐associates learning (PAL), pattern recognition matching‐delayed (PRM‐del) and executive function task ‘One‐touch‐stockings‐of‐Cambridge’ (OTS). We performed two independent cross‐sectional analyses:
(1) Top‐down.
We manually created good/poor performance regimes for each test, resulting in 16 test‐by‐performance combinations, and sorted subjects according to their performance.
(2) Bottom‐up.
We performed a K‐means cluster analysis.

Result

(1) Top‐down. The 5 combinations with the highest number of participants (total of 85%) show progression of cognitive decline from the loss of SWM, through the losses of PAL, PRM‐del, and finally OTS (Table 1, left columns of numbers). (2) Bottom‐up. K‐means cluster analysis produced 5 categories with same cognitive profiles (Table 1, right columns). Both results show the number of healthy controls decreasing and the number of symptomatic participants increasing across groups. The two methods are also highly concordant in determining individual participants’ cognitive profiles: 80% of the participants from the 5 most numerous manually‐generated categories were assigned to the analogous group by the cluster analysis; 19% were assigned to an adjacent category (Table 2).

Conclusion

The performance pattern on tests of different cognitive domains, relevant to clinical stages of AD, shows separation between groups with progressive levels of cognitive decline. This type of at‐home, self‐administered, testing on a personal device can evaluate current cognitive ability and may predict the next domain of cognitive loss. Results imply that an individual with AD would pass through these stages of cognitive decline over time, a hypothesis that needs to be tested in a longitudinal study.
Community‐based housing and NPI‐care practices for adults with intellectual disability and dementia
Authors: Janicki Matthew
Published: December 2020

Background

Aging persons with intellectual disability (ID) represent a vulnerable population with respect to cumulative neuropathological conditions, including dementia. Adults with Down syndrome (DS), a subset, have a recognized high risk for Alzheimer’s disease. With dementia present, how to provide post‐diagnostic supports is challenging. Dementia care group homes (GHs) along with NPIs are emerging as a mode for providing out‐of‐home community supports. Data from a longitudinal study provide insights on what care organizations need to consider when organizing specialty group home care. The study, begun in 2011, followed three co‐located homes providing NPIs to 15 adults with dementia. Findings revealed trajectories of changes over time, housing need/function level patterning, and health status outcomes. Key findings noted 3 age‐of‐admission clusters (□; = 50.5; □; = 57.1; χ = 66.8); overall mortality (□;age‐death = 65.4; ID = 69.3; DS = 56.3) – half of original entrants died within 7 years; age at entry (□; = 59.1); years from entry to death (□; = 5.4 yrs); LOS (□; = 49.4 months/4.12 yrs); morbidities (number of co‐morbidities decreased among survivors). In same period, 8/15 deaths in GHs vs 3/15 deaths in Controls. NPI‐related practices included day program activities (adults in mid‐ to later stages were engaged in regular off‐site day activities that agency provided; adults with advanced dementia remained in homes), staffing patterns differed based on level of care – more staff assigned to homes with residents with advanced dementia, and staff training included dementia capable communications, engagement, and managing daily routines. Trends showed adults with Down syndrome were admitted to homes earlier but had more life‐years in the GHs than older adults admitted at later age but who succumbed earlier to disease complications. Dementia care GHs should expect varied trajectories of decline; mortality linked to complexity of pre‐existing conditions and progression of dementia; changes in the focus of care needs over time (including advanced dementia and end‐of‐life care). Dementia care GHs can enable provision of in‐community group housing and quality care in accord with stage‐defined functional changes and needs if structured in a planful way (factoring in dementia‐stage, dementia type, mortality expectations, health status, patterns of care needs, dementia‐related behaviors, aging‐related issues, and probable trajectories of decline of the residents).
Receptor for advanced glycation end products mediates meningitis‐triggered amyloid‐β accumulation and cognitive impairment
Authors: Barichello Tatiana , Generoso Jaqueline S , Giridharan Vijayasree V , Collodel Allan , Dominguini Diogo , Petronilho Fabricia , Dal‐Pizzol Felipe
Published: December 2020

Background

Pneumococcal meningitis is a life‐threatening infection of the central nervous system (CNS), and half of the survivors of meningitis suffer from neurological sequelae. We hypothesized that pneumococcal meningitis causes CNS inflammation via the disruption of the blood‐brain barrier (BBB) and by increasing the expression of the receptor for advanced glycation end products (RAGE) in the brain, which then causes glial cell activation and cognitive impairment, triggering similar Alzheimer's disease pathology.

Method

To test our hypothesis, sixty‐day‐old male Wistar rats were subjected to meningitis by receiving an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid (aCSF) as a control group and were treated with a high‐affinity RAGE‐specific inhibitor (FPS‐ZM1) in saline or placebo. Rats also received ceftriaxone 100 mg/kg, i.p., bid, and fluid replacements. We evaluate the blood‐brain barrier at 12, 18, and 24 hours after meningitis induction or aCSF. At ten days after the meningitis induction, we evaluate behavioral tasks, including open field, novel object recognition task, and Morris water maze. After the behavioral tasks, the brain of the animals was removed to evaluate RAGE, amyloid‐beta (Aβ1‐42), and glial cells activation.

Result

We demonstrated that experimental pneumococcal meningitis triggered BBB disruption at 12, 18, and 24 hours after meningitis induction, and FPS‐ZM1 treatment significantly suppressed BBB disruption. Ten days after meningitis induction, surviving animals were free from infection, but they presented increased levels of TNF‐α and IL‐1β in the prefrontal cortex (PFC); high expression levels of RAGE and Aβ1‐42, high levels of microglial cell activation in the prefrontal cortex (PFC) and hippocampus, and memory impairment, as evaluated by the open field, novel object recognition task, and Morris water maze behavioral tasks.

Conclusion

Pneumococcal meningitis can increase the RAGE and Aβ1‐42 in the brain of the animals. Targeting RAGE inhibition was able to reduce cytokine levels, decrease the expression of RAGE and Aβ1‐42, inhibit microglial cell activation, and improve cognitive deficits in meningitis survivor rats.
Performance of validated microRNA biomarkers for Alzheimer’s disease in mild cognitive impairment
Authors: Saugstad Julie A
Published: December 2020

Background

Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer’s Disease (AD) have been identified, but have not been evaluated in prodromal AD, including Mild Cognitive Impairment (MCI). Here we evaluated the expression of our previously validated CSF miRNA biomarkers for AD in MCI.

Method

We measured the expression of 17 validated miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively unimpaired controls. We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOEɛ4) genotype and amyloid‐β42 to total tau ratio (Aβ42:T‐Tau). We identified predicted targets of trending miRNAs using pathway analysis.

Result

Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T‐Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T‐Tau was weak.

Conclusion

Selected miRNAs combined with Aβ42:T‐Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite weak correlation with Aβ42:T‐Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.
Heightened sensitivity of people with Alzheimer’s disease to the side effects of antipsychotic drug amisulpride may be mediated through an interaction with glucose transporter 1 at the blood‐brain barrier
Authors: Boyanova Sevda , Wang Hao , Fleckney Alice L , Gatt Ariana , Farag Doaa B , Rahman K Miraz , Vizcay‐Barrena Gema , Fleck Roland , Reeves Suzanne J , Thomas Sarah A
Published: December 2020

Background

Amisulpride is an atypical antipsychotic which antagonises dopamine (D2, D3) receptors in vitro and in vivo (Schoemaker et al., 1997). Older people, particularly those with dementia are more susceptible to antipsychotic side effects, including amisulpride (Reeves et al., 2017). Clinical and basic science research suggested that blood‐brain barrier (BBB) disruption underpins this heightened sensitivity by increasing central drug access (Sekhar et al., 2019; Harwood et al., 1994). The current study examines healthy and Alzheimer’s disease (AD) physiology to further understand this increased sensitivity.

Method

We investigated the BBB transport of amisulpride in 5xFamilial Alzheimer’s mouse model (5xFAD), and in age‐matched wild type mice (WT, C57/BL6) (12‐15 months old). 5xFAD mice express human amyloid precursor protein and presenilin 1 transgenes with five AD‐linked mutations, they develop Aβ plaques and cognitive impairments (Oakley et al., 2006). All experiments were performed according the Animal Scientific Procedures Act (1986) and Amendment Regulations 2012. Anaesthesia was applied via intraperitoneal injection of medetomidine hydrochloride and ketamine mixture. The mice were perfused with artificial plasma, containing [3H]amisulpride (6.5 nM) and [14C]sucrose (9.4 μM). Brain amyloid plaques were confirmed in 5xFAD mice by transmission electron microscopy. In silico molecular docking using AuDock Vina and GOLD software identified transporters of interest for our model substrate. Amisulpride was considered a substrate for a given transporter, if it had free energy binding lower than ‐5 kcal/mole and high chem score.

Result

Compared to WT (n=6), the 5xFAD (n=7) mice had increased striatal [3H]amisulpride uptake of 79% (t=1.975, df=11, p=0.0370). The [14C]sucrose (passive permeability measure) permeability was not significantly changed. Preliminary in silico analysis suggested that amisulpride is a substrate for glucose transporter 1 (GLUT1) and a very weak substrate for multidrug and toxin extrusion transporter (MATE2) (Table 1).

Conclusion

In silico studies suggested amisulpride interacts with BBB solute carrier (SLC) transporters: organic cation transporter (OCT1), plasma membrane monoamine transporter (PMAT), MATE1 (Sekhar et al., 2019), GLUT1 and MATE2, but not with the adenosine triphosphate binding cassette (ABC) transporter P‐glycoprotein. The increased brain permeability to amisulpride in 5xFAD mice suggests altered BBB transporter function, possibly due to SLC transporter expression changes associated with AD.
Ablation of astrocytes affects Aβ degradation, microglia activation and synaptic connectivity in an ex vivo model of Alzheimer’s disease
Authors: Davis Nicola , Mota Bibiana Castagna , Stead Larissa , Palmer Emily OC , Lombardero Laura , Rodriguez‐Puertas Rafael , de Paola Vincenzo , Barnes Samuel J , Sastre Magdalena
Published: December 2020

Background

Astrocytes provide vital support to neurons in normal and pathological conditions. In Alzheimer's disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms through which they affect neuroinflammation, amyloid pathology and synaptic density in AD remain unclear.

Method

To explore the role of astrocytes on amyloid pathology and neuroinflammatory markers, we pharmacologically ablated astrocytes in organotypic brain culture slices (OBCSs) generated from the 5XFAD mouse model of amyloidosis with selective astrocytic toxin L‐alphaaminoadipate (L‐AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy‐1‐GFP transgenic mice incubated with synthetic amyloid‐beta (Aβ)42, or double transgenics Thy‐1‐GFP/5XFAD mice treated with L‐AAA or vehicle for 24h.

Result

Treatment of OBCSs with L‐AAA resulted in an increased expression of proinflammatory cytokines, such as TNF‐α in conditioned media, without changes in microglial density. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, associated with reduced expression of Neprilysin and Apolipoprotein E, which are involved in Aβ clearance. In addition, OBSCs from wild‐type mice treated with L‐AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of the Aβ degrading enzyme IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reduction in their density following L‐AAA treatment in all groups analysed. In addition, pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control.

Conclusion

Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.
DNA damage induced neuroinflammation in neurodegenerative disease
Authors: Song Xuan , AW Theeng Mei , Ma Fulin , Leung Danny , Herrup Karl
Published: December 2020

Background

The neurological symptom is highly related to the activation of innate immune system in the brain in neurodegenerative disease. The robust activation of microglia, which includes an overproduction of cytokines, creates a pro‐inflammatory environment that greatly contributes to the neuronal cell damage.

Method

DNA damage was induced by either direct triggers of double strands break or blocking DNA damage repair. Conditioned media from microglia culture was collected and treated to the neuronal culture. Different neuronal parameters, including the morphological changes, synaptic counts and death markers, were measured afterwards.

Result

In microglia, DNA damage induces elevated level of cytoplasmic DNA, which primes the anti‐virus innate immune response via the cytosolic DNA sensor, STING. Knockdown of STING or inhibition of STING activity rescued the inflammatory response, specifically, the overproduction of cytokines. Cytosolic DNA species also works through the AIM2‐containing inflammasome to process pro‐IL‐1β to its active form, IL‐1β. DNA damage in microglia leads to the secretion of pro‐inflammatory cytokines to the conditioned with sever neuronal cell damage.

Conclusion

The present work pointed out the fundamentality of accumulated DNA damage in triggering the activation of pro‐inflammatory pathway in the immune cells. Upon DNA damage, brain microglia, the major immune cells of the central nervous system become activated and assume a neurotoxic pro‐inflammatory phenotype. This also calls attention to the importance of the microglia‐neuron interaction in brain diseases. Meanwhile, the evidence for the presence of cytoplasmic DNA in other cell types under different disease conditions are also relevant to our understanding of a wider range of neurodegenerative diseases.
Loneliness and social engagement in older adults based in Lombardy during COVID‐19 lockdown: The long‐term effects of social networking sites training course
Authors: Rolandi Elena , Vaccaro Roberta , Abbondanza Simona , Casanova Georgia , Pettinato Laura , Colombo Mauro , Guaita Antonio
Published: December 2020

Background

Older people are at greater risk of infection and mortality from COVID‐19 and 52.3% of the deceased in Italy are Lombardy’s residents. Moreover, lockdown measurements may disproportionately affect elderly, since they are less familiar with communication technology used to overcome the lack of in person social contacts. The present study aimed at exploring how older adults residing in Lombardy are experiencing the lockdown period, in relation to loneliness, social isolation and use of communication technology.

Method

In the first two weeks of May (2020) a telephone interview was conducted with people aged between 81 and 85, residing in the community, who participated in a study aimed at evaluating the impact of Social Networking Sites (SNS) use and older people’s social relationship (clinicaltrials.gov: NCT04242628). We collected information on SNS use, self‐perceived loneliness (UCLA scale 3‐item), social engagement with family and friends (Lubben Social Network Scale 6‐item). Among the eligible individuals (N=144), 1 deceased, 4 refused and 9 were unreachable, resulting in a sample of 130 interviewed. For the aim of the present investigation, participants were stratified as trained (N=60) and untrained (N=70) for SNS use, based on their attendance to group courses held last year as part of the main experimental study.

Result

Trained and untrained participants were comparable for age, sex, education, percentage of living alone, global cognition, depressive symptoms and comorbidity (Table 1). Participants trained for SNS use reported significantly higher usage of Facebook and WhatsApp and reduced feeling of being left out during the COVID‐19 lockdown (Table 2). Moreover, a trend toward significance was found for an inverse relationship between WhatsApp usage frequency and feeling of lack of companionship (rs = ‐0.257, p = 0.051; Table 3).

Conclusion

Though SNS are unable to completely replace in person contact, these preliminary results support the utility to train older adults for SNS use in order to improve their social inclusion, even in extreme conditions of self‐isolation and vulnerability due to COVID‐19 pandemic.
Lysosome‐autophagosome defects mediate proteinopathy in early stages of Alzheimer’s disease
Authors: Mustaly Sarah H , Beaman Kenneth D , Gilman‐Sachs Alice , Schrank Sean , Marr Robert , Stutzmann Grace E
Published: December 2020

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal protein aggregation and synaptic deficits. To regulate normal cellular recycling of cellular debris, lysosomes require an acidic environment which is maintained by an active vacuolar H+‐ATPase (V‐ATPase proton pump). The acidic pH in lysosomes is essential for autophagy, a catabolic pathway to degrade cellular proteins. In AD, V‐ATPase disruption can lead to abnormal β‐amyloid and tau accumulation. A candidate mechanism concurrent with V‐ATPase defects is Ca2+ dyshomeostasis, which alters the ion exchange and thus pH within these organelles. We hypothesize that altered Ca2+ signaling disrupts V‐ATPase ion exchange and instigates AD pathology.

Method

Immunohistochemistry in fixed brain slices was used to determine expression of V‐ATPase subunits (V1B2, V0a1), lysosomes (Lamp1), hyperphosphorylated tau (S262) and mature autophagosomes (LC3B) in 4‐month old 3xTg‐AD mice and non‐transgenic (NTg) controls with or without a 30‐day Ryanodex treatment (NAM of RyR; 10mg/kg). Lysosomal pH upon RyR stimulation with caffeine (20mM) was measured in RyR‐overexpressing HEK cells and iN using Lysosensor. Induced human neurons (iN) transformed from AD patient fibroblasts were used to measure, autophagosomes, β‐amyloid, and hyperphosphorylated tau levels after500nM bafilomycin V‐ATPase inhibitor treatment.

Result

V‐ATPase and lysosome markers are diminished in brains of 3xTg‐AD mice relative to NTg, whereas LC3B expression is increased. These phenotypes were restored to NTg levels after Ryanodex treatment in 3xTg‐AD mice. Additionally, increased aberrant RyR‐Ca2+ signaling alkalizes lysosomes and increases expression of hyperphosphorylated tau and autophagosomes in iN and RyR‐overexpressing HEK cells, with no significant difference with of β‐amyloid levels.

Conclusion

Prior to overt histopathology or cognitive deficits, decreased V‐ATPase expression on acidic compartments and increased autophagosomes in 3xTg‐AD mice reflects impaired lysosomal activity, which is mediated through upstream RyR‐Ca2+ dyshomeostatis. Increased RyR‐mediated Ca2+ release alkalizes lysosomes pH resulting in abnormal intracellular protein aggregates, demonstrating that aberrant intracellular Ca2+ signaling in early AD disrupts autophagy and protein clearance.
Formic Acid‐Assisted Selective Hydrogenolysis of 5‐Hydroxymethylfurfural to 2,5‐Dimethylfuran over Bifunctional Pd Nanoparticles Supported on N‐Doped Mesoporous Carbon
Authors: Hu Bin , Warczinski Lisa , Li Xiaoyu , Lu Mohong , Bitzer Johannes , Heidelmann Markus , Eckhard Till , Fu Qi , Schulwitz Jonas , Merko Mariia , Li Mingshi , Kleist Wolfgang , Hättig Christof , Muhler Martin , Peng Baoxiang
Published: December 2020

Biomass‐derived 5‐hydroxymethylfurfural (HMF) is regarded as one of the most promising platform chemicals to produce 2,5‐dimethylfuran (DMF) as a potential liquid transportation fuel. Pd nanoparticles supported on N‐containing and N‐free mesoporous carbon materials were prepared, characterized, and applied in the hydrogenolysis of HMF to DMF under mild reaction conditions. Quantitative conversion of HMF to DMF was achieved in the presence of formic acid (FA) and H2 over Pd/NMC within 2 h. The reaction mechanism, especially the multiple roles of FA, was explored through a detailed comparative study by varying hydrogen source, additive, and substrate as well as by applying in situ ATR‐IR spectroscopy. The major role of FA is to shift the dominant reaction pathway from the hydrogenation of the aldehyde group to the hydrogenolysis of the hydroxymethyl group via the protonation by FA at the C‐OH group, lowering the activation barrier of the C−O bond cleavage and thus significantly enhancing the reaction rate. XPS results and DFT calculations revealed that Pd2+ species interacting with pyridine‐like N atoms significantly enhance the selective hydrogenolysis of the C−OH bond in the presence of FA due to their high ability for the activation of FA and the stabilization of H−.
Morphology, mechanical, and physical properties of wet‐spun cellulose acetate fiber in different solvent‐coagulant systems and in‐situ crosslinked environment
Authors: Swapnil Soham Irtiza , Datta Nondita , Mahmud Md Musavvir , Jahan Rumana A. , Arafat M. Tarik
Published: December 2020

Wet spinning is a popular fiber manufacturing process where the effects of solvent and coagulant on the wet‐spun fiber are significant. In this study, we have explored the effect of solvent‐coagulant interaction and in‐situ crosslinking on the wet‐spun cellulose acetate (CA) fiber. Investigation on 12 different solvent‐coagulant systems revealed that variation in the systems resulted in significant variance in morphology and mechanical property of the fiber. Remarkable increase in mechanical property was observed after in‐situ crosslinking with citric acid and polyethylene glycol (PEG). Inclusion of sodium hypophosphite (NaH2PO2) as catalyst further increased tensile modulus (~407%) and crystallinity index (~46%) compared to CA fiber crosslinked with only citric acid. It was established that fiber from CA‐DMSO solution crosslinked with 10% citric acid and 10% PEG extruded in ethanol showed the highest tensile modulus (~30 MPa). This in‐depth study found an appropriate combination of solvent‐coagulant for forming stable CA fiber, with the addition of crosslinkers and catalyst further increasing the strength and usability of the fiber.
Sex Differences in Gender‐Diverse Expressions and Identities among Youth with Autism Spectrum Disorder
Authors: Brunissen Ludivine , Rapoport Eli , Chawarska Katarzyna , Adesman Andrew
Published: December 2020

A growing body of evidence supports a potential link between autism spectrum disorder (ASD) and gender dysphoria, yet few studies have looked at sex differences in the co‐occurrence of gender diversity and ASD. The aim of this study was to characterize sex differences in gender‐diverse expressions and identities, as well as gender‐related concerns, in youth with ASD. Parents of youth with ASD ages 6–21 (n = 163) completed an online questionnaire about their child's gender expression and identity. Sex‐typed behaviors during childhood were measured using the Gender Identity Questionnaire (GIQ). Semi‐partial Kendall correlations and chi‐square tests were used to compare gender non‐conformity, gender‐diverse identities, and gender‐related concerns between sexes. Sex‐based differences in mean GIQ score and individual GIQ items were evaluated using a linear regression and semi‐partial Kendall correlations, respectively. All regressions and correlations controlled for child age. Parents of girls were more likely to report child appearances and mannerisms that were less concordant with their child's birth sex. Based on parent‐report, girls had lower mean GIQ scores, indicating greater cross‐gendered/fewer same‐gendered behaviors in childhood. Lastly, parents of girls with ASD were more likely to report that their daughters experienced anxiety due to gender‐related concerns and discomfort during puberty than parents of boys. These findings suggest that girls with ASD seem more likely have gender‐diverse preferences, mannerisms, and appearances that fall outside of traditional gender norms. Gender‐related concerns appear to be a source of real distress in girls with ASD, highlighting the need for individualized support, especially during puberty.

Lay Summary

Despite evidence of a potential link between autism and gender diversity, few studies have explored differences in gender identity/expression between boys and girls with autism. Based on parent responses, we found that girls with autism are more likely than boys to have appearances and mannerisms, as well as behaviors during childhood, that fall outside of the traditional gender role. The unique profile of girls with autism and their elevated distress over gender‐related concerns call for individualized support during adolescence.
Attend Less, Fear More: Elevated Distress to Social Threat in Toddlers With Autism Spectrum Disorder
Authors: Macari Suzanne L. , Vernetti Angelina , Chawarska Katarzyna
Published: December 2020

Differential emotional reactivity to social and nonsocial stimuli has been hypothesized but rarely examined empirically in ASD despite its potential importance for development of social motivation, cognition, and comorbid psychopathology. This study examined emotional reactivity, regulation, and attention to social and nonsocial threat in toddlers with ASD (n = 42, Mage: 22 months) and typically developing (TD) toddlers (n = 22, Mage: 23 months), and their mutual associations with autism symptom severity. Participants were exposed to social (stranger), nonsocial (mechanical objects), and ambiguous (masks) threats, and their intensity of distress (iDistress), attention to threat (Attention), and presence of emotion regulation (ER) strategies were measured. Autism symptom severity was quantified using the Autism Diagnostic Observation Schedule‐2. In response to social threat, toddlers with ASD exhibited elevated iDistress (P < 0.038) but lower Attention (P < 0.002) and a wider variety of ER strategies (P < 0.040) compared to TD controls, though their ER strategies were less likely to be social. However, nonsocial and ambiguous threat elicited lower iDistress in ASD than in TD toddlers (P = 0.012 and P = 0.034, respectively), but comparable Attention and ER strategy use. Autism severity was not associated with iDistress. The study demonstrates elevated emotional salience but diminished attentional salience of social threat in ASD. A failure to attend adequately to social threats may restrict opportunities to appraise their threat value and engender often observed in ASD negative emotional responses to novel social situations. Early atypical emotional reactivity may independently contribute to the shaping of complex autism phenotypes and may be linked with later emerging affective and behavioral symptoms.

Lay Summary

Compared to typically developing toddlers, toddlers with ASD show diminished attention yet enhanced distress in response to social threat. Poor attention to potential social threat may limit opportunities to assess its threat value and thus contribute to often observed negative emotional responses to novel social situations. Identifying the precursors of atypical emotional reactivity in infancy and its links with later psychopathology will inform about novel treatment targets and mechanisms of change in the early stages of ASD. Autism Res 2021, 14: 1025–1036. © 2020 International Society for Autism Research, Wiley Periodicals, LLC
The Anti‐G0 Manifesto: Should a problematic construct (G0) with no biological reality be removed from the cell cycle? Yes!
Authors: Cooper Stephen
Published: December 2020

It is widely accepted that there exists a “resting” or “quiescent” state where a growing cell leaves the cell cycle to enter what is often called the “G0‐phase.” I propose that there is no biological reality to the “G0‐phase.” The experimental basis for proposing a G0‐phase is re‐examined and re‐analyzed here showing that the G0‐phase is an anthropomorphic construct with no biological reality.
A rapid and sensitive ultra‐high‐pressure liquid chromatography–tandem mass spectrometry method for the determination of notoginsenoside Ft1 in rat plasma with application to pharmacokinetic study
Authors: Ju Zhengcai , He Chunyong , Li Jia , Yang Li , Wang Zhengtao
Published: December 2020

Notoginsenoside Ft1 (NGFt1), a dammarane triterpene glycoside isolated from Panax notoginseng, showed potent effective in stimulating platelet aggregation in our previous assay, yet its pharmacokinetic behavior is still unclear. This study describes a rapid and sensitive ultra‐high‐pressure LC–tandem mass spectrometry assay for determining of NGFt1 in rat plasma. Methanol‐mediated precipitation was used for sample pre‐treatment. Chromatographic separation was achieved on a C18 column with gradient elution using water and acetonitrile as mobile phase. Determination was obtained using an electrospray ionization source in negative selected reaction monitoring (SRM) mode at the transitions of m/z 915.9 → m/z 783.8 and m/z 799.8 → m/z 637.8 for NGFt1 and internal standard, respectively. The assay was linear over the concentration range 0.25–2500 ng/mL (r > 0.995) with the lower limit of quantification of 0.25 ng/mL. The intra‐ and inter‐day precisions (relative standard deviation, %) ranged 1.65%–9.84% and 2.46%–13.49%, respectively, whereas accuracy (relative recovery, %) ranged from 96.21% to 99.45%, respectively. The recovery ranged from 95.09% to 102.22% and the matrix effect from 98.29% to 100.13%. The analyte was stable under tested storage conditions. The method has been successfully applied to a preclinical pharmacokinetic study in rats after a single intravenous (2 mg/kg) and oral (50 mg/kg) administration.
Validated HPLC‐MS/MS method for quantitation of AMG 510, a KRAS G12C inhibitor, in mouse plasma and its application to a pharmacokinetic study in mice
Authors: Madhyastha Naveena , Samantha Swapan Kumar , Dittakavi Sreekanth , Markose Meenu , Mallurwar Sadanand Rangnathrao , Zainuddin Mohd , Mullangi Ramesh
Published: December 2020

AMG 510 is the first‐in‐class KRASG12C inhibitor, currently in phase 2 clinical trials as an orphan drug to treat non‐small cell lung cancer patients. We developed and validated a sensitive, selective, and high‐throughput HPLC‐MS/MS method for the quantitation of AMG 510 in mouse plasma per the regulatory guideline of the US Food and Drug and Administration. AMG 510 and the IS (MRTX‐1257) were extracted from mouse plasma using tert‐butyl methyl ether and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 25:75, v/v) at a flow rate of 0.65 mL/min on an Atlantis dC18 column. AMG 510 and the IS eluted at ~0.95 and 0.73 min, respectively. AMG 510 and the IS were detected by positive electrospray ionization in multiple reaction monitoring using transition pair (Q1 → Q3) m/z 561.1 → 134.1 and m/z 566.5 → 98.2, respectively. Excellent linearity was achieved in the concentration range of 1.08–5040 ng/mL (r > 0.0996). No matrix effect and carryover were observed. Intra‐ and inter‐day accuracies and precisions were within the acceptance range. AMG 510 was demonstrated to be stable under the tested storage conditions. This novel method has been applied to a pharmacokinetic study in mice.
Global metabolic profiling of hemorrhagic shock and resuscitation
Authors: Xu Ping , Xu Wei , Gao Songyan , Che Yanting , Zhao Ping , Lu Shengfang , Wang Yong , Chen Xiaoqing , Zhang Qun , Chen Junjie , Zheng Xingfeng , Huang Gang , He Guibing , Liu Xinru
Published: December 2020

Hemorrhagic shock (HS) is a medical emergency during trauma. Significant loss of tissue perfusion may result in cellular hypoxia, organ damage and death. The primary treatment of HS is control of the source of bleeding as soon as possible and fluid replacement (crystalloid solutions and blood transfusion). Metabolomics can identify novel biomarkers for various functional and organic diseases. Therefore, systematic exploration of the biological mechanisms of HS and blood transfusion enables the optimization of treatments for HS to reduce the occurrence of organ damage. In this study, a global metabolic profiling strategy is applied to evaluate metabolic changes in the HS rat model. A serum metabolic network with 58 significant metabolites was constructed for HS and resuscitation. Our investigation will offer insights into the pathogenesis.
Evaluation of alkylamines and stationary phases to improve LC–MS of oligonucleotides
Authors: Bartlett Michael G. , Omuro Shogo
Published: December 2020

This study evaluated four bridged‐ethylene hybrid (BEH) columns containing C18 (130 Å), peptide C18 (300 Å), phenyl, or a mixed‐mode charged surface hybrid (CSH C18) using a wide range of antisense oligonucleotide therapeutics. The BEH C18, peptide, and phenyl columns were all capable of providing significant retention of oligonucleotide samples across multiple ion‐pairing systems using alkylamines and 1,1,1,3,3,3,‐hexafluoroisopropanol (HFIP). The retention of the oligonucleotides varied depending on the choice of alkylamine, with the order of retention being dimethylcyclohexylamine > diisopropylethylamine > triethylamine. The selectivity of these columns for several closely eluting impurities was similar. Although overall the C18, peptide, and phenyl columns were all found to be capable of analyzing oligonucleotide therapeutics, the phenyl column was found to be the most retentive and the C18 column provided the best peak shape. The CSH C18 column was found to be degraded by the alkylamine‐HFIP mobile phase despite the mobile phase being within the pH stability range of the column.