Lifestyle factors and metabolomic aging biomarkers: Meta-analysis of cross-sectional and longitudinal associations in three prospective cohorts.

Biological age uses biophysiological information to capture a person's age-related risk of adverse outcomes. MetaboAge and MetaboHealth are metabolomics-based biomarkers of biological age trained on chronological age and mortality risk, respectively. Lifestyle factors contribute to the extent chronological and biological age differ. The association of lifestyle factors with MetaboAge and MetaboHealth, potential sex differences in these associations, and MetaboAge's and MetaboHealth's sensitivity to lifestyle changes have not been studied yet. Linear regression analyses and mixed-effect models were used to examine the cross-sectional and longitudinal associations of scaled lifestyle factors with scaled MetaboAge and MetaboHealth in 24,332 middle-aged participants from the Doetinchem Cohort Study, Rotterdam Study, and UK Biobank. Random-effect meta-analyses were performed across cohorts. Repeated metabolomics measurements had a ten-year interval in the Doetinchem Cohort Study and a five-year interval in the UK Biobank. In the first study incorporating longitudinal information on MetaboAge and MetaboHealth, we demonstrate associations between current smoking, sleeping ≥8 hours/day, higher BMI, and larger waist circumference were associated with higher MetaboHealth, the latter two also with higher MetaboAge. Furthermore, adhering to the dietary and physical activity guidelines were inversely associated with MetaboHealth. Lastly, we observed sex differences in the associations between alcohol use and MetaboHealth.

Torpor induces reversible tau hyperphosphorylation and accumulation in mice expressing human tau.

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer's disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies.

Fractionated brain X-irradiation profoundly reduces hippocampal immature neuron numbers without affecting spontaneous behavior in mice.

Whole brain radiotherapy (WBRT) is used to improve tumor control in patients with primary brain tumors, or brain metastasis from various primary tumors to improve tumor control. However, WBRT can lead to cognitive decline in patients. We assessed whether fractionated WBRT (fWBRT) affects spontaneous behavior of mice in automated home cages and cognition (spatial memory) using the Barnes maze. Male C57Bl/6j mice received bi-lateral fWBRT at a dosage of 4 Gy/day on 5 consecutive days. In line with previous reports, immunohistochemical analysis of doublecortin positive cells in the dentate gyrus showed a profound reduction in immature neurons 4 weeks after fWBRT. Surprisingly, spontaneous behavior as measured in automated home cages was not affected. Moreover, learning and memory measured with Barnes maze, was also not affected 4-6 weeks after fWBRT. At 10-11 weeks after fWBRT a significant difference in escape latency during the learning phase, but not in the probe test of the Barnes maze was observed. In conclusion, although we confirmed the serious adverse effect of fWBRT on neurogenesis 4 weeks after fWBRT, we did not find similar profound effects on spontaneous behavior in the automated home cage nor on learning abilities as measured by the Barnes maze. The relationship between the neurobiological effects of fWBRT and cognition seems more complex than often assumed and the choice of animal model, cognitive tasks, neurobiological parameters, and experimental set-up might be important factors in these types of experiments.

The multi-faceted nature of age-associated osteoporosis.

Age-associated osteoporosis (AAOP) poses a significant health burden, characterized by increased fracture risk due to declining bone mass and strength. Effective prevention and early treatment strategies are crucial to mitigate the disease burden and the associated healthcare costs. Current therapeutic approaches effectively target the individual contributing factors to AAOP. Nonetheless, the management of AAOP is complicated by the multitude of variables that affect its development. Main intrinsic and extrinsic factors contributing to AAOP risk are reviewed here, including mechanical unloading, nutrient deficiency, hormonal disbalance, disrupted metabolism, cognitive decline, inflammation and circadian disruption. Furthermore, it is discussed how these can be targeted for prevention and treatment. Although valuable as individual targets for intervention, the interconnectedness of these risk factors result in a unique etiology for every patient. Acknowledgement of the multifaceted nature of AAOP will enable the development of more effective and sustainable management strategies, based on a holistic, patient-centered approach.

Implementing systematic melanoma risk assessment and risk-tailored surveillance in a skin cancer focussed dermatology clinic: A qualitative study of feasibility and acceptability to patients and clinic staff.

BACKGROUND: International bodies recommend that melanoma risk assessment should be integrated into skin cancer care provision, but evidence to support implementation is lacking. AIM: To explore the acceptability and feasibility of implementing personalised melanoma risk assessment and tailored patient education and skin surveillance within routine clinical care. METHODS: This prospective qualitative implementation study was informed by the Theoretical Framework of Acceptability (TFA). Personalised, systematic melanoma risk assessment was implemented in the dermatology clinic at the Melanoma Institute Australia, Sydney, Australia February-May 2021. Pre- and post-implementation observations and semi-structured interviews with patients and staff were conducted (September 2020-March 2021). Observational notes and interview transcript data were analysed thematically using the TFA as a classifying framework. RESULTS: A total of 37 h of observations were made, and 29 patients and 12 clinic staff were interviewed. We found that the delivery of personalised melanoma risk estimates did not impact on patient flow through the clinic. Dermatologists reported that the personalised risk information enhanced their confidence in assessing patient risk and recommending tailored surveillance schedules. Most patients reported that the risk assessment and tailored information were a beneficial addition to their care. Among patients whose risk deviated from their expectations, some reported feeling worried, confused or mistrust in the risk information, including those at lower risk who were recommended to decrease surveillance frequency. CONCLUSIONS: It is feasible and acceptable to patients and clinic staff to calculate and deliver personalised melanoma risk information and tailored surveillance as part of routine clinical care within dermatology clinics.

A protocol for isolating and imaging large extracellular vesicles or midbody remnants from mammalian cell culture.

Traditionally, midbody remnants (MBRs) are isolated from cell culture medium using ultracentrifugation, which is expensive and time consuming. Here, we present a protocol for isolating MBRs or large extracellular vesicles (EVs) from mammalian cell culture using either 1.5% polyethylene glycol 6000 (PEG6000) or PEG5000-coated gold nanoparticles. We describe steps for growing cells, collecting media, and precipitating MBRs and EVs from cell culture medium. We then detail characterization of MBRs through immunofluorescent antibody staining and immunofluorescent imaging.

Point-of-care ultrasound assessment of a swollen limb following snakebite envenomation - an adjunct to avoid fasciotomy.

SUMMARY: Acute limb compartment syndrome can occur with cytotoxic snake envenomation. Ultrasound (US) assessment of the affected limb has been suggested as an adjunct to the administration of snakebite polyvalent antivenom to ameliorate the systemic and local effects. US may also aid in the diagnosis of compartment syndrome and the need for fasciotomy to prevent limb loss. This report presents an adult male who had severe soft tissue swelling from a puff adder bite to the wrist and highlights the use of US in assessing and monitoring the degree of swelling in subcutaneous and fascial compartments of the arm. This US monitoring in conjunction with frequent physical examination avoided the need for a fasciotomy and its attendant morbidity, resulting in complete resolution of the swelling and full recovery of limb function.

The association of body mass index with safety and effectiveness of first-line carboplatin-based chemotherapy in patients with metastatic non-small cell lung cancer.

INTRODUCTION: Carboplatin is an anticancer drug used for treatment of various types of cancer including non-small cell lung cancer (NSCLC). Dosing is based on estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula. In overweight patients, the GFR is more likely overestimated, resulting in a potentially overdose of carboplatin affecting treatment response. This study investigated the association of body mass index (BMI) on overall survival (OS) and progression-free survival (PFS) in stage-IV NSCLC patients treated with first-line carboplatin-based chemotherapy. Secondary safety endpoints were thrombocytopenia and toxicity-related hospitalizations. MATERIALS AND METHODS: This was a retrospective multicenter cohort study. Patients were categorized according to BMI<25.0 kg/m2 (normal weight and reference), 25.0-29.9 kg/m2 (overweight) or ≥30.0 kg/m2 (obese). For survival analyses adjusted hazard ratios [aHR] were calculated using multivariate Cox regression analysis. Secondary outcomes were analyzed using multivariate logistic regression providing adjusted odd ratios [aOR]. RESULTS: Overweight patients (n=174) had a significantly better OS (aHR=0.72, 95%-CI:0.59-0.89) and PFS (aHR=0.74, 95%-CI:0.61-0.90) compared to normal weight patients (n=268). OS nor PFS were different in obese (n=51) compared to normal weight patients. However, obesity was associated with significantly higher incidences of thrombocytopenia grade ≥3 (aOR=3.47, 95%-CI:1.75-6.90). CONCLUSION: This study shows a significantly longer survival for overweight compared to normal weight patients. Obese patients have an increased risk for grade ≥3 thrombocytopenia without a difference in survival following carboplatin-based chemotherapy. The implications for clinical practice are to use the Cockcroft-Gault formula with caution in patients with BMI≥30.0 kg/m2, and to verify calculated dosing of carboplatin for appropriateness.

Dysregulation of synaptic and developmental transcriptomic/proteomic profiles upon depletion of MUNC18-1.

Absence of presynaptic protein MUNC18-1 (gene: Stxbp1) leads to neuronal cell death at an immature stage before synapse formation. Here, we performed transcriptomic and proteomic profiling of immature Stxbp1 knockout (KO) cells to discover which cellular processes depend on MUNC18-1. Hippocampi of Stxbp1 KO mice showed cell-type specific dysregulation of 2123 transcripts primarily related to synaptic transmission and immune response. To further investigate direct, neuron-specific effects of MUNC18-1 depletion, a proteomic screen was performed on murine neuronal cultures at two developmental timepoints prior to onset of neuron degeneration. 399 proteins were differentially expressed, which were primarily involved in synaptic function (especially synaptic vesicle exocytosis) and neuron development. We further show that many of the downregulated proteins upon loss of MUNC18-1 are normally upregulated during this developmental stage. Thus, absence of MUNC18-1 extensively dysregulates the transcriptome and proteome, primarily affecting synaptic and developmental profiles. Lack of synaptic activity is unlikely to underlie these effects, as the changes were observed in immature neurons without functional synapses, and minimal overlap was found to activity-dependent proteins. We hypothesize that presence of MUNC18-1 is essential to advance neuron development, serving as a 'checkpoint' for neurons to initiate cell death in its absence.Significance StatementPresynaptic protein MUNC18-1 is essential for neuronal functioning. Pathogenic variants in its gene, STXBP1, are among the most common found in patients with developmental delay and epilepsy. To discern the pathogenesis in these patients, a thorough understanding of MUNC18-1's function in neurons is required. Here, we show that loss of MUNC18-1 results in extensive dysregulation of synaptic and developmental proteins in immature neurons before synapse formation. Many of the downregulated proteins are normally upregulated during this developmental stage. This indicates that MUNC18-1 is a critical regulator of neuronal development, which could play an important role in the pathogenesis of STXBP1 variant carriers.

Benefit of sequential bilateral cochlear implantation in children between 5 to 18 years old: A prospective cohort study.

OBJECTIVE: To determine the benefit of sequential cochlear implantation after a long inter-implantation interval in children with bilateral deafness receiving their second implant between 5 and 18 years of age. STUDY DESIGN: Prospective cohort-study. SETTING: Tertiary multicenter. PATIENTS: 85 children with bilateral deafness and unilateral implantation receiving a contralateral cochlear implant at the age of 5 to 18 years. METHOD: The primary outcomes were speech recognition in quiet and noise (CVC) scores. The secondary outcomes were language outcomes and subjective hearing abilities, all measured before and 12 months after sequential bilateral cochlear implantation. Medians of the paired data were compared using the Wilcoxon signed-rank test. Univariable linear regression analyses was used to analyze associations between variables and performance outcomes. RESULTS: A significant benefit was found for speech recognition in quiet (96% [89-98] vs 91% [85-96]; p < 0.01) and noise (65% [57-75] vs 54% [47-71]; p = 0.01) in the bilateral CI condition compared to unilateral (n = 75, excluded 10 non-users). No benefit was seen for language outcomes. The subjective sound quality score was statistically significant higher in bilateral compared to the unilateral CI condition. Pre-operative residual hearing level in the ear of the second implant, the inter-implant interval and age at time of second implantation was not significantly associated with performance scores. CONCLUSION: After 12 months of use, sequential bilateral cochlear implantation showed improved speech perception in quiet and noise and improved subjective sound quality outcomes in children despite a great inter-implantation interval (median of 8 years [range 1-16 years]).

The AGE Reader: A non-invasive method to assess long-term tissue damage.

AIMS: Advanced glycation endproducts (AGEs) are sugar-modified adducts which arise during non-enzymatic glycoxidative stress. These compounds may become systemically elevated in disease states, and accumulate in tissue, especially on long-lived proteins. AGEs have been implicated in various acute, and chronic diseases, stressing the need for reliable and comprehensive measuring techniques. Measurement of AGEs in tissue such as skin requires invasive skin biopsies. The AGE Reader has been developed to assess skin autofluorescence (SAF) non-invasively using the fluorescent properties of several AGEs. RESULTS/CONCLUSION: Various studies have shown that SAF is a useful marker of disease processes associated with oxidative stress. It is prospectively associated with the development of cardiovascular events in patients with diabetes, renal or cardiovascular disease, and it predicts diabetes, cardiovascular disease, and mortality in the general population. However, when measuring SAF in individual subjects, several factors may limit the reliability of the measurement. These include endogenous factors present in the skin that absorb emission light such as melanin in dark-skinned subjects, but also factors that lead to temporal changes in SAF such as acute diseases and strenuous physical exercise associated with glycoxidative stress. Also, exogenous factors could potentially influence SAF levels inadvertently such as nutrition, and for example the application of skin care products. This review will address the AGE Reader functionality and the endogenous, and exogenous factors which potentially influence the SAF assessment in individual subjects.

Midwifery students' perspectives of physical and virtual mobility activities including preferences for e-learning: A cross-sectional survey.

BACKGROUND: Contemporary higher education requires that all midwifery students have insight and understanding of global health practice and demonstrate intercultural sensitivity. However, the mobility models currently offered do not often fit the lives of large numbers of midwifery students. OBJECTIVES: To investigate midwifery students' international physical mobility activities and factors that affect mobility; to determine midwifery students' learning needs and preferences for related e-learning packages. DESIGN: Multi-centre, descriptive quantitative survey. SETTINGS: Four European Higher Education Institutions based in the United Kingdom, Estonia, Italy and the Netherlands offering an undergraduate midwifery programme. PARTICIPANTS: The sample included 205 midwifery students from Italy (n = 93), the Netherlands (n = 51); United Kingdom (n = 35) and Estonia (n = 26). METHODS: Data were collected in June-July 2020 through an online cross-sectional, bespoke questionnaire and analysed using summary statistical analysis. RESULTS: There is a high level of interest across a range of mobility opportunities, especially those of shorter duration. Barriers to mobility comprised finance, caring responsibilities, concerns about fitting mobility activities into the midwifery programme, negative impact on studies and language barriers. The most frequently identified facilitators of mobility included professional perspectives such as interest in other cultures and midwifery in other settings and an endorsement that mobility would add value to their development as a midwife. When engaging in virtual learning, the most preferred resources mentioned by the students were videos, video calls with peers, choice quiz and discussion forum. CONCLUSIONS: The barriers identified require new approaches to enable all midwifery students to benefit from transnational learning. The survey findings provide insights into midwifery students' perspectives from which a new mobility model can be developed.

Differences in characteristics between people with tinnitus that seek help and that do not.

Knowledge on characteristics of people that seek help for tinnitus is scarce. The primary objective of this study was to describe differences in characteristics between people with tinnitus that seek help compared to those who do not seek help. Next, we described differences in characteristics between those with and without tinnitus. In this cross-sectional study, we sent a questionnaire on characteristics in different domains; demographic, tinnitus-specific, general- and psychological health, auditory and noise- and substance behaviour. We assessed if participants had sought help or planned to seek help for tinnitus. Tinnitus distress was defined with the Tinnitus Functional Index. Differences between groups (help seeking: yes/no, tinnitus: yes/no) were described. 932 people took part in our survey. Two hundred and sixteen participants were defined as having tinnitus (23.2%). Seventy-three of those sought or planned to seek help. A constant tinnitus pattern, a varying tinnitus loudness, and hearing loss, were described more frequently in help seekers. Help seekers reported higher TFI scores. Differences between help seekers and people not seeking help were mainly identified in tinnitus- and audiological characteristics. These outcomes might function as a foundation to explore the heterogeneity in tinnitus patients.

Prediction models for clinical outcome after cochlear implantation: a systematic review.

OBJECTIVES: Cochlear implants (CIs) are implantable hearing devices with a wide variation in clinical outcome between patients. We aim to provide an overview of the literature on prediction models and their performance for clinical outcome after cochlear implantation in bilateral hearing loss or deafness. STUDY DESIGN AND SETTING: In this systematic review, studies describing the development or external validation of a multivariable model for predicting clinical CI outcome were eligible for selection. RESULTS: A total of 4,042 references were screened. We included nine development studies and one external validation study. The outcome measure of all development studies was speech perception performance after cochlear implantation. The most commonly used model predictors were duration of hearing loss or deafness (n = 7), different types of preoperative measurements (n = 5), and etiology (n = 3). In three studies, crucial information to enable the model to be used for individual risk prediction was missing. One study performed internal validation,two models were externally validated. One study reported specific discrimination or calibration performance measures. CONCLUSION: Although many articles describe development studies of prediction models for speech perception performance after cochlear implantation, the value of most of these models for their application in clinical practice remains unclear. Therefore, research should focus on increasing the clinical relevance of existing CI outcome prediction models.

Tinnitus treatment by vagus nerve stimulation: A systematic review.

BACKGROUND: Tinnitus is a phantom sensation of sound, which can have a negative impact on quality of life of those affected. No curative treatments are currently known. Neuromodulation by vagus nerve stimulation has emerged as a new treatment option for tinnitus, though till date the effectiveness remains unclear. Therefore, we aim to review the effect of vagus nerve stimulation on tinnitus distress and tinnitus symptom severity in patients with chronic tinnitus. METHODS: We searched Pubmed, Embase and the Cochrane Library systematically for RCTs, observational studies and case studies on the effect of VNS treatment for tinnitus on October 29, 2019. Studies including adult patients with subjective tinnitus, comparing transcutaneous or implantable VNS to placebo or no treatment or before and after application of VNS treatment on tinnitus distress and tinnitus symptom severity measured with a validated questionnaire were eligible. The risk of bias was assessed with the appropriate tool for each type of study. RESULTS: Our search identified 9 primary studies of which 2 RCTs, 5 cohort studies and 2 case series or reports. 5 studies used transcutaneous VNS treatment and 4 used implanted VNS treatment. 6 studies combined VNS treatment with sound therapy. There was a serious risk of bias in all studies, especially on confounding. Most studies reported a small decrease in tinnitus distress or tinnitus symptom severity. CONCLUSION: Due to methodological limitations and low reporting quality of the included studies, the effect of VNS on tinnitus remains unclear. To draw conclusions for which patient population and to what extent (t)VNS is beneficial in the treatment of tinnitus, a randomised controlled trial should be considered.

Microtia and cholesteatoma: Implications for the reconstructive surgeon.

Infection after reconstructive surgery for microtia is a technical challenge. This can be a sign of cholesteatoma formation by entrapment of epithelium in the middle or outer ear, specifically when the patient does not respond to first choice antibiotic therapy and debridement. Two patients with microtia presented themselves with severe infections after ear reconstruction. In both cases cholesteatoma was diagnosed as the cause of the infection. After cholesteatoma management an additional surgical procedure was necessary to improve the esthetic outcome. The plastic surgeon should identify possible signs of cholesteatoma after reconstruction of the auricle.

Hearing-related quality of life, developmental outcomes and performance in children and young adults with unilateral conductive hearing loss due to aural atresia.

BACKGROUND: While research has shown that children with single sided deafness have a lower quality of life and developmental outcomes compared to normal hearing peers, little is known about these domains in children with unilateral congenital conductive hearing loss due to aural atresia. OBJECTIVES: This study aims to investigate the hearing-related quality of life, developmental outcomes and educational performance in children and young adults with unilateral conductive hearing loss due to aural atresia. METHODS: Nineteen children and young adults with unilateral aural atresia received a set of five questionnaires. Hearing-related quality of life (SSQ), general quality of life (Kidscreen-27), speech and language development (CCC-2-Nl), educational performance and problems in social-emotional and behavioral domains (CBCL/YSR/ASR) were measured with validated questionnaires. Scores on the questionnaires were compared to their norm scores. Mann-Whitney U tests and independent t-tests were used to identify significant differences between age groups. RESULTS: Mean scores on the SSQ subscales were speech 6.78, spatial 5.00 and quality 6.98. Mean scores on the Kidscreen-27, CCC-2-NL, CBCL/YSR/ASR fell within normal or non-clinical range. A high number of cases needed speech therapy (60.7%) or special measures in class (79.3%) or showed grade repetition (>30%) in primary or secondary school. CONCLUSION: Children and young adults with unilateral conductive hearing loss due to congenital aural atresia showed lower scores regarding hearing-related quality of life compared to normal-hearing peers. The result show similarities with children with single sided deafness. Regarding general quality of life, speech and language development and in social-emotional and behavioral domains the studied children and young adults seem to develop according to norm scores. It is important to observe these children closely as they may need guidance during education to allow them to thrive.

Carbon nanotubes affect early growth, flowering time and phytohormones in tomato.

Carbon nanotube (CNT) applications are increasing in consumer products, including agriculture devices, making them an important contaminant to study in the field of plant nanotoxicology. Several studies have observed the uptake and effects of CNTs in plants. However, in other studies differing results were observed on growth and physiology depending on the plant species and type of CNT. This study focused on the effects of CNTs on plant phenotype with growth, time to flowering, fruiting time as endpoints, and physiology, through amino acid and phytohormone content, in tomato after exposure to multiple types of CNTs. Plants grown in CNT-contaminated soil exhibited a delay in early growth and flowering (especially in treatments of 1 mg/kg multi-walled nanotubes (MWNTs), 10 mg/kg MWNTs, and 1 mg/kg MWNTs-COOH). However, CNTs did not affect plant growth or height later in the life cycle. No significant differences in abscisic acid (ABA) and citrulline content were observed between the treated and control plants. However, single-walled nanotube (SWNT) exposure significantly increased salicylic acid (SA) content in tomato. These results suggest that SWNTs may elicit a stress response in tomatoes. Results from this study offer more insight into how plants respond and acclimate to CNTs. These results will lead to a better understanding of CNT impact on plant phenotype and physiology.

Comparison of Nanoarchitecture to Porous Media Diffusion Models in Reduced Graphene Oxide/Aramid Nanofiber Electrodes for Supercapacitors.

Structural electrodes made of reduced graphene oxide (rGO) and aramid nanofiber (ANF) are promising candidates for future structural supercapacitors. In this study, the influence of nanoarchitecture on the effective ionic diffusivity, porosity, and tortuosity in rGO/ANF structural electrodes is investigated through multiphysics computational modeling. Two specific nanoarchitectures, namely, "house of cards" and "layered" structures, are evaluated. The results obtained from nanoarchitecture computational modeling are compared to the porous media approach and show that the widely used porous electrode theories, such as Bruggeman or Millington-Quirk relations, overestimate the effective diffusion coefficient. Also, the results from nanoarchitecture modeling are validated with experimental measurements obtained from electrochemical impedance spectroscopy and cyclic voltammetry. The effective diffusion coefficients obtained from nanoarchitectural modeling show better agreement with experimental measurements. Evaluation of microscopic properties such as porosity, tortuosity, and effective diffusivity through both experiment and simulation is essential to understand the material behavior and to improve its performance.

Stitching the synapse: Cross-linking mass spectrometry into resolving synaptic protein interactions.

Synaptic transmission is the predominant form of communication in the brain. It requires functionally specialized molecular machineries constituted by thousands of interacting synaptic proteins. Here, we made use of recent advances in cross-linking mass spectrometry (XL-MS) in combination with biochemical and computational approaches to reveal the architecture and assembly of synaptic protein complexes from mouse brain hippocampus and cerebellum. We obtained 11,999 unique lysine-lysine cross-links, comprising connections within and between 2362 proteins. This extensive collection was the basis to identify novel protein partners, to model protein conformational dynamics, and to delineate within and between protein interactions of main synaptic constituents, such as Camk2, the AMPA-type glutamate receptor, and associated proteins. Using XL-MS, we generated a protein interaction resource that we made easily accessible via a web-based platform (http://xlink.cncr.nl) to provide new entries into exploration of all protein interactions identified.