In vivo quasi-elastic light scattering detects molecular changes in the lenses of adolescents with Down syndrome.

Down syndrome (DS) is the most common chromosomal disorder in humans. DS is associated with increased prevalence of several ocular sequelae, including characteristic blue-dot cerulean cataract. DS is accompanied by age-dependent accumulation of Alzheimer's disease (AD) amyloid-ß (Aß) peptides and amyloid pathology in the brain and comorbid early-onset Aß amyloidopathy and colocalizing cataracts in the lens. Quasi-elastic light scattering (QLS) is an established optical technique that noninvasively measures changes in protein size distributions in the human lens in vivo. In this cross-sectional study, lenticular QLS correlation time was decreased in adolescent subjects with DS compared to age-matched control subjects. Clinical QLS was consistent with alterations in relative particle hydrodynamic radius in lenses of adolescents with DS. These correlative results suggest that noninvasive QLS can be used to evaluate molecular changes in the lenses of individuals with DS.

Individual-specific change points in circadian rest-activity rhythm and sleep in individuals tapering their antidepressant medication: an actigraphy study.

Group-level studies showed associations between depressive symptoms and circadian rhythm elements, though whether these associations replicate at the within-person level remains unclear. We investigated whether changes in circadian rhythm elements (namely, rest-activity rhythm, physical activity, and sleep) occur close to depressive symptom transitions and whether there are differences in the amount and direction of circadian rhythm changes in individuals with and without transitions. We used 4 months of actigraphy data from 34 remitted individuals tapering antidepressants (20 with and 14 without depressive symptom transitions) to assess circadian rhythm variables. Within-person kernel change point analyses were used to detect change points (CPs) and their timing in circadian rhythm variables. In 69% of individuals experiencing transitions, CPs were detected near the time of the transition. No-transition participants had an average of 0.64 CPs per individual, which could not be attributed to other known events, compared to those with transitions, who averaged 1 CP per individual. The direction of change varied between individuals, although some variables showed clear patterns in one direction. Results supported the hypothesis that CPs in circadian rhythm occurred more frequently close to transitions in depression. However, a larger sample is needed to understand which circadian rhythm variables change for whom, and more single-subject research to untangle the meaning of the large individual differences.

Gadolinium Deposition in the Rat Brain Measured with Quantitative MRI versus Elemental Mass Spectrometry.

Background T1-weighted MRI and quantitative longitudinal relaxation rate (R1) mapping have been used to evaluate gadolinium retention in the brain after gadolinium-based contrast agent (GBCA) administration. Whether MRI measures accurately reflect gadolinium regional distribution and concentration in the brain remains unclear. Purpose To compare gadolinium retention in rat forebrain measured with in vivo quantitative MRI R1 and ex vivo laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) mapping after gadobenate, gadopentetate, gadodiamide, or gadobutrol administration. Materials and Methods Adult female Sprague-Dawley rats were randomly assigned to one of five groups (eight per group) and administered gadobenate, gadopentetate, gadodiamide, gadobutrol (2.4 mmol/kg per week for 5 weeks), or saline (4.8 mL/kg per week for 5 weeks). MRI R1 mapping was performed at baseline and 1 week after the final injection to determine R1 and ΔR1. Postmortem brains from the same rats were analyzed with LA-ICP-MS elemental mapping to determine regional gadolinium concentrations. Student t tests were performed to compare results between GBCA and saline groups. Results Rats that were administered gadobenate showed gadolinium-related MRI ΔR1 in 39.5% of brain volume (ΔR1 = 0.087 second-1 ± 0.051); gadopentetate, 20.6% (ΔR1 = 0.069 second-1 ± 0.018); gadodiamide, 5.4% (ΔR1 = 0.055 second-1 ± 0.019); and gadobutrol, 2.2% (ΔR1 = 0.052 second-1 ± 0.041). Agent-specific gadolinium-related ΔR1 was detected in multiple forebrain regions (neocortex, hippocampus, dentate gyrus, thalamus, and caudate-putamen) in rats treated with gadobenate or gadopentetate, whereas rats treated with gadodiamide showed gadolinium-related ΔR1 in caudate-putamen. By contrast, LA-ICP-MS elemental mapping showed a similar regional distribution pattern of heterogeneous retained gadolinium in the forebrain of rats treated with gadobenate, gadopentetate, or gadodiamide, with the average gadolinium concentration of 0.45 µg · g-1 ± 0.07, 0.50 µg · g-1 ± 0.10, and 0.60 µg · g-1 ± 0.11, respectively. Low levels (0.01 µg · g-1 ± 0.00) of retained gadolinium were detected in the forebrain of gadobutrol-treated rats. Conclusion Differences in in vivo MRI longitudinal relaxation rate versus ex vivo elemental mass spectrometry measures of retained gadolinium in rat forebrains suggest that some forms of retained gadolinium may escape detection with MRI. © RSNA, 2022 Online supplemental material is available for this article.

Electronic cigarette vaping with aged coils causes acute lung injury in mice.

Electronic cigarettes (e-cigarettes) have been used widely as an alternative to conventional cigarettes and have become particularly popular among young adults. A growing body of evidence has shown that e-cigarettes are associated with acute lung injury and adverse effects in multiple other organs. Previous studies showed that high emissions of aldehydes (formaldehyde and acetaldehyde) in aerosols were associated with increased usage of the same e-cigarette coils. However, the impact on lung function of using aged coils has not been reported. We investigated the relationship between coil age and acute lung injury in mice exposed to experimental vaping for 1 h (2 puffs/min, 100 ml/puff). The e-liquid contains propylene glycol and vegetable glycerin (50:50, vol) only. The concentrations of formaldehyde and acetaldehyde in the vaping aerosols increased with age of the nichrome coils starting at 1200 puffs. Mice exposed to e-cigarette aerosols produced from 1800, but not 0 or 900, puff-aged coils caused acute lung injury, increased lung wet/dry weight ratio, and induced lung inflammation (IL-6, TNF-α, IL-1ß, MIP-2). Exposure to vaping aerosols from 1800 puff-aged coils decreased heart rate, respiratory rate, and oxygen saturation in mice compared to mice exposed to air or aerosols from new coils. In conclusion, we observed that the concentration of aldehydes (formaldehyde and acetaldehyde) increased with repeated and prolonged usage of e-cigarette coils. Exposure to high levels of aldehyde in vaping aerosol was associated with acute lung injury in mice. These findings show significant risk of lung injury associated with prolonged use of e-cigarette devices.

Designing daily-life research combining experience sampling method with parallel data.

BACKGROUND: Ambulatory monitoring is gaining popularity in mental and somatic health care to capture an individual's wellbeing or treatment course in daily-life. Experience sampling method collects subjective time-series data of patients' experiences, behavior, and context. At the same time, digital devices allow for less intrusive collection of more objective time-series data with higher sampling frequencies and for prolonged sampling periods. We refer to these data as parallel data. Combining these two data types holds the promise to revolutionize health care. However, existing ambulatory monitoring guidelines are too specific to each data type, and lack overall directions on how to effectively combine them. METHODS: Literature and expert opinions were integrated to formulate relevant guiding principles. RESULTS: Experience sampling and parallel data must be approached as one holistic time series right from the start, at the study design stage. The fluctuation pattern and volatility of the different variables of interest must be well understood to ensure that these data are compatible. Data have to be collected and operationalized in a manner that the minimal common denominator is able to answer the research question with regard to temporal and disease severity resolution. Furthermore, recommendations are provided for device selection, data management, and analysis. Open science practices are also highlighted throughout. Finally, we provide a practical checklist with the delineated considerations and an open-source example demonstrating how to apply it. CONCLUSIONS: The provided considerations aim to structure and support researchers as they undertake the new challenges presented by this exciting multidisciplinary research field.

Alzheimer's disease amyloid-ß pathology in the lens of the eye.

Neuropathological hallmarks of Alzheimer's disease (AD) include pathogenic accumulation of amyloid-ß (Aß) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated Aß neuropathology begins decades before onset of cognitive symptoms and slowly progresses over the course of the disease. We previously reported discovery of Aß deposition, ß-amyloidopathy, and co-localizing supranuclear cataracts (SNC) in lenses from people with AD, but not other neurodegenerative disorders or normal aging. We confirmed AD-associated Aß molecular pathology in the lens by immunohistopathology, amyloid histochemistry, immunoblot analysis, epitope mapping, immunogold electron microscopy, quantitative immunoassays, and tryptic digest mass spectrometry peptide sequencing. Ultrastructural analysis revealed that AD-associated Aß deposits in AD lenses localize as electron-dense microaggregates in the cytoplasm of supranuclear (deep cortex) fiber cells. These Aß microaggregates also contain αB-crystallin and scatter light, thus linking Aß pathology and SNC phenotype expression in the lenses of people with AD. Subsequent research identified Aß lens pathology as the molecular origin of the distinctive cataracts associated with Down syndrome (DS, trisomy 21), a chromosomal disorder invariantly associated with early-onset Aß accumulation and Aß amyloidopathy in the brain. Investigation of 1249 participants in the Framingham Eye Study found that AD-associated quantitative traits in brain and lens are co-heritable. Moreover, AD-associated lens traits preceded MRI brain traits and cognitive deficits by a decade or more and predicted future AD. A genome-wide association study of bivariate outcomes in the same subjects identified a new AD risk factor locus in the CTNND2 gene encoding δ-catenin, a protein that modulates Aß production in brain and lens. Here we report identification of AD-related human Aß (hAß) lens pathology and age-dependent SNC phenotype expression in the Tg2576 transgenic mouse model of AD. Tg2576 mice express Swedish mutant human amyloid precursor protein (APP-Swe), accumulate hAß peptides and amyloid pathology in the brain, and exhibit cognitive deficits that slowly progress with increasing age. We found that Tg2576 trangenic (Tg+) mice, but not non-transgenic (Tg-) control mice, also express human APP, accumulate hAß peptides, and develop hAß molecular and ultrastructural pathologies in the lens. Tg2576 Tg+ mice exhibit age-dependent Aß supranuclear lens opacification that recapitulates lens pathology and SNC phenotype expression in human AD. In addition, we detected hAß in conditioned medium from lens explant cultures prepared from Tg+ mice, but not Tg- control mice, a finding consistent with constitutive hAß generation in the lens. In vitro studies showed that hAß promoted mouse lens protein aggregation detected by quasi-elastic light scattering (QLS) spectroscopy. These results support mechanistic (genotype-phenotype) linkage between Aß pathology and AD-related phenotypes in lens and brain. Collectively, our findings identify Aß pathology as the shared molecular etiology of two age-dependent AD-related cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD-related Aß pathology outside the brain and point to lens Aß as an optically-accessible AD biomarker for early detection and longitudinal monitoring of this devastating neurodegenerative disease.

Overnight affective dynamics and sleep characteristics as predictors of depression and its development in women.

STUDY OBJECTIVES: We examined (1) differences in overnight affective inertia (carry-over of evening affect to the next morning) for positive (PA) and negative affect (NA) between individuals with past, current, and no depression; (2) how sleep duration and quality influence overnight affective inertia in these groups, and (3) whether overnight affective inertia predicts depression development. METHODS: We used data of 579 women from the East-Flanders Prospective Twin Survey. For aim 1 and 2, individuals with past (n = 82), current (n = 26), and without (lifetime) depression (n = 471) at baseline were examined. For aim 3, we examined individuals who did (n = 58) and did not (n = 319) develop a depressive episode at 12-month follow-up. Momentary PA and NA were assessed 10 times a day for 5 days. Sleep was assessed daily with sleep diaries. Affective inertia was operationalized as the influence of evening affect on morning affect. Linear mixed-effect models were used to test the hypotheses. RESULTS: Overnight affective inertia for NA was significantly larger in the current compared to the non-depressed group, and daytime NA inertia was larger in the past compared to the non-depressed group. Overnight NA inertia was differently associated with shorter sleep duration in both depression groups and with lower sleep quality in the current compared to the non-depressed group. Overnight affective inertia did not predict depression development at 12-month follow-up. CONCLUSIONS: Current findings demonstrate the importance of studying complex affect dynamics such as overnight affective inertia in relation to depression and sleep characteristics. Replication of these findings, preferably with longer time-series, is needed.

Screening for Depression in Daily Life: Development and External Validation of a Prediction Model Based on Actigraphy and Experience Sampling Method.

BACKGROUND: In many countries, depressed individuals often first visit primary care settings for consultation, but a considerable number of clinically depressed patients remain unidentified. Introducing additional screening tools may facilitate the diagnostic process. OBJECTIVE: This study aimed to examine whether experience sampling method (ESM)-based measures of depressive affect and behaviors can discriminate depressed from nondepressed individuals. In addition, the added value of actigraphy-based measures was examined. METHODS: We used data from 2 samples to develop and validate prediction models. The development data set included 14 days of ESM and continuous actigraphy of currently depressed (n=43) and nondepressed individuals (n=82). The validation data set included 30 days of ESM and continuous actigraphy of currently depressed (n=27) and nondepressed individuals (n=27). Backward stepwise logistic regression analysis was applied to build the prediction models. Performance of the models was assessed with goodness-of-fit indices, calibration curves, and discriminative ability (area under the receiver operating characteristic curve [AUC]). RESULTS: In the development data set, the discriminative ability was good for the actigraphy model (AUC=0.790) and excellent for both the ESM (AUC=0.991) and the combined-domains model (AUC=0.993). In the validation data set, the discriminative ability was reasonable for the actigraphy model (AUC=0.648) and excellent for both the ESM (AUC=0.891) and the combined-domains model (AUC=0.892). CONCLUSIONS: ESM is a good diagnostic predictor and is easy to calculate, and it therefore holds promise for implementation in clinical practice. Actigraphy shows no added value to ESM as a diagnostic predictor but might still be useful when ESM use is restricted.

Level and timing of physical activity during normal daily life in depressed and non-depressed individuals.

Engaging in physical activity is known to reduce depressive symptoms. However, little is known which behavioral factors are relevant, and how patterns of activity change during depressive episodes. We expected that compared to controls, in depressed individuals the level of activity would be lower, the amplitude of 24-h-actigraphy profiles more dampened and daytime activities would start later. We used 14-day continuous-actigraphy data from participants in the Netherlands Study of Depression and Anxiety (NESDA) who participated in an ambulatory assessment study. Participants with a depression diagnosis in the past 6 months (n = 58) or its subsample with acute depression (DSM diagnosis in the past 1 month, n = 43) were compared to controls without diagnoses (n = 63). Depression was diagnosed with a diagnostic interview. Actigraphy-derived variables were activity mean levels (MESOR), the difference between peak and mean level (amplitude) and the timing of the activity peak (acrophase), which were estimated with cosinor analysis. Compared to the control group, both depression groups (total: B = -0.003, p = 0.033; acute: B = -0.004, p = 0.005) had lower levels of physical activity. Amplitude was also dampened, but in the acute depression group only (total: B = -0.002, p = 0.065; acute: B = -0.003, p = 0.011). Similarly, the timing of activity was marginally significant towards a later timing of activity in the acute, but not total depression group (total: B = 0.206, p = 0.398; acute: B = 0.405, p = 0.084). In conclusion, our findings may be relevant for understanding how different aspects of activity (level and timing) contribute to depression. Further prospective research is needed to disentangle the direction of the association between depression and daily rest-activity rhythms.

In Vivo Quasi-Elastic Light Scattering Eye Scanner Detects Molecular Aging in Humans.

The absence of clinical tools to evaluate individual variation in the pace of aging represents a major impediment to understanding aging and maximizing health throughout life. The human lens is an ideal tissue for quantitative assessment of molecular aging in vivo. Long-lived proteins in lens fiber cells are expressed during fetal life, do not undergo turnover, accumulate molecular alterations throughout life, and are optically accessible in vivo. We used quasi-elastic light scattering (QLS) to measure age-dependent signals in lenses of healthy human subjects. Age-dependent QLS signal changes detected in vivo recapitulated time-dependent changes in hydrodynamic radius, protein polydispersity, and supramolecular order of human lens proteins during long-term incubation (~1 year) and in response to sustained oxidation (~2.5 months) in vitro. Our findings demonstrate that QLS analysis of human lens proteins provides a practical technique for noninvasive assessment of molecular aging in vivo.

Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players.

Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood-brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood-brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.

Nonhomogeneous Gadolinium Retention in the Cerebral Cortex after Intravenous Administration of Gadolinium-based Contrast Agent in Rats and Humans.

Background Gadolinium retention after repeated gadolinium-based contrast agent (GBCA) exposure has been reported in subcortical gray matter. However, gadolinium retention in the cerebral cortex has not been systematically investigated. Purpose To determine whether and where gadolinium is retained in rat and human cerebral cortex. Materials and Methods The cerebral cortex in Sprague-Dawley rats treated with gadopentetate dimeglumine (three doses over 4 weeks; cumulative gadolinium dose, 7.2 mmol per kilogram of body weight; n = 6) or saline (n = 6) was examined with antemortem MRI. Two human donors with repeated GBCA exposure (three and 15 doses; 1 and 5 months after exposure), including gadopentetate dimeglumine, and two GBCA-naive donors were also evaluated. Elemental brain maps (gadolinium, phosphorus, zinc, copper, iron) for rat and human brains were constructed by using laser ablation inductively coupled plasma mass spectrometry. Results Gadopentetate dimeglumine-treated rats showed region-, subregion-, and layer-specific gadolinium retention in the neocortex (anterior cingulate cortex: mean gadolinium concentration, 0.28 µg ∙ g-1 ± 0.04 [standard error of the mean]) that was comparable (P > .05) to retention in the allocortex (mean gadolinium concentration, 0.33 µg ∙ g-1 ± 0.04 in piriform cortex, 0.24 µg ∙ g-1 ± 0.04 in dentate gyrus, 0.17 µg ∙ g-1 ± 0.04 in hippocampus) and subcortical structures (0.47 µg ∙ g-1 ± 0.10 in facial nucleus, 0.39 µg ∙ g-1 ± 0.10 in choroid plexus, 0.29 µg ∙ g-1 ± 0.05 in caudate-putamen, 0.26 µg ∙ g-1 ± 0.05 in reticular nucleus of the thalamus, 0.24 µg ∙ g-1 ± 0.04 in vestibular nucleus) and significantly greater than that in the cerebellum (0.17 µg ∙ g-1 ± 0.03, P = .01) and white matter tracts (anterior commissure: 0.05 µg ∙ g-1 ± 0.01, P = .002; corpus callosum: 0.05 µg ∙ g-1 ± 0.02, P = .001; cranial nerve: 0.02 µg ∙ g-1 ± 0.01, P = .004). Retained gadolinium colocalized with parenchymal iron. T1-weighted MRI signal intensification was not observed. Gadolinium retention was detected in the cerebral cortex, pia mater, and pia-ensheathed leptomeningeal vessels in two GBCA-exposed human brains but not in two GBCA-naive human brains. Conclusion Repeated gadopentetate dimeglumine exposure is associated with gadolinium retention in specific regions, subregions, and layers of cerebral cortex that are critical for higher cognition, affect, and behavior regulation, sensorimotor coordination, and executive function. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kanal in this issue.

Spectroscopic Properties of some Hydroxylated 2-Stilbazole Derivatives.

The spectroscopic properties for a number of new hydroxylated 2-stilbazoles were studied by absorption and fluorescence spectroscopy. The maximum absorption and emission wavelengths, the molar extinction coefficients, and the Stokes shift values of derivatives were given. The dependence of the spectral characteristics on pH was shown. The possibility of creating molecular logic systems and fluorescent dyes for bioimaging based on these derivatives was demonstrated. The dependence of fluorescence on the medium redox properties was established for an one of derivatives. The possibility of a fluorescent probe creating on its basis to assess the oxidative state of living systems was demonstrated. The probe has good biocompatibility and can be successfully used for fluorescence imaging in cells.

Submicron-Sized Nanocomposite Magnetic-Sensitive Carriers: Controllable Organ Distribution and Biological Effects.

Although new drug delivery systems have been intensely developed in the past decade, no significant increase in the efficiency of drug delivery by nanostructure carriers has been achieved. The reasons are the lack of information about acute toxicity, the influence of the submicron size of the carrier and difficulties with the study of biodistribution in vivo. Here we propose, for the first time in vivo, new nanocomposite submicron carriers made of bovine serum albumin (BSA) and tannic acid (TA) and containing magnetite nanoparticles with sufficient content for navigation in a magnetic field gradient on mice. We examined the efficacy of these submicron carriers as a delivery vehicle in combination with magnetite nanoparticles which were systemically administered intravenously. In addition, the systemic toxicity of this carrier for intravenous administration was explicitly studied. The results showed that (BSA/TA) carriers in the given doses were hemocompatible and didn't cause any adverse effect on the respiratory system, kidney or liver functions. A combination of gradient-magnetic-field controllable biodistribution of submicron carriers with fluorescence tomography/MRI imaging in vivo provides a new opportunity to improve drug delivery efficiency.

Pathophysiology of Concussion.

Although concussion has been a subject of interest for centuries, this condition remains poorly understood. The mechanistic underpinnings and accepted definition of concussion remain elusive. To make sense of these issues, this article presents a brief history of concussion studies, detailing the evolution of motivations and experimental conclusions over time. Interest in concussion as a subject of scientific inquiry has increased with growing concern about the long-term consequences of mild traumatic brain injury (TBI). Although concussion is often associated with mild TBI, these conditions-the former a neurological syndrome, the latter a neurological event-are distinct, both mechanistically and pathobiologically. Modern research primarily focuses on the study of the biomechanics, pathophysiology, potential biomarkers and neuroimaging to distinguish concussion from mild TBI. In addition, mild TBI and concussion outcomes are influenced by age, sex, and genetic differences in people. With converging experimental objectives and methodologies, future concussion research has the potential to improve clinical assessment, treatment, and preventative measures.

Amylase-Sensitive Polymeric Nanoparticles Based on Dextran Sulfate and Doxorubicin with Anticoagulant Activity.

This study looked into the synthesis and study of Dextrane Sulfate-Doxorubicin Nanoparticles (DS-Dox NP) that are sensitive to amylase and show anticoagulant properties. The particles were obtained by the method of solvent replacement. They had a size of 305 ± 58 nm, with a mass ratio of DS:Dox = 3.3:1. On heating to 37 °C, the release of Dox from the particles was equal to 24.2% of the drug contained. In the presence of amylase, this ratio had increased to 42.1%. The study of the biological activity of the particles included an assessment of the cytotoxicity and the effect on hemostasis and antitumor activity. In a study of cytotoxicity on the L929 cell culture, it was found that the synthesized particles had less toxicity, compared to free doxorubicin. However, in the presence of amylase, their cytotoxicity was higher than the traditional forms of the drug. In a study of the effect of DS-Dox NP on hemostasis, it was found that the particles had a heparin-like anticoagulant effect. Antitumor activity was studied on the model of ascitic Zaidel hepatoma in rats. The frequency of complete cure in animals treated with the DS-Dox nanoparticles was higher, compared to animals receiving the traditional form of the drug.

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.

Considerations for Experimental Animal Models of Concussion, Traumatic Brain Injury, and Chronic Traumatic Encephalopathy-These Matters Matter.

Animal models of concussion, traumatic brain injury (TBI), and chronic traumatic encephalopathy (CTE) are widely available and routinely deployed in laboratories around the world. Effective animal modeling requires careful consideration of four basic principles. First, animal model use must be guided by clarity of definitions regarding the human disease or condition being modeled. Concussion, TBI, and CTE represent distinct clinical entities that require clear differentiation: concussion is a neurological syndrome, TBI is a neurological event, and CTE is a neurological disease. While these conditions are all associated with head injury, the pathophysiology, clinical course, and medical management of each are distinct. Investigators who use animal models of these conditions must take into account these clinical distinctions to avoid misinterpretation of results and category mistakes. Second, model selection must be grounded by clarity of purpose with respect to experimental questions and frame of reference of the investigation. Distinguishing injury context ("inputs") from injury consequences ("outputs") may be helpful during animal model selection, experimental design and execution, and interpretation of results. Vigilance is required to rout out, or rigorously control for, model artifacts with potential to interfere with primary endpoints. The widespread use of anesthetics in many animal models illustrates the many ways that model artifacts can confound preclinical results. Third, concordance between key features of the animal model and the human disease or condition being modeled is required to confirm model biofidelity. Fourth, experimental results observed in animals must be confirmed in human subjects for model validation. Adherence to these principles serves as a bulwark against flawed interpretation of results, study replication failure, and confusion in the field. Implementing these principles will advance basic science discovery and accelerate clinical translation to benefit people affected by concussion, TBI, and CTE.

Spectrally engineered broadband photon source for two-photon quantum interferometry.

We present a new approach to engineering broadband sources of entangled photon pairs for quantum interferometry. The source is based on quasi-phase-matched spontaneous parametric down conversion in a titanium diffused periodically poled lithium niobate waveguide with a strongly-chirped poling period. The proposed non-standard asymmetric poling mitigates phase distortions associated with the process of chirping. Asymmetric poling significantly broadens the entangled source bandwidth while preserving high visibility quantum interferometric sensing.

Method for the calibration of the spectral irradiance of tungsten filament transfer standard sources traceable to synchrotron radiation.

The spectral irradiance calibration of tungsten strip and spiral filament lamps applying synchrotron radiation revealed that the spectral irradiance in the wavelength range from 280 to 400 nm can be well approximated by blackbody radiation according to Planck's law. Consequently, the spectral irradiance of the filament lamp can then be described by an effective irradiance temperature, which would be beneficial for practical measurements. Including the emissivity of tungsten into the approximation, the model can be expanded to visible and near-infrared wavelength regions. The effective irradiance temperature dependence of the lamp current was investigated and appeared to be close to linear.