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Objective Previous work on temporally sparse multifocal methods suggests that the results are correlated with disability and progression in people with multiple sclerosis (PwMS). Here, we assess the diagnostic power of three cortically mediated sparse multifocal pupillographic objective perimetry (mfPOP) methods that quantified response-delay and light-sensitivity at up to 44 regions of both visual fields concurrently. Methods One high-spatial-resolution mfPOP method, P129, and two rapid medium-resolution methods, W12 and W20, were tested on 44 PwMS and controls. W12 and W20 took 82 s to test both visual fields concurrently, providing response delay and sensitivity at each field location, while P129 took 7 min. Diagnostic power was assessed using areas under the receiver operating characteristic (AUROC) curves and effect-size (Hedges’ g). Linear models examined significance. Concurrent testing of both eyes permitted assessment of between-eye asymmetries. Results Per-region response delays and asymmetries achieved AUROCs of 86.6% ± 4.72% (mean ± SE) in relapsing–remitting MS, and 96.5% ± 2.30% in progressive MS. Performance increased with increasing disability scores, with even moderate EDSS 2 to 4.5 PwMS producing AUROCs of 82.1 to 89.8%, Hedge’s g values up to 2.06, and p = 4.0e − 13. All tests performed well regardless of any history of optic neuritis. W12 and W20 performed as well or better than P129. Conclusion Overall, the 82-s tests (W12 and W20) performed better than P129. The results suggest that mfPOP assesses a correlate of disease severity rather than a history of inflammation, and that it may be useful in the clinical management of PwMS.

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Degradation of signaling proteins is one of the most powerful tumor-suppressive mechanisms by which a cell can control its own growth. Here, we identify RHOA as the molecular target by which autophagy maintains genomic stability. Specifically, inhibition of autophagosome degradation by the loss of the v-ATPase a3 (TCIRG1) subunit is sufficient to induce aneuploidy. Underlying this phenotype, active RHOA is sequestered via p62 (SQSTM1) within autolysosomes and fails to localize to the plasma membrane or to the spindle midbody. Conversely, inhibition of autophagosome formation by ATG5 shRNA dramatically increases localization of active RHOA at the midbody, followed by diffusion to the flanking zones. As a result, all of the approaches we examined that compromise autophagy (irrespective of the defect: autophagosome formation, sequestration, or degradation) drive cytokinesis failure, multinucleation, and aneuploidy, processes that directly have an impact upon cancer progression. Consistently, we report a positive correlation between autophagy defects and the higher expression of RHOA in human lung carcinoma. We therefore propose that autophagy may act, in part, as a safeguard mechanism that degrades and thereby maintains the appropriate level of active RHOA at the midbody for faithful completion of cytokinesis and genome inheritance. Cancer Res; 73(14); 4311–22. ©2013 AACR.

AVI file - 5901K, Video 5 (related to Fig. 2G) is a time-lapse recording of a mononucleate a3-/- cell that formed a tetranucleate cell after two rounds of abortive mitosis.

AVI file - 2112K, Video 4 (related to Fig. 2F) illustrates the failed abscission of a mononucleated a3-/- cell that exited mitosis as a binucleated cell after 18 attempts at cleavage furrow formation. Note that this cell developed ectopic furrows, which led to the formation of anuclear fragments that fused back to the cell.

AVI file - 645K, Video 6 (related to Fig. 6A) is a time-lapse recording showing that the ATG5-depleted A549 cells formed numerous ectopic furrows in addition to a wider-than-normal equatorial cleavage furrow.

AVI file - 2696K, Video 3 (related to Fig. 2E) is a time-lapse recording of four pairs of a3-/- cells that entered mitosis synchronously, likely bridged sister cells. Pairs of cells that entered mitosis synchronously are outlined in color in the first frame, and then marked with dots in the next frame to help visualize their progression in mitosis.

AVI file - 875K, Video 2 (related to Fig. 2D) shows the delayed abscission of an a3-/- cell that remained connected by an intracellular bridge for up to 8 h 45 min before separating.

Resume L’autophagie est un processus cellulaire ubiquitaire, permettant l’elimination et le recyclage des proteines et organelles endommagees. Au niveau basal, ce processus joue un role dans le controle qualite, participant ainsi a l’homeostasie cellulaire. L’autophagie peut egalement etre induite par differents stress, tels que la privation de nutriments ou l’hypoxie, afin de permettre a la cellule de survivre le temps que les conditions s’ameliorent. Ces dernieres annees, le role de ce processus a ete largement etudie dans de nombreuses pathologies telles que les maladies neurodegeneratives ou les cancers. Dans le tissu osseux, differents travaux ont montre que l’autophagie est impliquee dans la survie, la differenciation et l’activite des osteoblastes, des osteocytes et des osteoclastes. L’evolution de ces connaissances a permis de mettre en evidence de nouveaux mecanismes moleculaires physiopathologiques dans les pathologies osseuses. Cette revue rapporte l’etat actuel des connaissances sur le role de l’autophagie dans 4 pathologies osseuses : l’osteoporose, qui semble etre associee a une diminution de l’autophagie, l’osteopetrose et la maladie de Paget ou le deroulement du processus autophagique est perturbe, et enfin l’osteosarcome ou l’autophagie semble jouer un role protumoral. Une meilleure comprehension de l’implication de l’autophagie dans ces pathologies devrait a terme permettre d’identifier de nouvelles cibles therapeutiques potentielles.

We re-examined the per-region response amplitudes and delays obtained from multifocal pupillographic objective perimetry (mfPOP) after 10 years in 44 persons living with multiple sclerosis (PwMS), both to examine which parts of the visual field had progressed in terms of response properties and to examine if the baseline data could predict the overall progression of disease.Expanded Disability Status Scale (EDSS) scores were assessed in 2009 and 2019. Both eyes of each participant were concurrently tested at 44 locations/eye on both occasions. Several measures of clinical progression were examined, using logistic regression to determine the odds of progression.At the second examination the 44 PwMS (31 females) were aged 61.0 ± 12.2 y. Mean EDSS had not changed significantly (3.69 ± 1.23 in 2009, 3.81 ± 2.00 in 2019). mfPOP delay increased progressively from inferior to superior regions of the visual fields while amplitudes demonstrated a temporal to nasal gradient. The mean of the 3 most delayed visual field regions was correlated with progression of MS by 2019 (mfPOP may provide a rapid, convenient method of monitoring and predicting MS progression.

Background To examine the potential utility of five multifocal pupillographic objective perimetry (mfPOP) protocols, in the assessment of early diabetic retinopathy (DR) and generalised diabetes-related tissue injury in subjects with type 1 diabetes (T1D). Methods Twenty-five T1D subjects (age 41.8 ± 12.1 (SD) years, 13 male) with either no DR (n = 13) or non-proliferative DR (n = 12), and 23 age and gender-matched control subjects (age 39.7 ± 12.9 years, 9 male) were examined by mfPOP using five different stimulus methods differing in visual field eccentricity (central 30° and 60°), and colour (blue, yellow or green test-stimuli presented on, respectively, a blue, yellow or red background), each assessing 44 test-locations per eye. In the T1D subjects, we assessed 16 metabolic status and diabetes complications variables. These were summarised as three principal component analysis (PCA) factors. DR severity was assessed using Early Treatment of Diabetic Retinopathy Study (ETDRS) scores. Area under the curve (AUC) from receiver operator characteristic analyses quantified the diagnostic power of mfPOP response sensitivity and delay deviations for differentiating: (i) T1D subjects from control subjects, (ii) T1D subjects according to three levels of the identified PCA-factors from control subjects, and (iii) TID subjects with from those without non-proliferative DR. Results The two largest PCA-factors describing the T1D subjects were associated with metabolic variables (e.g. body mass index, HbA1c), and tissue-injury variables (e.g. serum creatinine, vibration perception). Linear models showed that mfPOP per-region response delays were more strongly associated than sensitivities with the metabolic PCA-factor and ETDRS scores. Combined mfPOP amplitude and delay measures produced AUCs of 90.4 ± 8.9% (mean ± SE) for discriminating T1D subjects with DR from control subjects, and T1D subjects with DR from those without of 85.9 ± 8.8%. The yellow and green stimuli performed better than blue on most measures. Conclusions/interpretation In T1D subjects, mfPOP testing was able to identify localised visual field functional abnormalities (retinal/neural reflex) in the absence or presence of mild DR. mfPOP responses were also associated with T1D metabolic status, but less so with early stages of non-ophthalmic diabetes complications.

International audience; In case of an incident in the nuclear industry or an act of war or terrorism, the dissemination of plutonium could contaminate the environment and, hence, humans. Human contamination mainly occurs via inhalation and/or wounding (and, less likely, ingestion). In such cases, plutonium, if soluble, reaches circulation, whereas the poorly soluble fraction (such as small colloids) is trapped in alveolar macrophages or remains at the site of wounding. Once in the blood, the plutonium is delivered to the liver and/or to the bone, particularly into its mineral part, mostly composed of hydroxyapatite. Countermeasures against plutonium exist and consist of intravenous injections or inhalation of diethylenetetraminepentaacetate salts. Their effectiveness is, however, mainly confined to the circulating soluble forms of plutonium. Furthermore, the short bioavailability of diethylenetetraminepentaacetate results in its rapid elimination. To overcome these limitations and to provide a complementary approach to this common therapy, we developed polymeric analogs to indirectly target the problematic retention sites. We present herein a first study regarding the decontamination abilities of polyethyleneimine methylcarboxylate (structural diethylenetetraminepentaacetate polymer analog) and polyethyleneimine methylphosphonate (phosphonate polymeric analog) directed against Th(IV), used here as a Pu(IV) surrogate, which was incorporated into hydroxyapatite used as a bone model. Our results suggest that polyethylenimine methylphosphonate could be a good candidate for powerful bone decontamination action.

International audience; In this paper, the design of a miniature antenna dedicated to be implanted in a small animal and intended to work in the European UHF RFID (865–868 MHz) band is presented. One of the goals of this work is the miniaturization of the radiating element while preserving its efficiency to allow a reliable communication between an external interrogating reader and the implanted device. The radiating element is a small rectangular loop antenna associated with a dipole allowing impedance matching. The antenna has dimensions of 2.4mm × 25.4mm × 0.5mm and integrates an Impinj Monza 4 chip presenting an impedance of 5.5−j74Ohms at 868 MHz. The antenna is designed and optimized by using the ANSYS HFSS software. The obtained results show a simulated radiation efficiency of 0.7% and simulated total gain of −17.5 dBi. A prototype is realized, and RSSI measurements have demonstrated the possibility of reliable wireless communications between the implanted antenna and an external reader. In addition, Specific Absorption Rate (SAR) calculation indicates that this implanted antenna meets the required safety regulations

Multifocal pupillographic objective perimetry (mfPOP) is being developed as an alternative to subjective threshold perimetry for the management of visual and neurological disorders. Here, we evaluate, in normal subjects, differences in signal quality between the original mfPOP method of spatially sparse Continuous stimulus presentation and the new Clustered Volleys (CVs) method. We hypothesized that the CVs method would lead to increased signal-to-noise ratios (SNRs) over the original method due to the stabilization of gain within the pupillary system.Data were collected from six separate studies where otherwise-identical pairs of mfPOP tests using either the original Continuous stimulus presentation method or the new CVs method were undertaken; 440 6-minute tests from 96 normal subjects of varying ages were included. Per-region SNRs were compared between the two methods.Mean SNRs for the CVs mfPOP variants were between 35% and 57% larger than the original Continuous mfPOP variants (P0.001 in five of six studies). Similarly, the goodness-of-fit measure (r2) demonstrated large and significant fold increases of between 2.3× and 3.4× over the original method (all P0.001). Significant improvements in SNRs were present in all of the 88 test regions (44/eye), ranging between 8.4% and 93.7%; mean SNRs were significantly larger in 98% of test subjects.The CVs mfPOP stimulus presentation method produced substantial increases in signal quality over the original method. This is likely due to the stabilization of pupillary gain during stimulus presentation.These improvements increase diagnostic accuracy and have enabled shorter, 80-second mfPOP tests to be developed.

General Fusion is building the Fusion Demonstration Plant to demonstrate a magnetized target fusion scheme in which a deuterium plasma is heated from 200 eV to 10 keV by piston-driven compression of a liquid-lithium liner. The multilayer coaxial time-of-flight (MCTOF) neutron emission spectrometer is designed to measure the ion temperature near peak compression at which time the neutron yield will approach $10^{18}$ neutrons/s. The neutron energy distribution is expected to be Gaussian since the machine uses no neutral beam or radiofrequency heating. In this case, analysis shows that as few as 500 coincidence events should be sufficient to accurately measure the ion temperature. This enables a fast time resolution of 10 $\mu s$, which is required to track the rapid change in temperature approaching peak compression. We overcome the challenges of neutron pileup and event ambiguity with a compact design having two layers of segmented scintillators. The error in the ion temperature measurement is computed as a function of the neutron spectrometer's geometric parameters and used to optimize the design for the case of reaching 10 keV at peak compression., Comment: The following article has been accepted by Review of Scientific Instruments. After it is published, it will be found at https://aip.scitation.org/toc/rsi/HTPD2022/1. High Temperature Plasma Diagnostics 2022 conference. 5 pages, 9 figures

To investigate safety and visual-field changes in people with epilepsy undergoing multifocal Pupillographic Objective Perimetry (mfPOP).15 people with epilepsy and 15 controls underwent mfPOP in the context of routine clinical EEG testing. Safety measures comprised the proportion of participants developing an aura or seizure, a photoparoxysmal response, or increased epileptiform activity on their EEG during mfPOP. Pupil responses were obtained concurrently from 44 regions/field of each eye. Changes in standardised amplitude of constriction and time-to-peak were compared between people with generalised and focal epilepsy, and controls.No participant developed an epileptic aura or clinical seizure during (or after) testing. One participant demonstrated EEG evidence of a focal subclinical seizure which began before mfPOP testing and continued unchanged during testing. Regional field sensitivities were increased in people with generalised epilepsy (+3.80 ± 1.43 dB compared to controls) but were reduced in individuals taking antiepileptic medication (-4.04 ± 1.74 dB). An extra delay of 24.9 ± 10.2 ms was seen in the time-to-peak of the responses in people with focal epilepsy. Based on receiver-operating characteristic analyses, discrimination of people with epilepsy from controls was greatest when using the 4 to 10 most abnormal visual field regions of each eye (%AUC 77.3 ± 9.70).In the absence of any safety signal, mfPOP appears harmless in people with epilepsy. The observed abnormalities in per-region sensitives and delays suggest that mfPOP may provide significant new insights into the study of epilepsy.

Purpose The purpose of this study was to compare central versus peripheral retinal sensitivities and delays in neovascular age-related macular degeneration (nAMD) using US Food and Drug Administration (FDA)-cleared multifocal pupillographic objective perimetry (mfPOP). Methods We recruited 18 patients with nAMD and commenced Pro re nata intravitreal anti- vascular endothelial growth factor (VEGF) injection. We compared macular (±15 degrees) and wide-field (±30 degrees) mfPOP variants. We examined temporal correlations between treated and untreated fellow eyes. We fitted linear models to selected treatment patterns, and compared the ability of central versus peripheral responses to predict the need for treatment. Results Central sensitivity decreased by −2.23 ± 0.051 dB/month (P < 0.0002) in treated eyes, and −0.17 ± 0.07 dB/month (P = 0.033) in untreated eyes. Treated eyes showed quicker central responses by 13.08 ± 3.77 ms than untreated eyes (P = 0.001). Based on peripheral responses, we identified two eye-types. Among positive-eyes peripheral sensitivity increased by 9.88 ± 4.41 dB (P = 0.042) before treatment; delays increased by 3.49 ± 1.75 ms/month (P = 0.049). For negative-eyes peripheral delays were shorter a month before treatment by 9.38 ± 3.59 ms (P = 0.013). Correlations between treatment and peripheral sensitivities or delays peaked at 1 to 2 months post-treatment. Peripheral data significantly determined treatment frequency and final acuity (all P < 0.044). Conclusions Peripheral macular function of treated and untreated eyes divided eyes into positive and negative groups. Those peripheral responses determined outcomes; changes preceding active disease by 1 to 3 months. Overall, mfPOP may provide potential biomarkers to assist nAMD management. Translational Relevance Objective perimetry may identify the requirement for treatment in nAMD that accords with the decision of a skilled clinician based on optical coherence tomography (OCT) and clinical findings.

To study the power of an 80-second multifocal pupillographic objective perimetry (mfPOP) test tailored to the ETDRS grid to diagnose age-related macular degeneration (AMD) by Age-Related Eye Disease Study (AREDS) severity grade.Evaluation of a diagnostic technology.We compared diagnostic power of acuity, ETDRS grid retinal thickness data, new 80-second M18 mfPOP test, and two wider-field 6-minute mfPOP tests (Macular-P131, Widefield-P129). The M18 stimuli match the size and shape of bifurcated ETDRS grid regions, allowing easy structure-function comparisons. M18, P129, and P131 stimuli test both eyes concurrently. We recruited 34 patients with early-stage AMD with a mean ± standard deviation (SD) age of 72.6 ± 7.06 years. The M18 and P129 plus P131 stimuli had 26 and 51 control participants, respectively with mean ± SD ages of 73.1 ± 8.17 years and 72.1 ± 5.83 years, respectively. Multifocal pupillographic objective perimetry testing used the Food and Drug Administration-cleared Objective FIELD Analyzer (OFA; Konan Medical USA).Percentage area under the receiver operator characteristic curve (AUC) and Hedge's g effect size.Acuity and OCT ETDRS grid thickness and volume produced reasonable diagnostic power (percentage AUC) for AREDS grade 4 eyes at 83.9 ± 9.98% and 90.2 ± 6.32% (mean ± standard error), respectively, but not for eyes with less severe disease. By contrast, M18 stimuli produced percentage AUCs from 72.8 ± 6.65% (AREDS grade 2) to 92.9 ± 3.93% (AREDS grade 4), and 82.9 ± 3.71% for all eyes. Hedge's g effect sizes ranged from 0.84 to 2.32 (large to huge). Percentage AUC for P131 stimuli performed similarly and for P129 performed somewhat less well.The rapid and objective M18 test provided diagnostic power comparable with that of wider-field 6-minute mfPOP tests. Unlike acuity or OCT ETDRS grid data, OFA tests produced reasonable diagnostic power in AREDS grade 1 to 3 eyes.

In cases of criminal dismemberment, the analysis of saw marks helps to determine the class of the saw used. The present study compared the microscopic features of experimental false starts performed on three freshly defleshed human femurs. 150 lesions were produced using three reciprocating blades and two hand saws of similar class. Two groups of tools were created according to the class of the blades: group 1 (teeth per inch = 6, alternating set) and group 2 (teeth per inch = 24, wavy set). The minimum width of the kerf was always thicker with reciprocating blades than that of the handsaw of the same class. This fact is linked to the thickness of the blades and not necessarily to the fast forth and back motion of the blades. Shape kerf profiles and shape of the walls were very confusing, with a lot of variation of the false starts caused by the reciprocating blades and the risk of misclassification (rip teeth versus crosscut teeth, alternating set versus wavy set). Striae on the kerf floor and bone islands were more consistent. The main conclusions are, first, that usual features of false starts achieved by reciprocating saw blades used in this work vary a great deal and may lead to misclassification of the saw class, and second, that no criterion has been found to differentiate reciprocating blades and handsaws. These results demonstrate that we have to be very prudent while estimating the possible saw from a false start in a real forensic case.

To study the pupillary system by combining mydriasis and multifocal pupillographic objective perimetry (mfPOP). In particular, we explored how the dynamics of recovery differ for concurrently measured direct and consensual sensitivity, response delay, and signal-to-noise ratios (SNRs) for binocular mydriasis. We recruited 26 normal participants, all with brown irides. The dichoptic mfPOP stimuli concurrently assessed 44-region/eye and both pupils. Two pre-dilation tests were followed by pairs of repeated tests at 1, 2, 4, 6, 8, 12, 24, and 48 h following dilation of both pupils with 1% tropicamide. Three subjects were retested with only the right pupil dilated. Linear models determined the independent effects of mydriasis upon the per-region and pupil measures over time. Post-dilation, the per-region delays initially decreased by 16.3 ± 6.02 ms (mean ± SE) (p < 0.0001, cf. baseline of 471.1 ± 4.36 ms), then increased to slower than baseline by 17.42 ± 5.57 ms after 4 h (p < 0.002), recovering to baseline at 8 h. By comparison, per-region sensitivities (constriction amplitudes) were still reduced by − 6.20 ± 0.70 μm at 8 h (p < 0.0001, cf. baseline of 21.1 ± 0.55 μm), recovered at 24 h, but rebounded at 48 h (p = 0.005). The SNRs for sensitivities and delays both recovered by 8–12 h. Across all the data, sensitivities reduced by 2.67 ± 0.25 μm/decade of age, and delay increased by 15.4 ± 1.98 ms/decade (both p < 0.00001). Data from 3 of the 26 subjects who repeated the testing for monocular dilation found that consensual response sensitivities were larger than direct for 8 h (p < 0.018). The per-region sensitivities were affected for longer than SNRs or delays. Strong early SNRs indicated proportionately lower pupil noise for larger pupil diameters. Following mydriasis with tropicamide 1%, the constriction amplitude measurements with mfPOP should be considered only after 48 h, but time-to-peak can be measured after 8–12 h.

Background To establish the effects of stimulating intrinsically-photosensitive retinal ganglion cells (ipRGCs) on migraine severity, and to determine if migraine produces objectively-measured visual field defects. Methods A randomized, open labelled, crossover study tested migraineurs and normal controls using multifocal pupillographic objective perimetry (mfPOP) with 44 test-regions/eye. A slow blue protocol (BP) stimulated ipRGCs, and a fast yellow protocol (YP) stimulated luminance channels. Migraine diaries assessed migraine severity. Per-region responses were analyzed according to response amplitude and time-to-peak. Results Thirty-eight migraineurs (42.0 ± 16.5 years, 23 females) and 24 normal controls (39.2 ± 15.2 years, 14 females) were tested. The proportion of subjects developing a migraine did not differ after either protocol, either during the 1st day (odds ratio 1.0; 95% confidence interval 0.2–4.4, p = 0.48) or during the first 3 days after testing (odds ratio 0.8; 95% confidence interval 0.3–2.1, p = 0.68). Migraine days/week did not increase following testing with either protocol in comparison to the baseline week (1.4 ± 1.6 pre-testing (mean ± SD), 1.3 ± 1.4 post-BP, and 1.3 ± 1.2 post-YP; p = 0.96), neither did other measures of severity. Migraine occurring up to 2 weeks before testing significantly lowered amplitudes, − 0.64 ± 0.14 dB (mean ± SE), while triptan use increased amplitudes by 0.45 ± 0.10 dB, both at p Conclusions Stimulating ipRGCs did not affect migraine occurrence or severity. Pupillary response characteristics were influenced by the occurrence of a recent migraine attack and a history of triptan use.

The authors would like to thank Chantal Cros and Colette Ricort for helpful technical assistance. The authors acknowledge the MARS beamline of SOLEIL synchrotron (Gif sur Yvette, France) that was used to perform XAS experiments and the IRCAN's Molecular and Cellular Core Imaging (PICMI) Facility which is supported by grants from the Ministère de l’Enseignement Supérieur, the Région PACA, the Conseil Départemental des Alpes Maritimes, INSERM, the FEDER, the GIS IBiSA, the Canceropole PACA and the foundation ARC.Funding; International audience; Uranium is widely spread in the environment due to its natural and anthropogenic occurrences, hence the importance of understanding its impact on human health. The skeleton is the main site of long-term accumulation of this actinide. However, interactions of this metal with biological processes involving the mineralized extracellular matrix and bone cells are still poorly understood. To get a better insight into these interactions, we developed new biomimetic bone matrices containing low doses of natural uranium (up to 0.85 µg of uranium per cm2). These models were characterized by spectroscopic and microscopic approaches before being used as a support for the culture and differentiation of pre-osteoclastic cells. In doing so, we demonstrate that uranium can exert opposite effects on osteoclast resorption depending on its concentration in the bone microenvironment. Our results also provide evidence for the first time that resorption contributes to the remobilization of bone matrix-bound uranium. In agreement with this, we identified, by HRTEM, uranium phosphate internalized in vesicles of resorbing osteoclasts. Thanks to the biomimetic matrices we developed, this study highlights the complex mutual effects between osteoclasts and uranium. This demonstrates the relevance of these 3D models to further study the cellular mechanisms at play in response to uranium storage in bone tissue, and thus better understand the impact of environmental exposure to uranium on human bone health.

Autophagy is a ubiquitous cellular process, allowing the removal and recycling of damaged proteins and organelles. At the basal level, this process plays a role in quality control, thus participating in cellular homeostasis. Autophagy can also be induced by various stresses, such as nutrient deprivation or hypoxia, to allow the cell to survive until conditions improve. In recent years, the role of this process has been widely studied in many pathologies such as neurodegenerative diseases or cancers. In bone tissue, various studies have shown that autophagy is involved in the survival, differentiation and activity of osteoblasts, osteocytes and osteoclasts. The evolution of this knowledge has led to the identification of new molecular pathophysiological mechanisms in bone pathologies. This review reports the current state of knowledge on the role of autophagy in 4 bone diseases: osteoporosis, which seems to be associated with a decrease in autophagy, osteopetrosis and Paget's disease where the course of the autophagic process is disturbed, and finally osteosarcoma where autophagy seems to play a protumoral role. A better understanding of the involvement of autophagy in these pathologies should eventually lead to the identification of new potential therapeutic targets.

Author(s): Carle, SF; Fogg, GE | Abstract: Uncertain or indirect “soft” data, such as geologic interpretation, driller’s logs, geophysical logs or imaging, offer potential constraints or “soft conditioning” to stochastic models of discrete categorical subsurface variables in hydrogeology such as hydrofacies. Previous bivariate geostatistical simulation algorithms have not fully addressed the impact of data uncertainty in formulation of the (co) kriging equations and the objective function in simulated annealing (or quenching). This paper introduces the geostatistical simulation code tsim-s, which accounts for categorical data uncertainty through a data “hardness” parameter. In generating geostatistical realizations with tsim-s, the uncertainty inherent to soft conditioning is factored into both 1) the data declustering and spatial correlation functions in cokriging and 2) the acceptance probability for change of category in simulated quenching. The degree or sensitivity to which soft data conditions a realization as a function of hardness can be quantified by mapping category probabilities derived from multiple realizations. In addition to point or borehole data, arrays of data (e.g., as derived from a depth-dependency function, probability map, or “prior realization”) can be used as soft conditioning. The tsim-s algorithm provides a theoretically sound and general framework for integrating datasets of variable location, resolution, and uncertainty into geostatistical simulation of categorical variables. A practical example shows how tsim-s is capable of generating a large-scale three-dimensional simulation including curvilinear features.

International audience; Autophagy is the major catabolic process in eukaryotic cells for the degradation and recycling of damaged macromolecules and organelles. It plays a crucial role in cell quality control and nutrient supply under stress conditions. Although autophagy is classically described as a degradative mechanism, it can also be involved in some secretion pathways, leading to the extracellular release of proteins, aggregates, or organelles.The role of autophagy in cancer is complex and depends on tumor development stage. While autophagy limits cancer development in the early stages of tumorigenesis, it can also have a protumoral role in more advanced cancers, promoting primary tumor growth and metastatic spread. In addition to its pro-survival role in established tumors, autophagy recently emerged as an active player in the crosstalk between tumor and stromal cells. The aim of this review is to analyze the impact of tumoral autophagy on the microenvironment and conversely the effect of stromal cell autophagy on tumor cells.

International audience; Cases of criminal dismemberment are encountered in forensic pathology and forensic anthropology. Saw mark analysis aims to determine the type of saw that was used: hand saw versus electrical saw, crosscut and universal saw versus rip saw, size of the teeth ("teeth per inch" TPI), and set type. The goal of this study was to analyze using a stereomicroscope a series of 60 experimental false starts (30 lesions for each saw) produced on human bones by two different handsaws with a high TPI (15 and 32). The lesions caused by these high TPI saws have rarely been described in the forensic literature. Saw 2 (rip hacksaw with a 32 TPI and a wavy set) displayed classical features. In contrast, saw 1 (universal panel saw, TPI 15, alternating set) did not produce the expected characteristics: the minimum width of the kerf was weak, the kerf walls were straight, the striae were straight, and the kerf profile was very peculiar with a succession of peaks and dips that has not yet been described.

Purpose To compare per-region macular sensitivity and delay from objective perimetry with Matrix perimetry and retinal thickness in mild diabetic macular edema (DMO). Methods Thirty-three patients with type 2 diabetes (T2D) aged 59.2 ± 10.5 years participated in a longitudinal study. Macular thickness, sensitivities and delays from the objectiveFIELD Analyzer (OFA), and Matrix perimeter sensitivities were mapped onto a common spatial layout to compute per-region correlations between structure/function measures. A generalized linear mixed-effects logistic regression model determined which variables contributed to clinical diagnosis of DMO. Results For OFA, the mean sensitivity differences compared with normal in patients with T2D were negative and the mean delay differences positive, indicating lowered sensitivities and prolonged delays, both increasing with diabetes duration. Shorter diabetes duration could produce either localized peripheral hypersensitivities or shorter delays. Functional change could occur when retinal thickness was stable. Peripheral macular thickness correlated with central and peripheral OFA sensitivity and delay, all P < 0.0012 in DMO and a median of P = 0.001 without DMO; this was not true for Matrix sensitivities. The logistic model determined that peripheral thickness, OFA sensitivity (P = 0.043), and time in the study (P = 0.001) contribute independently to the odds of DMO versus no DMO. Conclusions Mean sensitivities decreased and mean delays increased with duration of diabetes. Peripheral macular thickness correlated significantly with central and peripheral macular OFA sensitivity and delay. Peripheral macular thickness and functional measures may provide sensitive prognostic data. Translational Relevance Functional loss can precede structural change in DMO, so including such functional assessment for deciding on treatment may be beneficial.

In forensic anthropology, saw mark analysis plays an important role in cases of criminal dismemberment. Autopsy saw is not used by the perpetrator in cases of dismemberment, but the forensic pathologist may accidentally create false starts with this saw during an autopsy, especially while sampling bones for further analysis, and these autopsy false starts can be confused with false starts produced by the offender. In this study, the characteristics of 20 false starts were compared using stereomicroscopy (SM) and scanning electron microscopy (SEM). These bone false starts were selected at random from a previous study of 100 false starts created by an electrical oscillating autopsy saw on human femoral bones. That study had enabled the categorization of the lesions into two groups (“superficial group” and “deep group”) with a 0.52 mm depth cut off, based on the dramatic differences in lesion characteristics between these two groups. In the current study, SEM confirmed the characteristics of the false starts (walls and profile shapes, striae, bone islands and bone debris were studied), and above all explained the mechanism whereby oval bone islands in deep lesions are formed. Bone islands are due to the horizontal and vertical movement of the oscillating autopsy blade.

Since the early 40s when the first research related to the development of the atomic bomb began for the Manhattan Project, actinides (An) and their association with the use of nuclear energy for civil applications, such as in the generation of electricity, have been a constant source of interest and fear. In 1962, the first Society of Toxicology (SOT), led by H. Hodge, was established at the University of Rochester (USA). It was commissioned as part of the Manhattan Project to assess the impact of nuclear weapons production on workers’ health. As a result of this initiative, the retention and excretion rates of radioactive heavy metals, their physiological impact in the event of acute exposure and their main biological targets were assessed. In this context, the scientific community began to focus on the role of proteins in the transportation and in vivo accumulation of An. The first studies focused on the identification of these proteins. Thereafter, the continuous development of physico-chemical characterization techniques has made it possible to go further and specify the modes of interaction with proteins from both a thermodynamic and structural point of view, as well as from the point of view of their biological activity. This article reviews the work performed in this area since the Manhattan Project. It is divided into three parts: first, the identification of the most affine proteins; second, the study of the affinity and structure of protein-An complexes; and third, the impact of actinide ligation on protein conformation and function.

Once absorbed in the body, natural uranium [U(VI)], a radionucleotide naturally present in the environment, is targeted to the skeleton which is the long-term storage organ. We and others have reported the U(VI) negative effects on osteoblasts (OB) and osteoclasts (OC), the main two cell types involved in bone remodeling. In the present work, we addressed the U(VI) effect on osteocytes (OST), the longest living bone cell type and the more numerous (> 90%). These cells, which are embedded in bone matrix and thus are the more prone to U(VI) long-term exposure, are now considered as the chief orchestrators of the bone remodeling process. Our results show that the cytotoxicity index of OST is close to 730 µM, which is about twice the one reported for OB and OC. However, despite this resistance potential, we observed that chronic U(VI) exposure as low as 5 µM led to a drastic decrease of the OST mineralization function. Gene expression analysis showed that this impairment could potentially be linked to an altered differentiation process of these cells. We also observed that U(VI) was able to trigger autophagy, a highly conserved survival mechanism. Extended X-ray absorption fine structure analysis at the U LIII edge of OST cells exposed to U(VI) unambiguously shows the formation of an uranyl phosphate phase in which the uranyl local structure is similar to the one present in Autunite. Thus, our results demonstrate for the first time that OST mineralization function can be affected by U(VI) exposure as low as 5 µM, suggesting that prolonged exposure could alter the central role of these cells in the bone environment.