Tension at intercellular junctions is necessary for accurate orientation of cell division in the epithelium plane.

The direction in which a cell divides is set by the orientation of its mitotic spindle and is important for determining cell fate, controlling tissue shape, and maintaining tissue architecture. Divisions parallel to the epithelial plane sustain tissue expansion. By contrast, divisions perpendicular to the plane promote tissue stratification and lead to the loss of epithelial cells from the tissue-an event that has been suggested to promote metastasis. Much is known about the molecular machinery involved in orienting the spindle, but less is known about the contribution of mechanical factors, such as tissue tension, in ensuring spindle orientation in the plane of the epithelium. This is important as epithelia are continuously subjected to mechanical stresses. To explore this further, we subjected suspended epithelial monolayers devoid of extracellular matrix to varying levels of tissue tension to study the orientation of cell divisions relative to the tissue plane. This analysis revealed that lowering tissue tension by compressing epithelial monolayers or by inhibiting myosin contractility increased the frequency of out-of-plane divisions. Reciprocally, increasing tissue tension by elevating cell contractility or by tissue stretching restored accurate in-plane cell divisions. Moreover, a characterization of the geometry of cells within these epithelia suggested that spindles can sense tissue tension through its impact on tension at subcellular surfaces, independently of their shape. Overall, these data suggest that accurate spindle orientation in the plane of the epithelium relies on a threshold level of tension at intercellular junctions.

Memory as a scale of simulation depending on the trace distinctiveness.

It has been proposed that representations emerge from a single memory system organized along a continuum of specificity. This continuum is assumed to reflect a scale between the simulation of overlapping and specific features of the traces, which depends on trace distinctiveness. More specifically, higher trace distinctiveness facilitates the simulation of trace-specific features, which increase the discriminability of traces and lead to the emergence of a more specific representation. In two experiments, participants were asked to identify match (low task discrimination demand) or mismatch (high task discrimination demand) associations between actions and characters that were visually either highly or lowly distinctive. The results of Experiment 1 show that in the high-distinctiveness context, performance was better when identifying a mismatch rather than a match, while the opposite was true in the low-distinctiveness context. The results of Experiment 2 show that using a dynamic visual noise to interfere with the participants' ability to simulate the features of the characters also reduced the benefit of the high-distinctiveness context for the mismatch trials (Experiment 2a and 2b) and increased the benefit of the low-distinctiveness context for the match trials (Experiment 2b). Taken together, these results suggest that the simulation of trace-specific features underlies the emergence of specific representations, which can be beneficial when the discrimination demand of the task is high and detrimental when this demand is low. Memory might therefore be viewed as a scale of simulation between overlapping and specific trace features.

Executive deficits in schizophrenia: mediation by processing speed and its relationships with aging.

BACKGROUND: Executive deficits are a core characteristic of schizophrenia. Yet, the origin of these impairments remains unclear as they may be caused by processing slowing. This issue is of particular interest for aging insofar as cognitive aging is also associated with a decline in executive functioning and a slowing of processing speed. As schizophrenia patients' life expectancy increases, a better understanding of the origin of older patients' cognitive deficits becomes essential so that healthcare can be adapted to suit them. This study aims to determine whether processing speed mediates how schizophrenia affects executive functions and whether these relationships are moderated by age. METHODS: Sixty-two schizophrenia patients (27 women) and 62 healthy comparison subjects matched for age (range: 18-76 years), gender and education performed neurocognitive tests to evaluate their executive functions (shifting, updating, inhibition and access) and processing speed. RESULTS: Processing speed mediated the effect of schizophrenia on the four specific executive functions, and age moderated this mediation for shifting, updating and access, but in different ways. Age moderated the effect of processing speed on shifting, the direct effect of schizophrenia on access, and both the effect of processing speed and the direct effect of schizophrenia on updating. CONCLUSIONS: This research highlights the need to evaluate processing speed routinely during therapeutic follow-up, as it is easy and simple to assess and appears to be at the heart of the cognitive deficits in schizophrenia. Finally, processing speed abilities yield information about the evolution of cognition with aging in schizophrenia.

Playing "guess who?": when an episodic specificity induction increases trace distinctiveness and reduces memory errors during event reconstruction.

The constructive nature of memory implies a possible confusion between details of similar events. Memory interventions should thus target the reduction of memory errors. We postulate that a brief intervention called Episodic Specificity Induction (ESI) facilitates the sensorimotor simulation of event-related details by improving the distinctiveness of the event memory trace. As such, ESI should reduce memory errors only when event memory traces are strongly overlapping based on their sensorimotor features. Participants memorised videos showing characters performing an action on a given object. The characters were either visually very similar to each other or very distinct (low vs. high distinctiveness condition). Next, participants performed either an imagination version of the ESI or a control induction. Finally, a voice announced one of the actions seen and a character was then briefly displayed. The participants had to indicate whether the association was correct. For incorrect associations, in the low distinctiveness condition, false alarms were more likely than in the high distinctiveness condition and were reduced after the ESI. It suggests that facilitating the simulation of specific details through the ESI increased trace distinctiveness and reduced memory errors at the critical time of event reconstruction. Future clinical applications might be possible.

Actomyosin controls planarity and folding of epithelia in response to compression.

Throughout embryonic development and adult life, epithelia are subjected to compressive deformations. While these have been shown to trigger mechanosensitive responses such as cell extrusion and differentiation, which span tens of minutes, little is known about how epithelia adapt to compression over shorter timescales. Here, using suspended epithelia, we uncover the immediate response of epithelial tissues to the application of in-plane compressive strains (5-80%). We show that fast compression induces tissue buckling followed by actomyosin-dependent tissue flattening that erases the buckle within tens of seconds, in both mono- and multi-layered epithelia. Strikingly, we identify a well-defined limit to this response, so that stable folds form in the tissue when compressive strains exceed a 'buckling threshold' of ~35%. A combination of experiment and modelling shows that this behaviour is orchestrated by adaptation of the actomyosin cytoskeleton as it re-establishes tissue tension following compression. Thus, tissue pre-tension allows epithelia to both buffer against deformation and sets their ability to form and retain folds during morphogenesis.

Vitamin D Fortification of Consumption Cow's Milk: Health, Nutritional and Technological Aspects. A Multidisciplinary Lecture of the Recent Scientific Evidence.

Vitamin D is essential in assuring bone health at all stages of life, but its non-skeletal effects are also essential: This vitamin impacts the physiology of the immune system, skeletal muscles and adipose tissue, glucose metabolism, skin, cardiovascular and reproductive systems, neuro-cognitive functions and cell division. The incidence of vitamin D deficiency is widespread worldwide, at any age, in young and healthy subjects, as well as in pregnant women and the elderly population, due to several factors, including inadequate sunlight exposure, skin pigmentation and coverage, adiposity, lifestyle and low dietary intakes. To overcome this problem, the fortification of foods that are consumed on a daily basis, such as milk, is strongly advisable. This opinion paper aims to discuss, in a multidisciplinary way, the current evidence supporting the importance of vitamin D in health and disease and the role of milk as an optimal carrier of this vitamin, to promote adequate intakes, highlighting its unique physico-chemical characteristics linked to both fat globule membrane and casein micelle structure. Moreover, it addresses the impact of industrial processing and storage of consumption milk on the stability of these structures, thus in determining vitamin D bioavailability and the achievement of adequate intakes.

Profiling older community-dwellers with hypovitaminosis D: A classification tree analysis.

Despite the high prevalence of hypovitaminosis D in older adults, universal vitamin D supplementation is not recommended due to potential risk of intoxication. Our aim here was to determine the clinical profiles of older community-dwellers with hypovitaminosis D. The perspective is to build novel strategies to screen for and supplement those with hypovitaminosis D. A classification tree (CHAID analysis) was performed on multiple datasets standardizedly collected from 1991 older French community-dwelling volunteers ≥ 65 years in 2009-2012. Hypovitaminosis D was defined as serum 25-hydroxyvitamin D ≤ 50 nmol/L. CHAID analysis retained 5 clinical profiles of older community-dwellers with different risks of hypovitaminosis D up to 87.3%, based on various combinations of the following characteristics: polymorbidity, obesity, sadness and gait disorders. For instance, the probability of hypovitaminosis D was 1.42-fold higher [95CI: 1.27-1.59] for those with polymorbidity and gait disorders compared to those with no polymorbidity, no obesity and no sadness. In conclusion, these easily-recordable measures may be used in clinical routine to identify older community-dwellers for whom vitamin D supplementation should be initiated.

When motion improves working memory.

In the present study, we used a complex span task to explore how memory traces resulting from Self-Performed Task (SPT) and Verbal Task (VT) are maintained in working memory. Participants memorised series of five sentences describing an action either through SPT or VT. Between pairs of sentences, participants performed a concurrent task that varied according to its nature and its cognitive load. The concurrent task was either a verbal task, a low cognitive load motor task or a high cognitive load motor task. A control condition served as a baseline. First, we observed that performance in SPT and VT did not decrease with verbal or motor suppression, but was lower with an increase of the cognitive load. This suggests that memory traces are maintained through attentional refreshing whatever the encoding (SPT or VT). Second, while the enactment effect was replicated in the control condition, it tended to vanish with a verbal concurrent task; moreover, it was reversed with motor concurrent tasks. Surprisingly, the latter effect resulted from an increase of VT memory performance when participants repeated the same gesture between sentences. Finally, our results provide additional evidence that the enactment effect does not rely on attention.

Directional memory arises from long-lived cytoskeletal asymmetries in polarized chemotactic cells.

Chemotaxis, the directional migration of cells in a chemical gradient, is robust to fluctuations associated with low chemical concentrations and dynamically changing gradients as well as high saturating chemical concentrations. Although a number of reports have identified cellular behavior consistent with a directional memory that could account for behavior in these complex environments, the quantitative and molecular details of such a memory process remain unknown. Using microfluidics to confine cellular motion to a 1D channel and control chemoattractant exposure, we observed directional memory in chemotactic neutrophil-like cells. We modeled this directional memory as a long-lived intracellular asymmetry that decays slower than observed membrane phospholipid signaling. Measurements of intracellular dynamics revealed that moesin at the cell rear is a long-lived element that when inhibited, results in a reduction of memory. Inhibition of ROCK (Rho-associated protein kinase), downstream of RhoA (Ras homolog gene family, member A), stabilized moesin and directional memory while depolymerization of microtubules (MTs) disoriented moesin deposition and also reduced directional memory. Our study reveals that long-lived polarized cytoskeletal structures, specifically moesin, actomyosin, and MTs, provide a directional memory in neutrophil-like cells even as they respond on short time scales to external chemical cues.

Visual and auditory perceptual strength norms for 3,596 French nouns and their relationship with other psycholinguistic variables.

Perceptual experience plays a critical role in the conceptual representation of words. Higher levels of semantic variables such as imageability, concreteness, and sensory experience are generally associated with faster and more accurate word processing. Nevertheless, these variables tend to be assessed mostly on the basis of visual experience. This underestimates the potential contributions of other perceptual modalities. Accordingly, recent evidence has stressed the importance of providing modality-specific perceptual strength norms. In the present study, we developed French Canadian norms of visual and auditory perceptual strength (i.e., the modalities that have major impact on word processing) for 3,596 nouns. We then explored the relationship between these newly developed variables and other lexical, orthographic, and semantic variables. Finally, we demonstrated the contributions of visual and auditory perceptual strength ratings to visual word processing beyond those of other semantic variables related to perceptual experience (e.g., concreteness, imageability, and sensory experience ratings). The ratings developed in this study are a meaningful contribution toward the implementation of new studies that will shed further light on the interaction between linguistic, semantic, and perceptual systems.

Norms of conceptual familiarity for 3,596 French nouns and their contribution in lexical decision.

In the last decade, research has shown that word processing is influenced by the lexical and semantic features of words. However, norms for a crucial semantic variable-that is, conceptual familiarity-have not been available for a sizeable French database. We thus developed French Canadian conceptual familiarity norms for 3,596 nouns. This enriches Desrochers and Thompson's (2009) database, in which subjective frequency and imageability values are already available for the same words. We collected online data from 313 Canadian French speakers. The full database of conceptual familiarity ratings is freely available at http://lingualab.ca/fr/projets/normes-de-familiarite-conceptuelle . We then demonstrated the utility of these new conceptual familiarity norms by assessing their contribution to lexical decision times. We conducted a stepwise regression model with conceptual familiarity in the last step. This allowed us to assess the independent contribution of conceptual familiarity beyond the contributions of other well-known psycholinguistic variables, such as frequency, imageability, and age of acquisition. The results showed that conceptual familiarity facilitated lexical decision latencies. In sum, these ratings will help researchers select French stimuli for experiments in which conceptual familiarity must be taken into account.

Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis.

Cell division plays an important role in animal tissue morphogenesis, which depends, critically, on the orientation of divisions. In isolated adherent cells, the orientation of mitotic spindles is sensitive to interphase cell shape and the direction of extrinsic mechanical forces. In epithelia, the relative importance of these two factors is challenging to assess. To do this, we used suspended monolayers devoid of ECM, where divisions become oriented following a stretch, allowing the regulation and function of epithelial division orientation in stress relaxation to be characterized. Using this system, we found that divisions align better with the long, interphase cell axis than with the monolayer stress axis. Nevertheless, because the application of stretch induces a global realignment of interphase long axes along the direction of extension, this is sufficient to bias the orientation of divisions in the direction of stretch. Each division redistributes the mother cell mass along the axis of division. Thus, the global bias in division orientation enables cells to act collectively to redistribute mass along the axis of stretch, helping to return the monolayer to its resting state. Further, this behavior could be quantitatively reproduced using a model designed to assess the impact of autonomous changes in mitotic cell mechanics within a stretched monolayer. In summary, the propensity of cells to divide along their long axis preserves epithelial homeostasis by facilitating both stress relaxation and isotropic growth without the need for cells to read or transduce mechanical signals.

L-selectin shedding is activated specifically within transmigrating pseudopods of monocytes to regulate cell polarity in vitro.

L-selectin is a cell adhesion molecule that tethers free-flowing leukocytes from the blood to luminal vessel walls, facilitating the initial stages of their emigration from the circulation toward an extravascular inflammatory insult. Following shear-resistant adhesion to the vessel wall, L-selectin has frequently been reported to be rapidly cleaved from the plasma membrane (known as ectodomain shedding), with little knowledge of the timing or functional consequence of this event. Using advanced imaging techniques, we observe L-selectin shedding occurring exclusively as primary human monocytes actively engage in transendothelial migration (TEM). Moreover, the shedding was localized to transmigrating pseudopods within the subendothelial space. By capturing monocytes in midtransmigration, we could monitor the subcellular distribution of L-selectin and better understand how ectodomain shedding might contribute to TEM. Mechanistically, L-selectin loses association with calmodulin (CaM; a negative regulator of shedding) specifically within transmigrating pseudopods. In contrast, L-selectin/CaM interaction remained intact in nontransmigrated regions of monocytes. We show phosphorylation of L-selectin at Ser 364 is critical for CaM dissociation, which is also restricted to the transmigrating pseudopod. Pharmacological or genetic inhibition of L-selectin shedding significantly increased pseudopodial extensions in transmigrating monocytes, which potentiated invasive behavior during TEM and prevented the establishment of front/back polarity for directional migration persistence once TEM was complete. We conclude that L-selectin shedding directly regulates polarity in transmigrated monocytes, which affirms an active role for this molecule in driving later stages of the multistep adhesion cascade.

Carboplatin instead of cisplatin in combination with dexamethasone, high-dose cytarabine with or without rituximab (DHAC+/-R) is an effective treatment with low toxicity in Hodgkin's and non-Hodgkin's lymphomas.

The DHAP regimen (high-dose cytarabine in combination with dexamethasone and cisplatin) with or without rituximab (DHAP+/-R) is one of the most common regimens in daily practice. It is considered the standard treatment for relapse or refractory Hodgkin's and non-Hodgkin's lymphoma (NHL). Cisplatin nephrotoxicity is a major concern, and other platinum compounds are being tried. We performed a monocentric retrospective analysis to evaluate the use of carboplatin, so-called DHAC+/-R regimen. The purpose was to assess the toxicity of the DHAC+/-R regimen in real-life. The Dexamethasone, Cytarabine, Carboplatin (DHAC) regimen consisted of carboplatin AUC = 5 mg/ml/min (targeted area under the curve with Calvert's formula) on day 1, cytarabine 2 g/m2 twice a day on day 2 and IV dexamethasone 40 mg from days 1 to 4. Rituximab was administrated at 375 mg/m2 on day 1 for CD20+ NHL. The interval between courses was 21 days. During the period considered, 199 patients received DHAC+/-R. For the entire cohort, median follow-up is 24 months (range, 2-82), median OS is not reached (NR), estimated 2-year OS is 75% (95% CI, 69-83) and median progression-free survival (PFS) is 46 months (95% CI, 22-NA). Of 144 patients scheduled for autologous stem cell transplantation (ASCT), 102 (71%, NA = 2) were in response after DHAC+/-R and all except 4 underwent ASCT. Grade ≥ 3 haematological toxicities were mainly thrombocytopenia (n = 101) and anaemia (n = 95). Grade ≥ 3 neutropenia occurred in 10 patients. No grade ≥ 3 renal and one grade 3 neurological toxicity were reported. DHAC+/-R is feasible in daily practice, provides good response rates and jeopardises neither stem cell collection nor ASCT.

Formation of adherens junctions leads to the emergence of a tissue-level tension in epithelial monolayers.

Adherens junctions and desmosomes integrate the cytoskeletons of adjacent cells into a mechanical syncitium. In doing so, intercellular junctions endow tissues with the strength needed to withstand the mechanical stresses encountered in normal physiology and to coordinate tension during morphogenesis. Though much is known about the biological mechanisms underlying junction formation, little is known about how tissue-scale mechanical properties are established. Here, we use deep atomic force microscopy (AFM) indentation to measure the apparent stiffness of epithelial monolayers reforming from dissociated cells and examine which cellular processes give rise to tissue-scale mechanics. We show that the formation of intercellular junctions coincided with an increase in the apparent stiffness of reforming monolayers that reflected the generation of a tissue-level tension. Tension rapidly increased, reaching a maximum after 150 min, before settling to a lower level over the next 3 h as monolayers established homeostasis. The emergence of tissue tension correlated with the formation of adherens junctions but not desmosomes. As a consequence, inhibition of any of the molecular mechanisms participating in adherens junction initiation, remodelling and maturation significantly impeded the emergence of tissue-level tension in monolayers.

Rituximab maintenance after autologous stem cell transplantation prolongs response duration in non-naive rituximab follicular lymphoma patients: a single institution experience.

We retrospectively evaluated the role of rituximab (R) in maintenance treatment after autologous stem cell transplantation performed in patients with relapsed follicular lymphoma. We compared the outcome of 67 follicular lymphoma (FL) patients according to the use of rituximab maintenance (RM) or not. All patients received rituximab plus chemotherapy before autologous stem-cell transplantation (ASCT). Patients received median of two lines of prior therapy. The RM schedule was one injection of rituximab every 3 months for 2 years. Median follow-up is 4.6 years. The 3-year progression-free survival (PFS) after ASCT was 86 % with RM vs. 46 % without (p = 0.0045). Median is not reached in the RM arm vs. 31 months in non-RM arm. The 3-year OS was 96 % with RM vs. 78 % without (p = 0.059). The present monocentric study shows that 2 years of RM after ASCT significantly increases response duration for non-naive rituximab relapsed FL patients compared with observation.

Upfront allogeneic stem-cell transplantation for patients with nonlocalized untreated peripheral T-cell lymphoma: an intention-to-treat analysis from a single center.

BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases with dismal outcome when treated with chemotherapy alone. Because allogeneic stem-cell transplantation (allo-SCT) can cure relapse/refractory patients, we hypothesized that upfront allo-SCT may provide a better outcome. Therefore, all patients that presented with advanced PTCL in our institution at diagnosis were scheduled to undergo upfront allo-SCT after induction chemotherapy. PATIENTS AND METHODS: The aim of the present work was to assess the feasibility and toxicity of upfront allo-SCT. From 2004 to 2012, 49 newly diagnosed PTCL patients were scheduled to receive upfront allo-SCT. A human leukocyte antigen-matched donor was found for 42 patients: related to the patient in 15 cases, unrelated in 20 cases, and suitable cord blood units were used in 7 cases. RESULTS: After induction chemotherapy, 17 patients reached complete remission and 29 (60%) proceeded to upfront allo-SCT. For all patients, the 1 and 2-year overall survival (OS) rates were 59% [95% confidence interval (CI) 47-75] and 55% (95% CI 43-71), respectively. The most frequent reason we did not proceed to allo-SCT was disease progression or insufficient response after induction. For transplanted patients, the 1- and 2-year OS were 76% (95% CI 62-93) and 72.5% (95% CI 58-91), respectively. Toxicity-related mortality (TRM) 1 year after allo-SCT was only 8.2% (95% CI 0-18.5). The 2-year progression-free survival (PFS) rate of patients who did not proceed to allo-SCT (n = 20) was below 30%. The disease status at the time of transplantation was a strong predictive marker for both PFS and OS in transplant patients. CONCLUSIONS: Upfront allo-SCT in PTCLs is feasible with low TRM, and it provides long-term disease control. However, one-third of patients remain chemo-refractory and, thus, new therapeutic approaches are warranted. The role of upfront allo-SCT compared with other therapeutic approaches in PTCLs requires investigation in randomized studies.

Characterizing the mechanics of cultured cell monolayers.

One-cell-thick monolayers are the simplest tissues in multicellular organisms, yet they fulfill critical roles in development and normal physiology. In early development, embryonic morphogenesis results largely from monolayer rearrangement and deformation due to internally generated forces. Later, monolayers act as physical barriers separating the internal environment from the exterior and must withstand externally applied forces. Though resisting and generating mechanical forces is an essential part of monolayer function, simple experimental methods to characterize monolayer mechanical properties are lacking. Here, we describe a system for tensile testing of freely suspended cultured monolayers that enables the examination of their mechanical behavior at multi-, uni-, and subcellular scales. Using this system, we provide measurements of monolayer elasticity and show that this is two orders of magnitude larger than the elasticity of their isolated cellular components. Monolayers could withstand more than a doubling in length before failing through rupture of intercellular junctions. Measurement of stress at fracture enabled a first estimation of the average force needed to separate cells within truly mature monolayers, approximately ninefold larger than measured in pairs of isolated cells. As in single cells, monolayer mechanical properties were strongly dependent on the integrity of the actin cytoskeleton, myosin, and intercellular adhesions interfacing adjacent cells. High magnification imaging revealed that keratin filaments became progressively stretched during extension, suggesting they participate in monolayer mechanics. This multiscale study of monolayer response to deformation enabled by our device provides the first quantitative investigation of the link between monolayer biology and mechanics.