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This study explores the reliability of a phase‐change memory (PCM) cointegrated with an ovonic threshold switching (OTS) selector (one selector and one memory [1S1R] structure) based on an innovative double‐patterned self‐aligned architecture. The variability of the threshold voltage (Vth$\left(\text{V}\right)_{\text{th}}$) for both the SET and RESET states is examined, comparing different distribution models to validate the use of mean and standard deviation as viable metrics. The dispersion of Vth$\left(\text{V}\right)_{\text{th}}$ is tracked under different programming conditions to provide insight into the evolution of device behavior over SET/RESET, endurance cycles, and read cycles. The PCM device is based on a "wall" structure and on Ge2Sb2Te5 alloy, while the OTS is based on a GeSbSeN alloy. The analysis focuses on the programming characteristics and SET pulse optimization, studying current control and pulse fall times. The results are based on statistical data obtained from a kb‐sized memory array. A memory window of over 2 V is achieved. The research helps understanding the DPSA architecture, and PCM + OTS in general, offering insights into their programming, variability, and reliability targeting crossbar applications. [ABSTRACT FROM AUTHOR]

The thick late syn‐ to early post‐rift shallow water evaporites in the most distal part of wide rifted margins is paradoxical with the deep depression at crustal breakup time predicted by isostatically compensated lithospheric thinning. Elevation of the distal margin and water depth during deposition of the late syn‐rift evaporites in the central South Atlantic are not well constrained and remain to be quantified. We use forward 2‐D thermo‐mechanical modeling coupled with melt prediction and surface processes to assess the contribution of lithospheric and mantle processes on the distal margin topography and subsidence history during continental rifting. Models show that (a) counter‐flow of depleted lower lithospheric mantle during rifting explains the magma‐poor nature of these margins and (b) weak crust and syn‐rift sediment control the wide crustal necking and subsidence history of the distal margin. Integration of our modeling results with quantified geophysical and geological observations suggests that (a) base level was down to −600 m below present‐day global sea level (bsl) during distal margin formation in the Aptian before sag and evaporite deposition, (b) base level was about −300/−400 m bsl at the end of evaporite deposition, and (c) scenarios with a fixed shallow base level (−400 m bsl) or with an increasing base level from an initially deep position (−1,600 m bsl) during evaporite deposition can both fit the observed evaporite distribution. However, erosional features along the base of evaporites suggest a deep initial base level. Plain Language Summary: The opening of the Atlantic Ocean contributed to the fragmentation of the Pangaea supercontinent 100–200 millions years ago. Water depth in the basins formed during this process is not well constrained while it is fundamental to understand their environmental conditions. For instance, in the central South Atlantic that comprises the west African Gabon, Congo, and Angola margins and their conjugates along the Brazilian margin, a giant evaporite basin deposited during continental breakup in shallow water formed very far from the continent. In this study, we compiled data along these margins and used 2‐D numerical models to show that an initially deep basin isolated from global ocean can provide the conditions necessary for this giant evaporite basin to be deposited. Key Points: Weak lower crust and syn‐rift sedimentation rate are first‐order controls on the formation and geometry of wide distal rifted marginModeling suggests a base level ∼−600 m below present‐day global sea level (bsl) during the distal margin formation before evaporite depositionModeling suggests a base level of ∼−300/−400 m bsl at the end of evaporite deposition [ABSTRACT FROM AUTHOR]

Ocular prostheses have been used for centuries to restore patient confidence, psychosocial relationships and to improve quality of life. Methodology for producing accurate prostheses has improved with technological discoveries. Recently, hand painting ocular prostheses has been the go‐to method for creating life like prostheses. However, digital printing a print to envelope around an acrylic prosthesis has been shown to decrease treatment and rehabilitation times, whilst still producing high‐definition ocular prostheses. Despite these improvements, little is known about the colour stability of digitally printed ocular prostheses. To better understand the colour stability of digital prostheses 30 samples simulating ocular prostheses were created, containing 10 with blue iris, 10 combination/green iris and 10 with sepia (brown) irises. Colour measurements were taken using a data spectrophotometer, from two defined points, the iris and sclera for both pre‐polymerisation and post‐polymerisation to assess colour variance. Colour coordinate data was gathered and was analysed using a one‐way analysis of variance test and a paired t‐test, both with alpha = 0.05. Significant colour variations were found for each iris colour and for the sclera. The sclera showed the largest colour variation with a ΔE of 4.75, followed by the brown irises, the green irises and then blue irises with ΔE values of 3.29, 2.47 and 1.82, respectively. This is a significant decrease compared to current hand painting methods which have an average colour variance of ΔE = 20. This shows a large increase in colour stability which can drastically improve patient satisfaction and quality of life. [ABSTRACT FROM AUTHOR]

In this work, synchrotron radiation rocking curve imaging (RCI) is used to visualize and characterize dislocations and second‐phase defects in a highly perfect and absorbing CdTe(Zn) crystal. This technique requires recording a series of Bragg diffracted images along the rocking curve to produce maps of the 'local' integrated intensity, full width at half‐maximum and peak position. The diffraction conditions of the reported experiment are such that anomalous transmission (Borrmann effect) is a crucial ingredient for the formation of the image of the defects. The images recorded and maps produced allow the investigation of a series of topics that, to the authors' knowledge, have not been previously studied. The first of these topics is the variation of the position and width of the Borrmann image of a defect when sitting on the peak and on the flanks of the diffraction curve. The second topic is the way Borrmann images show up on the usual RCI maps. The final topic is the combination of Borrmann and weak‐beam images to infer the depth of the defect within the crystal. [ABSTRACT FROM AUTHOR]

Background and purpose: This study was undertaken to determine the role of optical coherence tomography (OCT) in predicting the final visual and structural outcome, and to evaluate the correlation between functional eye outcome and retinal changes, in patients with a first episode of optic neuritis (ON). Methods: In this prospective study, consecutive adult patients with acute ON underwent ophthalmological evaluation at baseline and at 1 and 12 months, including OCT measurements of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell and inner plexiform layer, and inner nuclear layer thicknesses; high‐ and low‐contrast visual acuity; visual field assessment; and baseline brain magnetic resonance imaging. Univariate and multivariate linear regressions were used to assess predictive factors of outcome. Correlations between 12‐month visual function and retinal structure were estimated by Spearman coefficients. Two groups of patients were analyzed, with or without multiple sclerosis (MS). Results: Among 116 patients, 79 (68.1%) had MS, and 37 (31.9%) had ON not related to MS (including 19 idiopathic [i.e., isolated] ON, and 13 and five with myelin oligodendrocyte glycoprotein and aquaporin‐4 antibodies, respectively). We found no independent predictive factor of visual and retinal outcome. Analysis of the relationship between the visual field test (mean deviation) and pRNFL thickness demonstrated a threshold of 75.4 μm and 66.4 μm, below which the mean deviation was worse, for patients with MS (p = 0.007) and without MS (p < 0.001), respectively. Conclusions: We found that inner retinal layer measurements during the first month are not predictive of final outcome. The critical threshold of axonal integrity, below which visual function is damaged, is different between patients with and without MS. [ABSTRACT FROM AUTHOR]

Background and purpose: This study was undertaken to validate a clinical score of vascular origin in patients with acute transient visual disturbances (TVDs) without diplopia. Methods: We conducted a prospective study in an ophthalmology emergency department and a transient ischemic attack (TIA) clinic. Patients underwent clinical evaluation including a tailored questionnaire, brain, vascular, and ophthalmologic investigations, and 3‐month follow‐up. TVDs were classified according to vascular or nonvascular origin by three independent experts based on all clinical, cerebrovascular, and ophthalmologic investigations, but blind to the questionnaire results. A clinical score was derived based on clinical variables independently associated with a vascular origin, and was externally validated in an independent cohort. Results: An ischemic origin of TVD was found in 45% (67/149) of patients in the derivation cohort. Age and six questions were independently associated with an ischemic origin. A nine‐point score (≥70 years old = 2; monocular visual loss = 2; black or white vision = 1; single episode = 1; lack of headache = 2; diffuse, constricted, altitudinal, or lateralized visual loss pattern on drawings = 1) showed good discriminative power in identifying ischemic origin (c‐statistic = 0.82) and was replicated in the validation cohort (n = 130, 25% of ischemic origin, c‐statistic = 0.75). With a score ≥ 4, sensitivity was 85% (95% confidence interval = 68−95) and specificity was 52% (95% confidence interval = 41−62). In both cohorts, ophthalmologic evaluation found a vascular cause in 4% and was noncontributive in 85%. After 3 months, no patients had a stroke, TIA, or retinal infarct. Conclusions: Our score may assist in predicting a vascular origin of TVD. Ophthalmologic evaluation, when not readily available, should not delay the neurovascular evaluation. [ABSTRACT FROM AUTHOR]

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf‐3 (DKK3) is identified as novel factor for organ regeneration using combined transcription‐factor‐induced reprogramming and RNA‐interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three‐germ‐layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3‐null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5+ liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical‐Wnt‐signaling in Dkk3‐null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog‐signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical‐Wnt‐, and Hedgehog‐signaling. [ABSTRACT FROM AUTHOR]

Background and purpose: Disease‐modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment. Methods: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. Results: Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7–31.9) were not receiving any DMT. Although patients with a relapsing‐remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2–15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing‐remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44–0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74–0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT. Conclusion: A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS. [ABSTRACT FROM AUTHOR]

Background and objective: The prognosis in myelin oligodendrocyte glycoprotein (MOG) antibody‐associated disease (MOGAD) is a matter of debate. Our aim was to assess the long‐term outcomes of patients with MOGAD. Methods: We retrospectively analysed the clinical and paraclinical data of patients from the French nationwide observatory study NOMADMUS who tested positive for MOG antibodies (MOG‐IgG) and who had clinical follow‐up of at least 8 years from their first episode. Results: Sixty‐one patients (median [range] age at onset 27 [3–69] years), with a median (mean; range) follow‐up of 177 (212.8; 98–657) months, were included. Among 58 patients with a relapsing course, 26.3% relapsed in the first year after onset. Of the 61 patients, 90.2% experienced at least one episode of optic neuritis. At last visit, the median (mean; range) Expanded Disability Status Scale (EDSS) score was 1 (2.12; 0–7.5), 12.5% had an EDSS score ≥6 and 37.5% had an EDSS score ≥3. Of 51 patients with final visual acuity (VA) data available, 15.7% had VA ≤0.1 in at least one eye and 25.5% had VA ≤0.5 in at least one eye. Bilateral blindness (VA ≤0.1) was present in 5.9% of patients. Finally, 12.5% of patients presented bladder dysfunction requiring long‐term urinary catheterization. No factor associated significantly with a final EDSS score ≥3 or with final VA ≤0.1 was found. Conclusion: Overall long‐term favourable outcomes were achieved in a majority of our patients, but severe impairment, in particular visual damage, was not uncommon. [ABSTRACT FROM AUTHOR]

We compared SimoaTM and EllaTM immunoassays to assess serum neurofilament‐light chain levels in 203 multiple sclerosis patients from the OFSEP HD study. There was a strong correlation (ρ = 0.86, p < 0.0001) between both platforms. The EllaTM instrument overestimated values by 17%, but as the data were linear (p = 0.57), it was possible to apply a correction factor to EllaTM results. As for SimoaTM, serum neurofilament‐light chain levels measured by EllaTM were correlated with age and EDSS and were significantly higher in active multiple sclerosis, suggesting that these assays are equivalent and can be used in routine clinical practice. [ABSTRACT FROM AUTHOR]

Background. COVID-19 interacts at multiple levels with the cardiovascular system. The prognosis of COVID-19 infection is known to be worse for patients with underlying cardiovascular diseases. Furthermore, the virus is responsible for many cardiovascular complications. Myocardial injury may affect up to 20% of the critically ill patients. However, echocardiography's impact on the management of patients affected by COVID-19 remains unknown. Objectives. To explore echocardiography's impact on the management of COVID-19 patients. Methods. This study was conducted from March 24th to April 14th, 2020, in a single center at Adolphe de Rothschild Foundation Hospital, Paris, France. All consecutive inpatients with laboratory and/or CT COVID-19 diagnosis were included in this study. Patients' characteristics (clinical, biological, and imaging) and treatment change induced by echocardiography were collected and analyzed. Patients with and without treatment change induced by echocardiography were compared. Results. A total of 56 echocardiographies in 42 patients with highly suspected or confirmed COVID-19 were included in the final analyses. The median age was 66 (IQR 60.5–74). Echocardiography induced a treatment change in 9 cases (16%). The analyzed clinical data were not associated with any treatment change induced by echocardiography. D-dimer and Troponin levels were the only biological predictors of the induced treatment change. On echocardiography, higher systolic pulmonary arterial pressure and documented cardiac thrombi were associated with treatment changes in these patients. Conclusions. Echocardiography may be useful for the management of selected COVID-19 patients, especially those with elevated D-Dimer and Troponin levels, in up to 16% of patients. [ABSTRACT FROM AUTHOR]

Background. Left ventricular ejection fraction (LVEF) and end diastolic volume (EDV) are measured using Simpson's biplane (SB), 3-dimensional method (3DE), and speckle tracking (STE). Comparisons between methods in routine practice are limited. Our purpose was to compare and to determine the correlations between these three methods in clinical setting. Methods. LVEF and EDV were measured by three methods in 474 consecutive patients and compared using multiple Bland–Altman (BA) plots. The correlations (R) between methods were calculated. Results. Median (IQR) LVEF_SB, LVEF_STE, and LVEF_3DE were 63.0% (60–69)%, 61% (57–65)%, and 62% (57–68)%. Median (IQR) EDV_SB, EDV_STE, and EDV_3DE were 85 ml (71–106) ml, 82 ml (69–100) ml, and 73 ml (59–89) ml. R between LVEF_SB and LVEF_3DE was 0.65 when echogenicity was good and 0.43 when poor. R for EDV_SB and EDV_3DE was 0.75 when echogenicity was good and 0.45 when poor. On BA analysis, biases were acceptable (<3.5% for LVEF) but limits of agreement (LOA) were large: 95% of the differences were between −15.4% and +18.8% for LVEF as evaluated by SB in comparison with 3DE, with a bias of 1.7%. In the comparison EDV_SB and EDV_3DE, the bias was 14 ml and the LOA were between −24 ml and +53 ml. On linear regressions, LVEF_3DE = 17.92 + 0.69 LVEF_SB and EDV_3DE = 18.94 + 0.63 EDV_SB. Conclusions. The three methods were feasible and led to acceptable bias but large LOA. Although these methods are not interchangeable, our results allow 3DE value prediction from SB, the most commonly used method. [ABSTRACT FROM AUTHOR]

Background and purpose: There are few clinico‐radiological data on optic neuritis (ON) with myelin oligodendrocyte glycoprotein antibody (MOG‐IgG). The objective was to characterize the clinico‐radiological phenotype and outcome of patients with MOG‐IgG‐related ON. Methods: The records of all adult patients admitted in three medical centres with MOG‐IgG‐associated ON who underwent orbital and brain magnetic resonance imaging (MRI) at the acute phase were reviewed. Spinal cord MRI within 1 month from the ON and all of the follow‐up MRI were reviewed. Results: Of 62 patients, 41.9% had bilateral ON and 66.2% optic disc swelling. On initial MRI, lesions were anterior (92%), extensive (63%) and associated with optic perineuritis (46.6%). Silent brain lesions were found in 51.8% of patients but were mainly non‐specific (81%). Of 39 individuals with spinal MRI at onset, nine had abnormal findings (four were asymptomatic). Two symptomatic patients had longitudinally extensive myelitis with concurrent H‐sign. At last follow‐up, 5% of patients had visual acuity ≤0.1. Brain MRI remained unchanged in 41 patients (87%). Conclusions: Our study supports a mostly benign ophthalmological course of MOG‐IgG‐associated ON, despite initially longitudinally extensive lesions and development of optic nerve atrophy on orbital MRI. Spinal MRI could be of interest in detecting silent suggestive lesions. [ABSTRACT FROM AUTHOR]

Background: Acute optic neuritis (AON) is a common optic nerve disease leading to retrograde degeneration of optic nerve axons, reflected by thinning of the inner retinal layers on optical coherence tomography. On the contrary, acute macular neuroretinopathy (AMN) type 2 is a rare outer retinal disorder that leads to thinning of the outer nuclear layers and is diagnosed by multimodal imaging. The aim of this study was to report a new association between these two diseases. Methods: Patients with a first episode of optic neuritis were invited to participate in a study that involved optical coherence tomography evaluation at baseline and the following 1, 3, 6 and 12 months. All the study patients underwent ophthalmologic evaluation that comprised of visual acuity, visual field and multimodal imaging as well as orbital and brain Magnetic Resonance Imaging. A diagnosis of multiple sclerosis was made according to the 2010 McDonald criteria. Results: Six of the 114 patients with acute optic neuritis also had acute macular neuroretinopathy, of whom three were positive for myelin oligodendrocyte glycoprotein antibodies (MOG‐Abs), two had relapsing–remitting multiple sclerosis and one had clinical isolated syndrome. Conclusion: Our study suggests that it is imperative to check for associated AMN in cases of AON, especially those associated with MOG‐Abs. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%. While pancreatic cancer is particularly difficult to treat, patients usually succumb not to the growth of the primary tumor, but to extensive metastasis; therefore, strategies to reduce the migratory and metastatic capacity of pancreatic cancer cells merit close attention. The vast majority of pancreatic cancers harbor RAS mutations. The outstanding relevance of the RAS/MEK/ERK pathway in pancreatic cancer biology has been extensively shown previously. Due to their high dependency on Ras mutations, pancreatic cancers might be particularly sensitive to inhibitors acting downstream of Ras. Herein, we use a genetically engineered mouse model of pancreatic cancer and primary pancreatic cancer cells were derived from this model to demonstrate that small-molecule MEK inhibitors functionally abrogate cancer stem cell populations as demonstrated by reduced sphere and organoid formation capacity. Furthermore, we demonstrate that MEK inhibition suppresses TGFβ-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is still the Achilles heel in modern oncology, with an increasing incidence accompanied by a persisting high mortality. The developmental process of PDAC is thought to be stepwise via precursor lesions and sequential accumulation of mutations. Thereby, current sequencing studies recapitulate this genetic heterogeneity in PDAC and show besides a handful of driver mutations (KRAS, TP53) a plethora of passenger mutations that allow to define subtypes. However, modeling the mutations of interest and their effects is still challenging. Interestingly, organoids have the potential to recapitulate in vitro, the in vivo characteristics of the tissue they originate from. Here, we could establish and develop tools allowing us to isolate, culture, and genetically modify ductal mouse organoids. Transferred to known effectors in the IPMN-PDAC sequence, we could reveal significantly increased proliferative and self-renewal capacities for PTEN and RNF43 deficiency in the context of oncogenic KRASG12D in mouse pancreatic organoids. Overall, we were able to obtain promising data centering ductal organoids in the focus of future PDAC research. [ABSTRACT FROM AUTHOR]

An investigation directed towards the preparation of α‐substituted propargyl thioureas from the corresponding propargylamine resulted in a tandem thioacylation/anti‐hydrosulfenylation and the formation of the corresponding thiazolidine in excellent (46–98 %) yields rather than the anticipated thiourea. Initial interpretation of this outcome was formulated in terms of the highly substituted nature of the α‐carbon of these amines resulting in steric acceleration, however, even simple propargylamines engage in this chemistry. In light of these observations, it was determined subsequently that the formation of the thiourea is quite rapid, but cyclization occurred during chromatographic purification and is in fact facilitated by silica gel. Control reactions and monitoring the progress of the reaction by NMR spectroscopy clearly indicate that the cyclization is relatively slow until either purification or the introduction of silica gel results in cyclization. Subsequently, it was found that even the parent system afforded the thiazolidine when the reaction was conducted on silica gel. Overall, the reaction is tolerant of a variety of substitution patterns, internal and terminal alkynes and isothiocyanates providing rapid access to 2‐aminothiazolidines. A metal‐free coupling reaction between propargylamines and isothiocyanates affords good yields of vinylidene substituted thiazolidines. Control reactions suggest that these reactions are in fact mediated by silica gel. A broad substrate scope and a variety of substitution patterns are accessible. [ABSTRACT FROM AUTHOR]

Background and purpose: Few recent data are available concerning idiopathic optic neuritis (ON). We aimed to describe a large cohort of patients with idiopathic ON. We compared this cohort with patients with ON related to myelin oligodendrocyte glycoprotein (MOG) or ON related to aquaporin‐4 (AQP4) antibodies. Methods: This was a monocentric retrospective observational study. Inclusion criteria for idiopathic ON were as follows: age ≥ 16 years, follow‐up of at least 2 years, negative for antibodies against MOG and AQP4 immunoglobulin G, and no magnetic resonance imaging (MRI) lesions suggestive of demyelination (two brain MRI scans, one at baseline and one during follow‐up, and one spinal cord MRI scan). Results: Among 23 patients with idiopathic ON (female, 82.6%; median age, 36 years; median follow‐up time, 41.4 months), 56.5% had recurrent ON (median time to a second ON episode, 6 months). The final visual acuity in this group (median, 0; mean, 0.43; range, 0–3) was similar to that in the AQP4 group (n = 18; P‐value after Bonferroni correction = 0.936) but worse than that in the MOG group (n = 25; P‐value after Bonferroni correction = 0.019). At the last evaluation, visual acuity levels were ≤0.5 and <0.2, respectively, in 36.8% and 21% of the idiopathic ON group, 58.3% and 26.7% of the AQP4 group, and 0% and 0% of the MOG group. Conclusion: The recovery of visual acuity among patients with idiopathic ON was poor, similar to that observed in the AQP4 group. Click here to view the accompanying paper in this volume. [ABSTRACT FROM AUTHOR]

Objective: Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease characterized by the production of various autoantibodies. The aim of this study was to investigate the presence of anti-ficolin-2 antibodies in SLE patients and to evaluate the association between the levels of these autoantibodies, clinical manifestations, and disease activity.Methods: This is a comparative study using a cohort of 165 SLE patients and 48 healthy subjects. SLE patients were further divided into 2 groups (low disease activity [SLE Disease Activity Index (SLEDAI) score ≤4, n = 88] and high disease activity [SLEDAI score >4, n = 77]). Clinical manifestations were defined according to the physician in charge. Active lupus nephritis (LN) was documented by kidney biopsy. Detection of anti-ficolin-2 antibodies was performed by enzyme-linked immunosorbent assay.Results: Levels of anti-ficolin-2 autoantibodies were significantly higher in SLE patients as compared to healthy subjects and associated with SLEDAI score. They were found to be positive in 61 of 165 SLE patients (37%). The presence of anti-ficolin-2 antibodies was significantly related only to renal involvement, with a very high prevalence (86%) of anti-ficolin-2 antibodies in SLE patients with active LN. Patients with active proliferative LN had significantly more positive anti-ficolin-2 antibodies than those with nonproliferative LN. The combination of anti-ficolin-2, anti-ficolin-3, and anti-C1q demonstrated a very high specificity (98%) for the diagnosis of active LN.Conclusion: Our results support the usefulness of anti-ficolin-2 as a complementary serologic biomarker for the diagnosis of active lupus with renal manifestations. [ABSTRACT FROM AUTHOR]

Aneustat (OMN54) is a multivalent, botanical anticancer candidate therapeutic. A recent Phase‐I clinical trial has indicated that it is well tolerated by patients and has immunomodulatory activity. In our study, using in vitro and in vivo prostate cancer models, we investigated Aneustat with regard to effects on (i) cancer‐generated immunosuppression based on aerobic glycolysis leading to acidification of the tumor microenvironment, and (ii) immune‐related processes such as macrophage differentiation and shifts in the intratumoral levels of host immune cells. Aneustat markedly reduced glucose consumption, lactic acid secretion, glycolysis‐related gene expressions and proliferation of human LNCaP prostate cancer cells. In addition, Aneustat induced differentiation of RAW264.7 macrophages to the M1 anticancer phenotype. Treatment of LNCaP xenografts and first‐generation patient‐derived prostate cancer tissue xenografts with Aneustat in both cases led to a marked shift in intratumoral host (mouse/patient) immune cell levels: a higher ratio of cytotoxic CD8+ T/Treg cells, higher numbers of NK cells, lower numbers of Treg cells and MDSCs, i.e. changes favoring the host anticancer immune response. Taken together, the data indicate that Aneustat has immunomodulatory activity based on inhibition of aerobic glycolysis which in patients may lead to reduction of cancer‐induced immunosuppression. Furthermore, first‐generation patient‐derived cancer tissue xenograft models may be used for screening compounds for immunomodulatory activity. [ABSTRACT FROM AUTHOR]

Abstract: Development of neuroendocrine prostate cancer (NEPC) is emerging as a major problem in clinical management of advanced prostate cancer (PCa). As increasingly potent androgen receptor (AR)‐targeting antiandrogens are more widely used, PCa transdifferentiation into AR‐independent NEPC as a mechanism of treatment resistance becomes more common and precarious, since NEPC is a lethal PCa subtype urgently requiring effective therapy. Reprogrammed glucose metabolism of cancers, that is elevated aerobic glycolysis involving increased lactic acid production/secretion, plays a key role in multiple cancer‐promoting processes and has been implicated in therapeutics development. Here, we examined NEPC glucose metabolism using our unique panel of patient‐derived xenograft PCa models and patient tumors. By calculating metabolic pathway scores using gene expression data, we found that elevated glycolysis coupled to increased lactic acid production/secretion is an important metabolic feature of NEPC. Specific inhibition of expression of MCT4 (a plasma membrane lactic acid transporter) by antisense oligonucleotides led to reduced lactic acid secretion as well as reduced glucose metabolism and NEPC cell proliferation. Taken together, our results indicate that elevated glycolysis coupled to excessive MCT4‐mediated lactic acid secretion is clinically relevant and functionally important to NEPC. Inhibition of MCT4 expression appears to be a promising therapeutic strategy for NEPC. [ABSTRACT FROM AUTHOR]

Background and purpose New criteria for the diagnosis of multiple sclerosis ( MS) and discovery of myelin oligodendrocyte glycoprotein ( MOG) or aquaporin-4 ( AQP4) antibodies (Abs) have changed the management of optic neuritis ( ON). Our aim was to specify, in view of these recent advances, the etiologies of acute demyelinating ON for consecutive patients. Methods Retrospective database analysis was undertaken of consecutive adult patients with acute ON admitted from 1 December 2014 to 31 January 2016. Diagnosis of MS was made according to the 2010 McDonald criteria. Patients with Abs to AQP4 or MOG were classified as ON- AQP4 and ON- MOG, respectively. Patients who did not fulfill the diagnostic criteria and were negative for AQP4 and MOG Ab tests were classified as having idiopathic ON. Results Of 110 patients assessed, 78 had ON related to MS (70.9%). All patients without MS were tested for AQP4 and MOG Abs: 11 had MOG Ab (10%), 5 had AQP4 Ab (4.5%) and 16 were considered as having idiopathic ON (14.5%). Presence of intrathecal IgG oligoclonal bands was strongly associated with MS (mean, 88.4% vs. 34.4% in patients without MS; after Bonferroni correction, P < 0.0001). Conclusions Optic neuritis related to MOG Ab was the second cause identified of demyelinating ON in our center. Idiopathic ON was as frequent as both ON- AQP4 and ON- MOG combined. [ABSTRACT FROM AUTHOR]

Objective: To develop a new composite disease activity score for gout and provide its first validation.Methods: Disease activity has been defined as the ongoing presence of urate deposits that lead to acute arthritis and joint damage. Every measure for each Outcome Measures in Rheumatology core domain was considered. A 3-step approach (factor analysis, linear discriminant analysis, and linear regression) was applied to derive the Gout Activity Score (GAS). Decision to change treatment or 6-month flare count were used as the surrogate criteria of high disease activity. Baseline and 12-month followup data of 446 patients included in the Kick-Off of the Italian Network for Gout cohort were used. Construct- and criterion-related validity were tested. External validation on an independent sample is reported.Results: Factor analysis identified 5 factors: patient-reported outcomes, joint examination, flares, tophi, and serum uric acid (sUA). Discriminant function analysis resulted in a correct classification of 79%. Linear regression analysis identified a first candidate GAS including 12-month flare count, sUA, visual analog scale (VAS) of pain, VAS global activity assessment, swollen and tender joint counts, and a cumulative measure of tophi. Alternative scores were also developed. The developed GAS demonstrated a good correlation with functional disability (criterion validity) and discrimination between patient- and physician-reported measures of active disease (construct validity). The results were reproduced in the external sample.Conclusion: This study developed and validated a composite measure of disease activity in gout. Further testing is required to confirm its generalizability, responsiveness, and usefulness in assisting with clinical decisions. [ABSTRACT FROM AUTHOR]

Centromere protein-A (CENP-A), a histone-H3 variant, plays an essential role in cell division by ensuring proper formation and function of centromeres and kinetochores. Elevated CENP-A expression has been associated with cancer development. This study aimed to establish whether elevated CENP-A expression can be used as a prognostic and predictive cancer biomarker. Molecular profiling of CENP-A in human cancers was investigated using genomic, transcriptomic and patient information from databases, including COSMIC, Oncomine, Kaplan-Meier plotter and cBioPortal. A network of CENP-A co-expressed genes was derived from cBioPortal and analyzed using Ingenuity Pathway Analysis (IPA) and Oncomine protocols to explore the function of CENP-A and its predictive potential. Transcriptional and post-transcriptional regulation of CENP-A expression was analyzed in silico. It was found that CENP-A expression was elevated in 20 types of solid cancer compared with normal counterparts. Elevated CENP-A expression highly correlated with cancer progression and poor patient outcome. Genomic analysis indicated that the elevated CENP-A expression was not due to alterations in the sequence or copy number of the CENP-A gene. Furthermore, CENP-A can be regulated by key oncogenic proteins and tumor-suppressive microRNAs. CENP-A co-expression network analysis indicated that CENP-A function is associated with cell cycle progression. Oncomine analysis showed a strong correlation between elevated CENP-A expression and oncolytic response of breast cancer patients to taxane-based chemotherapy. In conclusion, elevated CENP-A expression is coupled to malignant progression of numerous types of cancer. It may be useful as a biomarker of poor patient prognosis and as a predictive biomarker for taxane-based chemotherapy. [ABSTRACT FROM AUTHOR]

This study describes normal fault zones formed in foreland arkosic turbidites (the Grès d'Annot Formation, SW French Alps) under deep diagenesis conditions (~200 °C) and highlights the occurrence of two markedly different fault-rock types: (1) the foliated fault rocks of the Moutière-Restefond area; and (2) the dilatant fault rocks of the Estrop area. The deformation of (1) is dominated by intra- and transgranular fracturing, pressure solution of quartz and feldspar grains and syn-kinematic phyllosilicate precipitation resulting from feldspar alteration. The combination of these mechanisms results in a strongly anisotropic strain with intense shortening normal to the foliation (pressure solution) and extension parallel to the foliation (quartz- and calcite-sealed extension veins). This deformation implies local mass transfer that may be achieved without (or with limited) volume change. The deformation of (2) is expressed as dilatant quartz-sealed veins and breccia textures in which the main mechanisms are transgranular fracturing and quartz precipitation. Type (2) implies fault volume increase, isotropy of deformation and mass transfer at distances larger than in type (1). This study discusses the origins of (1) and (2) and shows that the permeability of (1) is anisotropic, with higher values than the host rocks parallel to the Y main deformation axis (i.e. perpendicular to the slip vector), whereas the permeability of (2) is isotropic and equivalent to that of the host rocks. [ABSTRACT FROM AUTHOR]

A supramolecular approach to model the active sites of metalloenzymes is to associate a cavity with a tripodal coordination core. One key feature of many enzymes is the possible binding of two different ligands in cis positions relative to each other, which has not yet been described for cavity complexes. Here, the bowl shape of resorcinarene allows such a coordination environment for ZnII complexes. A detailed NMR study with various carboxylic acids evidences size-, shape-, and, thus, regioselectivity for carboxylate coordination in the endo position, the exo position, or both. The coordination of diketonates unambiguously demonstrates the relative cis position of the two labile sites present in the tris(imidazole)zinc(II) bowl complex. An interesting intramolecular exchange process was also observed. Finally, a comparison with calix[6]arene-based complexes (so-called funnel complexes) further highlights the key role of the cavity in the control of properties of the metal ion. [ABSTRACT FROM AUTHOR]

The current first‐line treatment for advanced metastatic prostate cancer, i.e. docetaxel‐based therapy, is only marginally effective. The aim of the present study was to determine whether such therapy can be improved by combining docetaxel with Aneustat (OMN54), a multivalent botanical drug candidate shown to have anti‐prostate cancer activity in preliminary in vitro experiments, which is currently undergoing a Phase‐I Clinical Trial. Human metastatic, androgen‐independent C4‐2 prostate cancer cells and NOD‐SCID mice bearing PTEN‐deficient, metastatic and PSA‐secreting, patient‐derived subrenal capsule LTL‐313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, alone and in combination. In vitro, Aneustat markedly inhibited C4‐2 cell replication in a dose‐dependent manner. When Aneustat was combined with docetaxel, the growth inhibitions of the drugs were essentially additive. In vivo, however, the combination of docetaxel and Aneustat enhanced anti‐tumor activity synergistically and very markedly, without inducing major host toxicity. Complete growth inhibition and shrinkage of the xenografts could be obtained with the combined drugs as distinct from the drugs on their own. Analysis of the gene expression of the xenografts using microarray indicated that docetaxel + Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the single drugs. Our findings, obtained with a highly clinically relevant prostate cancer model, suggest, for the first time, that docetaxel‐based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat. Highlights: First‐line, docetaxel‐based therapy of advanced prostate cancer is only marginally effective.The efficacy of docetaxel combined with Aneustat was determined in a metastatic xenograft model.Anti‐tumor activity was synergistically and markedly enhanced without major host toxicity.Gene expression analysis indicated docetaxel + Aneustat led to expanded anticancer activity.Docetaxel‐based therapy of advanced prostate cancer may be improved by combining docetaxel with Aneustat. [ABSTRACT FROM AUTHOR]

The coordination of CuI to a poly(imidazole) core is of the most importance in biology as it is present in most enzymes as well as in peptides involved in pathological processes. Here, we report a detailed study of the binding of CuI to a tris(imidazole) core constructed on a resorcinarene scaffold. NMR and IR spectroscopy as well as cyclic voltammetry have been used to characterize the different species obtained in solution as a function of the presence or absence of exogenous ligands, mainly CO and MeCN, but also Cl-. Within the resorcinarene scaffold, the metal ion can switch from a dynamic two-coordinate to a four-coordinate environment upon binding to a π acceptor. A comparison with previously reported calix[6]arene-based tris(imidazole) Cu complexes highlights several key points: (1) the importance of the shape and size of the macrocycle that forms the pocket in which the metal center is partly embedded, (2) the importance of the flexibility of the system as it undergoes induced-fit processes (calixarene) or not (resorcinarene), (3) the consequences on the affinity of the metal center for CO and MeCN in relation to its π-backbonding capabilities, and finally (4), the redox behavior of the system. [ABSTRACT FROM AUTHOR]

Optic Neuritis (ON) has been associated to both parvocellular dysfunction and to an alteration of the magnocellular pathway. After objective visual field and acuity recovery, ON patients may complain about their vision suggesting a residual subclinical deficit. To better characterize visual abnormalities, 8 patients recovering from a first ON episode as well as 16 healthy controls performed a simple detection task and a more complex categorization task of images presented in low spatial frequencies (to target the magnocellular system) or in high spatial frequencies (to target the parvocellular system) or of non-filtered images. When completing the tasks with their (previously) pathologic eye, optic neuritis patients showed lower accuracy compared to controls or to their healthy eye for low spatial frequency images only. Conjointly, the longest reaction times were observed with the previously pathologic eye regardless the type of images and to a greater extent in the categorization task than in the detection task. Such data suggest two distinct, although associated, types of residual dysfunction in ON: a magnocellular pathway alteration and a more general (magno and parvocellular) visual dysfunction that could implicate the cognitive levels of visual processing. [ABSTRACT FROM AUTHOR]

The common preference of cancers for lactic acid-generating metabolic energy pathways has led to proposals that their reprogrammed metabolism confers growth advantages such as decreased susceptibility to hypoxic stress. Recent observations, however, suggest that it generates a novel way for cancer survival. There is increasing evidence that cancers can escape immune destruction by suppressing the anti-cancer immune response through maintaining a relatively low pH in their micro-environment. Tumours achieve this by regulating lactic acid secretion via modification of glucose/glutamine metabolisms. We propose that the maintenance by cancers of a relatively low pH in their micro-environment, via regulation of their lactic acid secretion through selective modification of their energy metabolism, is another major mechanism by which cancers can suppress the anti-cancer immune response. Cancer-generated lactic acid could thus be viewed as a critical, immunosuppressive metabolite in the tumour micro-environment rather than a 'waste product'. This paradigm shift can have major impact on therapeutic strategy development. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The race structure and genotypic diversity of four Leptosphaeria maculans populations isolated from Brassica oleracea (broccoli, cauliflower, cabbage, etc.) in central Mexico (Aguascalientes, Guanajuato and Zacatecas states) were analysed. Race structure was characterized by an unusually low diversity at three locations out of four. Fourteen minisatellite markers revealed a high proportion of repeated multilocus genotypes in these populations, combined with a significant linkage disequilibrium and strong clonal fraction (65-87%). The occurrence of the mating-type idiomorphs always significantly departed from the 1:1 proportion expected in the case of random mating. Each population thus consists of a few (four to nine) multilocus genotypes which are specific to each location. These data strongly support the hypothesis of exclusive, or a high rate of, clonal multiplication. Comparison of cropping practices between B. oleracea and B. napus indicate that the shift in reproductive behaviour of the fungus is chiefly man-mediated. [ABSTRACT FROM AUTHOR]

ABSTRACT Although there is now a considerable literature on the inhibition of leaf respiration (CO2 evolution) by light, little is known about the effect of other environmental conditions on day respiratory metabolism. In particular, CO2 and O2 mole fractions are assumed to cause changes in the tricarboxylic acid pathway (TCAP) but the amplitude and even the direction of such changes are still a matter of debate. Here, we took advantage of isotopic techniques, new simple equations and instant freeze sampling to follow respiratory metabolism in illuminated cocklebur leaves ( Xanthium strumarium L.) under different CO2/O2 conditions. Gas exchange coupled to online isotopic analysis showed that CO2 evolved by leaves in the light came from 'old' carbon skeletons and there was a slight decrease in 13C natural abundance when [CO2] increased. This suggested the involvement of enzymatic steps fractionating more strongly against 13C and thus increasingly limiting for the metabolic respiratory flux as [CO2] increased. Isotopic labelling with 13C2-2,4-citrate lead to 13C-enriched Glu and 2-oxoglutarate (2OG), clearly demonstrating poor metabolism of citrate by the TCAP. There was a clear relationship between the ribulose-1,5-bisphosphate oxygenation-to-carboxylation ratio ( vo/ vc) and the 13C commitment to 2OG, demonstrating that 2OG and Glu synthesis via the TCAP is positively influenced by photorespiration. [ABSTRACT FROM AUTHOR]

Abstract: Coenzyme A synthase (CoAsy) is a bifunctional enzyme which facilitates the last two steps of Coenzyme A biogenesis in higher eukaryotes. Here we describe that CoAsy forms a complex with enhancer of mRNA-decapping protein 4 (EDC4), a central scaffold component of processing bodies. CoAsy/EDC4 complex formation is regulated by growth factors and is affected by cellular stresses. EDC4 strongly inhibits the dephospho-CoA kinase activity of CoAsy in vitro. Transient overexpression of EDC4 decreases cell proliferation, and further co-expression of CoAsy diminishes this effect. Here we report that EDC4 might contribute to regulation of CoA biosynthesis in addition to its scaffold function in processing bodies. Structured summary of protein interactions: CoAsy physically interacts with EDC4 by anti bait coimmunoprecipitation (View Interaction: 1, 2, 3) [Copyright &y& Elsevier]

Untransformed HTLV-1 positive CD4+ cells from infected individuals are selected for expressing tax and displaying morphological features consistent with telomere dysfunctions. We show that in resting HTLV-1 positive CD4+ cells cloned from patients, hTERT expression parallels tax expression and cell cycling. Upon activation, these cells dramatically augment tax expression, whereas their increase in telomerase activity is about 20 times lower than that of their uninfected counterpart. Activated HTLV-1 positive CD4+ but not uninfected CD4+ or CD8+ clones also repress the transcription of TRF1, TPP1, TANK1, POT1, DNA-PKc and Ku80. Both infected and uninfected lymphocytes from infected individuals shared common telomere gene deregulations toward a pattern consistent with premature senescence. ATLL cells displayed the highest telomerase activity (TA) whereas recovered a telomere gene transcriptome close to that of normal CD4+ cells. In conclusion HTLV-1-dependent telomere modulations seem involved in clonal expansion, immunosuppression, tumor initiation and progression. [ABSTRACT FROM AUTHOR]

Pathogen introductions into novel areas can lead to the emergence of new fungal diseases of plants. Understanding the origin, introduction pathways, possible changes in reproductive system and population size of fungal pathogens is essential in devising an integrated strategy for the control of these diseases. We used minisatellite markers to infer the worldwide invasion history of the fungal plant pathogen Leptosphaeria maculans, which causes stem canker (blackleg) of oilseed and vegetable brassicas. Clustering analyses partitioned genotypes into distinct populations corresponding to major geographic regions, along with two differentiated populations in Western Canada. Comparison of invasion scenarios using Approximate Bayesian Computation suggested an origin of the pathogen in the USA, the region where epidemics were first recorded, and independent introductions from there over the last few decades into Eastern Canada (Ontario), Europe and Australia. The population in Western Canada appeared to be founded from a source in Ontario and the population in Chile resulted from an admixture between multiple sources. A bottleneck was inferred for the introduction into Western Canada but not into Europe, Ontario or Australia. Clonality appeared high in Western Canada, possibly because environmental conditions there were less conducive to sexual reproduction. Leptosphaeria maculans is a model invasive pathogen with contrasting features in different regions: shallow population structure, high genetic variability and regular sexual recombination in some regions, by comparison with reduced genetic variability, high rates of asexual multiplication, strong population structure or admixture in others. [ABSTRACT FROM AUTHOR]

Inorganic phosphate (Pi) homeostasis in multi-cellular eukaryotes depends not only on Pi influx into cells, but also on Pi efflux. Examples in plants for which Pi efflux is crucial are transfer of Pi into the xylem of roots and release of Pi at the peri-arbuscular interface of mycorrhizal roots. Despite its importance, no protein has been identified that specifically mediates phosphate efflux either in animals or plants. The Arabidopsis thaliana PHO1 gene is expressed in roots, and was previously shown to be involved in long-distance transfer of Pi from the root to the shoot. Here we show that PHO1 over-expression in the shoot of A. thaliana led to a two- to threefold increase in shoot Pi content and a severe reduction in shoot growth. P-NMR in vivo showed a normal initial distribution of intracellular Pi between the cytoplasm and the vacuole in leaves over-expressing PHO1, followed by a large efflux of Pi into the infiltration medium, leading to a rapid reduction of the vacuolar Pi pool. Furthermore, the Pi concentration in leaf xylem exudates from intact plants was more than 100-fold higher in PHO1 over-expressing plants compared to wild-type. Together, these results show that PHO1 over-expression in leaves leads to a dramatic efflux of Pi out of cells and into the xylem vessel, revealing a crucial role for PHO1 in Pi efflux. [ABSTRACT FROM AUTHOR]

Inorganic phosphate (Pi) is one of the most limiting nutrients for plant growth in both natural and agricultural contexts. Pi-deficiency leads to a strong decrease in shoot growth, and triggers extensive changes at the developmental, biochemical and gene expression levels that are presumably aimed at improving the acquisition of this nutrient and sustaining growth. The Arabidopsis thaliana PHO1 gene has previously been shown to participate in the transport of Pi from roots to shoots, and the null pho1 mutant has all the hallmarks associated with shoot Pi deficiency. We show here that A. thaliana plants with a reduced expression of PHO1 in roots have shoot growth similar to Pi-sufficient plants, despite leaves being strongly Pi deficient. Furthermore, the gene expression profile normally triggered by Pi deficiency is suppressed in plants with low PHO1 expression. At comparable levels of shoot Pi supply, the wild type reduces shoot growth but maintains adequate shoot vacuolar Pi content, whereas the PHO1 underexpressor maintains maximal growth with strongly depleted Pi reserves. Expression of the Oryza sativa (rice) PHO1 ortholog in the pho1 null mutant also leads to plants that maintain normal growth and suppression of the Pi-deficiency response, despite the low shoot Pi. These data show that it is possible to unlink low shoot Pi content with the responses normally associated with Pi deficiency through the modulation of PHO1 expression or activity. These data also show that reduced shoot growth is not a direct consequence of Pi deficiency, but is more likely to be a result of extensive gene expression reprogramming triggered by Pi deficiency. [ABSTRACT FROM AUTHOR]

•Nitrogen assimilation in leaves requires primary NH2 acceptors that, in turn, originate from primary carbon metabolism. Respiratory metabolism is believed to provide such acceptors (such as 2-oxoglutarate), so that day respiration is commonly seen as a cornerstone for nitrogen assimilation into glutamate in illuminated leaves. However, both glycolysis and day respiratory CO2 evolution are known to be inhibited by light, thereby compromising the input of recent photosynthetic carbon for glutamate production. •In this study, we carried out isotopic labelling experiments with 13CO2 and 15N-ammonium nitrate on detached leaves of rapeseed ( Brassica napus), and performed 13C- and 15N-nuclear magnetic resonance analyses. •Our results indicated that the production of 13C-glutamate and 13C-glutamine under a 13CO2 atmosphere was very weak, whereas 13C-glutamate and 13C-glutamine appeared in both the subsequent dark period and the next light period under a 12CO2 atmosphere. Consistently, the analysis of heteronuclear (13C–15N) interactions within molecules indicated that most 15N-glutamate and 15N-glutamine molecules were not 13C labelled after 13C/15N double labelling. That is, recent carbon atoms (i.e. 13C) were hardly incorporated into glutamate, but new glutamate molecules were synthesized, as evidenced by 15N incorporation. •We conclude that the remobilization of night-stored molecules plays a significant role in providing 2-oxoglutarate for glutamate synthesis in illuminated rapeseed leaves, and therefore the natural day : night cycle seems critical for nitrogen assimilation. [ABSTRACT FROM AUTHOR]

Human type 3 adenovirus dodecahedron (a virus like particle made of twelve penton bases) features the ability to enter cells through Heparan Sulphate Proteoglycans (HSPGs) and integrins interaction and is used as a versatile vector to deliver DNA or proteins. Cryo-EM reconstruction of the pseudoviral particle with Heparan Sulphate (HS) oligosaccharide shows an extradensity on the RGD loop. A set of mutants was designed to study the respective roles of the RGD sequence (RGE mutant) and of a basic sequence located just downstream. Results showed that the RGE mutant binding to the HS deficient CHO-2241 cells was abolished and unexpectedly, mutation of the basic sequence (KQKR to AQAS) dramatically decreased integrin recognition by the viral pseudoparticle. This basic sequence is thus involved in integrin docking, showing a close interplay between HSPGs and integrin receptors. [ABSTRACT FROM AUTHOR]