Green synthesis and characterization of ruthenium oxide nanoparticles using Gunnera perpensa for potential anticancer activity against MCF7 cancer cells.

The use of green methods for ruthenium oxide nanoparticles (RuONPs) synthesis is gaining attention due to their eco-friendliness, cost-effectiveness, and availability. However, reports on the green synthesis and characterization of RuONPs are limited compared to other metal nanoparticles. The green synthesis and characterization of RuONPs using water extracts of Gunnera perpensa leaves as a reducing agent is reported in this study. The RuONPs were characterized using X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and Ultraviolet spectroscopy (UV-VIS). MTT assay was used to assess the cytotoxicity of the RuONPs against MCF7 and Vero cell lines. X-ray diffraction analysis results revealed the presence of crystalline and amorphous forms of RuONPs, while IR spectroscopy revealed the presence of functional groups associated with G. perpensa leaves. SEM showed that the RuONPs consisted predominantly of hexagonal and cuboid-like structures with a considerable degree of agglomeration being observed. The cell culture results indicated a low anticancer efficacy of RuONPs against MCF7 and Vero cell lines, suggesting that RuONPs may not be a good lead for anti-cancer drugs. This study highlights the potential of using green synthesis methods to produce RuONPs and their characterization, as well as their cytotoxicity against cancer cells.

Mars 2020 Perseverance Rover Studies of the Martian Atmosphere Over Jezero From Pressure Measurements.

The pressure sensors on Mars rover Perseverance measure the pressure field in the Jezero crater on regular hourly basis starting in sol 15 after landing. The present study extends up to sol 460 encompassing the range of solar longitudes from L s  âˆ¼ 13°-241° (Martian Year (MY) 36). The data show the changing daily pressure cycle, the sol-to-sol seasonal evolution of the mean pressure field driven by the CO2 sublimation and deposition cycle at the poles, the characterization of up to six components of the atmospheric tides and their relationship to dust content in the atmosphere. They also show the presence of wave disturbances with periods 2-5 sols, exploring their baroclinic nature, short period oscillations (mainly at night-time) in the range 8-24 min that we interpret as internal gravity waves, transient pressure drops with duration ∼1-150 s produced by vortices, and rapid turbulent fluctuations. We also analyze the effects on pressure measurements produced by a regional dust storm over Jezero at L s  âˆ¼ 155°.

Mesorectal failure after chemoradiotherapy for squamous cell carcinoma of the anus: is sphincter-saving surgery reasonable?

BACKGROUND: Abdominoperineal resection (APR) is today the standard treatment for improving survival in case of mesorectal failure without anal canal recurrence after chemoradiotherapy (CRT) for squamous cell carcinoma of the anus (SCC). The aim of this study was to assess if a sphincter-saving surgery is a safe alternative to classical salvage APR in these patients. METHODS: A retrospective study was conducted on all patients who had total mesorectal excision (TME) with sphincter-saving surgery either with coloanal or low colorectal anastomosis, for mesorectal failure after CRT for SCC between 2012 and 2020 at our institution. The main endpoint of our study was oncological results at the end of follow-up. Postoperative morbidity and mortality were secondary endpoints. RESULTS: There were 10 patients, (8 women, median age 55 years [range 45-61 years]). On TME specimens, R0 resections were noted in five (50%), R1 resection in four (40%) and R2 resection in one (10%). After a median follow-up of 42 months (4-74 months), five patients were alive, and four (40%) were alive at 5-year follow-up. During follow-up, locoregional failure after TME was noted in two patients (20%), distant relapse in three patients (30%) and both locoregional plus distant failure in two patients (20%). Only two patients (20%) had anal recurrence, one in the anal canal, the other in the peri-anastomotic area. Long- term local control was achieved in 2 of the 5 patients (40%) who underwent R0 resection versus only 1/4 patients (25%) with R1 resection. CONCLUSIONS: Our preliminary study suggested that sphincter-saving surgery could be proposed in selected patients with SCC presenting mesorectal failure after CRT, providing a feasible R0 resection.

The sound of a Martian dust devil.

Dust devils (convective vortices loaded with dust) are common at the surface of Mars, particularly at Jezero crater, the landing site of the Perseverance rover. They are indicators of atmospheric turbulence and are an important lifting mechanism for the Martian dust cycle. Improving our understanding of dust lifting and atmospheric transport is key for accurate simulation of the dust cycle and for the prediction of dust storms, in addition to being important for future space exploration as grain impacts are implicated in the degradation of hardware on the surface of Mars. Here we describe the sound of a Martian dust devil as recorded by the SuperCam instrument on the Perseverance rover. The dust devil encounter was also simultaneously imaged by the Perseverance rover's Navigation Camera and observed by several sensors in the Mars Environmental Dynamics Analyzer instrument. Combining these unique multi-sensorial data with modelling, we show that the dust devil was around 25 m large, at least 118 m tall, and passed directly over the rover travelling at approximately 5 m s-1. Acoustic signals of grain impacts recorded during the vortex encounter provide quantitative information about the number density of particles in the vortex. The sound of a Martian dust devil was inaccessible until SuperCam microphone recordings. This chance dust devil encounter demonstrates the potential of acoustic data for resolving the rapid wind structure of the Martian atmosphere and for directly quantifying wind-blown grain fluxes on Mars.

Dust, Sand, and Winds Within an Active Martian Storm in Jezero Crater.

Rovers and landers on Mars have experienced local, regional, and planetary-scale dust storms. However, in situ documentation of active lifting within storms has remained elusive. Over 5-11 January 2022 (LS 153°-156°), a dust storm passed over the Perseverance rover site. Peak visible optical depth was ∼2, and visibility across the crater was briefly reduced. Pressure amplitudes and temperatures responded to the storm. Winds up to 20 m s-1 rotated around the site before the wind sensor was damaged. The rover imaged 21 dust-lifting events-gusts and dust devils-in one 25-min period, and at least three events mobilized sediment near the rover. Rover tracks and drill cuttings were extensively modified, and debris was moved onto the rover deck. Migration of small ripples was seen, but there was no large-scale change in undisturbed areas. This work presents an overview of observations and initial results from the study of the storm.

In situ recording of Mars soundscape.

Before the Perseverance rover landing, the acoustic environment of Mars was unknown. Models predicted that: (1) atmospheric turbulence changes at centimetre scales or smaller at the point where molecular viscosity converts kinetic energy into heat1, (2) the speed of sound varies at the surface with frequency2,3 and (3) high-frequency waves are strongly attenuated with distance in CO2 (refs. 2-4). However, theoretical models were uncertain because of a lack of experimental data at low pressure and the difficulty to characterize turbulence or attenuation in a closed environment. Here, using Perseverance microphone recordings, we present the first characterization of the acoustic environment on Mars and pressure fluctuations in the audible range and beyond, from 20 Hz to 50 kHz. We find that atmospheric sounds extend measurements of pressure variations down to 1,000 times smaller scales than ever observed before, showing a dissipative regime extending over five orders of magnitude in energy. Using point sources of sound (Ingenuity rotorcraft, laser-induced sparks), we highlight two distinct values for the speed of sound that are about 10 m s-1 apart below and above 240 Hz, a unique characteristic of low-pressure CO2-dominated atmosphere. We also provide the acoustic attenuation with distance above 2 kHz, allowing us to explain the large contribution of the CO2 vibrational relaxation in the audible range. These results establish a ground truth for the modelling of acoustic processes, which is critical for studies in atmospheres such as those of Mars and Venus.

Discontinuation of tyrosine kinase inhibitor in chronic myeloid leukemia: a retrospective cohort in east occitania.

Tyrosine kinase inhibitor (TKI) discontinuation in chronic phase chronic myeloid leukemia (CML) patients has been examined in a real-life setting in the east occitania region of France. We have collected sex, age, prognostic scores, pre-TKI treatment, TKI length and response, relapse data from patients who had stopped TKI in prolonged complete molecular remission (CMR), and analyzed relapse risk factors. Sixty consecutive patients were included from january 2010 to december 2016. Sixteen received pre-TKI treatment. Fifty-three received a first-generation TKI, and seven had a second-generation TKI in first-line therapy. The median TKI time to achieve CMR was 20.5 months [5-137]. The median TKI length before discontinuation treatment was 73 months [12-158]. Twenty-two patients (37%) relapsed with a median time to relapse of 6 months [3-27]. An intermediate or high Sokal score was the only relapse risk factor (HR = 3.32, p < 0.05) associated with relapse after TKI discontinuation. TKI discontinuation was possible without relapse for half of the patients in chronic phase CML. In a real-life cohort, a high-risk Sokal score at diagnosis appears to be an adverse prognosis feature for TKI discontinuation.

[Right heart intra-cavitar echogenic foci following mesenteric ischemia]. / L'image du mois. Hyper-échogénicités intra-cavitaires cardiaques droites au décours d'une ischémie mésentérique.

This clinical case demonstrates the pivotal role of repeated cardioechography in both diagnosis and follow-up of well selected ER and ICU inpatients. We report the finding of right heart intra-cavitar hyper-echogenic foci ultimately leading to the diagnosis of mesenteric ischemia.

Ce cas clinique démontre l'importance de l'échocardiographie dans le diagnostic et le suivi de patients dûment sélectionnés aussi bien dans les services d'Urgences que de Soins intensifs. Nous rapportons la mise en évidence d'images hyper-échogènes au sein des cavités cardiaques droites aboutissant finalement au diagnostic d'une ischémie mésentérique.

Multi-model Meteorological and Aeolian Predictions for Mars 2020 and the Jezero Crater Region.

Nine simulations are used to predict the meteorology and aeolian activity of the Mars 2020 landing site region. Predicted seasonal variations of pressure and surface and atmospheric temperature generally agree. Minimum and maximum pressure is predicted at Ls ∼ 145 ∘ and 250 ∘ , respectively. Maximum and minimum surface and atmospheric temperature are predicted at Ls ∼ 180 ∘ and 270 ∘ , respectively; i.e., are warmest at northern fall equinox not summer solstice. Daily pressure cycles vary more between simulations, possibly due to differences in atmospheric dust distributions. Jezero crater sits inside and close to the NW rim of the huge Isidis basin, whose daytime upslope (∼east-southeasterly) and nighttime downslope (∼northwesterly) winds are predicted to dominate except around summer solstice, when the global circulation produces more southerly wind directions. Wind predictions vary hugely, with annual maximum speeds varying from 11 to 19 ms - 1 and daily mean wind speeds peaking in the first half of summer for most simulations but in the second half of the year for two. Most simulations predict net annual sand transport toward the WNW, which is generally consistent with aeolian observations, and peak sand fluxes in the first half of summer, with the weakest fluxes around winter solstice due to opposition between the global circulation and daytime upslope winds. However, one simulation predicts transport toward the NW, while another predicts fluxes peaking later and transport toward the WSW. Vortex activity is predicted to peak in summer and dip around winter solstice, and to be greater than at InSight and much greater than in Gale crater. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11214-020-00788-2.

Crystal Structures of Neurotrophin Receptors Kinase Domain.

Neurotrophins and their receptors (Trk) play key roles in the development of the nervous system and in cell survival. Trk receptors are therefore attractive pharmacological targets for brain disorders as well as for cancers. While the druggability of the extracellular domain of the receptors, that specifically binds neurotrophins, is yet to be proven, the intracellular kinase domains are attractive targets for small-molecule binding. The recent crystal structures of the three isoforms of the Trk family, TrkA, TrkB, and TrkC have been described in their apo forms and in complex with potent and selective pan-Trk inhibitors. The description of the kinase domain of each of the isoforms will be discussed in their apo forms or bound to potent inhibitors of interest in cancer therapy. Nononcology indications and selectivity issues will also be discussed.

Conformations of tissue plasminogen activator (tPA) orchestrate neuronal survival by a crosstalk between EGFR and NMDAR.

Tissue-type plasminogen activator (tPA) is a pleiotropic serine protease of the central nervous system (CNS) with reported neurotrophic and neurotoxic functions. Produced and released under its single chain form (sc), the sc-tPA can be cleaved by plasmin or kallikrein in a two chain form, tc-tPA. Although both sc-tPA and tc-tPA display a similar fibrinolytic activity, we postulated here that these two conformations of tPA (sc-tPA and tc-tPA) could differentially control the effects of tPA on neuronal survival. Using primary cultures of mouse cortical neurons, our present study reveals that sc-tPA is the only one capable to promote N-methyl-D-aspartate receptor (NMDAR)-induced calcium influx and subsequent excitotoxicity. In contrast, both sc-tPA and tc-tPA are capable to activate epidermal growth factor receptors (EGFRs), a mechanism mediating the antiapoptotic effects of tPA. Interestingly, we revealed a tPA dependent crosstalk between EGFR and NMDAR in which a tPA-dependent activation of EGFRs leads to downregulation of NMDAR signaling and to subsequent neurotrophic effects.

Molecular requirements for safer generation of thrombolytics by bioengineering the tissue-type plasminogen activator A chain.

BACKGROUND: Thrombolysis with tissue-type plasminogen activator (t-PA) is the only treatment approved for acute ischemic stroke. Although t-PA is an efficient clot lysis enzyme, it also causes damage to the neurovascular unit, including hemorrhagic transformations and neurotoxicity. OBJECTIVES: On the basis of the mechanism of action of t-PA on neurotoxicity, we aimed at studying the molecular requirements to generate safer thrombolytics. METHODS: We produced original t-PA-related mutants, including a non-cleavable single-chain form with restored zymogenicity (sc*-t-PA) and a t-PA modified in the kringle 2 lysine-binding site (K2*-t-PA). Both sc*-t-PA and K2*-t-PA showed fibrinolytic activities similar to that of wild-type t-PA on both euglobulin-containing and plasma-containing clots. In contrast to wild-type t-PA, the two mutants did not promote N-methyl-d-aspartate receptor-mediated neurotoxicity. CONCLUSIONS: We designed t-PA mutants with molecular properties that, in contrast to t-PA, do not induce neurotoxicity.

The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition.

The Trk family of neurotrophin receptors, which includes the three highly homologous proteins TrkA, TrkB and TrkC, is strongly associated with central and peripheral nervous system processes. Trk proteins are also of interest in oncology, since Trk activation has been observed in several cancer types. While Trk kinases are attractive oncology targets, selectivity might be more of an issue than for other kinases due to potential CNS side effects if several Trk kinases are simultaneously targeted. In order to address this issue, we present here the first structures of human TrkA and TrkB kinase domains and three complexes between TrkB and Trk inhibitors. These structures reveal different conformations of the kinase domain and suggest new regions of selectivity among the Trk family.

Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity.

Unlike other serine proteases that are zymogens, the single-chain form of tissue plasminogen activator (sc-tPA) exhibits an intrinsic activity similar to that of its cleaved two-chain form (tc-tPA), especially in the presence of fibrin. In the central nervous system tPA controls brain functions and dysfunctions through its proteolytic activity. We demonstrated here, both in vitro and in vivo, that the intrinsic activity of sc-tPA selectively modulates N-methyl-D-aspartate receptor (NMDAR) signaling as compared with tc-tPA. Thus, sc-tPA enhances NMDAR-mediated calcium influx, Erk(½) activation and neurotoxicity in cultured cortical neurons, excitotoxicity in the striatum and NMDAR-dependent long-term potentiation in the hippocampal CA-1 network. As the first demonstration of a differential function for sc-tPA and tc-tPA, this finding opens a new area of investigations on tPA functions in the absence of its allosteric regulator, fibrin.

Proteolytic activity and expression of the 20S proteasome are increased in psoriasis lesional skin.

BACKGROUND: Deregulation of the proteasome pathway has been shown to be involved in the pathogenesis of several inflammatory disorders. To date limited information exists on proteasome and immunoproteasome expression and activity in psoriasis skin. OBJECTIVES: To investigate the potential role of proteasomes in the pathogenesis of psoriasis. METHODS: Thirty-six patients with psoriasis and 40 healthy subjects were included. The protein and mRNA expression levels and proteolytic activity of proteasome and immunoproteasome subunits were determined using immunohistochemistry, quantitative polymerase chain reaction and fluorogenic peptide substrate in lesional and nonlesional psoriasis skin. We additionally measured the plasmatic proteasome (p-proteasome) levels using enzyme-linked immunosorbent assay. RESULTS: We reveal an increased expression of proteasome and immunoproteasome subunits but stable mRNA levels in lesional psoriasis skin as compared with nonlesional psoriasis skin (n = 19), suggesting that proteasome and immunoproteasome expression is regulated post-transcriptionally. This proteasome overexpression was associated with a significant increase of the proteasomal chymotrypsin-like activity that was threefold higher in lesional skin than in nonlesional skin (n = 3). p-Proteasome levels were enhanced in patients with psoriasis (mean ± SEM 3960 ± 299 ng mL(-1) , range 1484-8987) when compared with controls (2535±187 ng mL(-1) , range 654-6446, P<0·001) and were significantly higher in psoriatic arthritis (4937±572 ng mL(-1) , range 2600-8987). In addition, they were correlated to the body surface area involved and appeared thus as a new biomarker of psoriasis severity. CONCLUSIONS: Altogether these results strongly suggest the involvement of the proteasome system in the pathogenesis of psoriasis and support the relevance of proteasome inhibitors in local or systemic treatment of psoriasis.

Structural basis for human monoglyceride lipase inhibition.

Monoglyceride lipase (MGL) is a serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. 2-AG is an endogenous ligand of cannabinoid receptors, involved in various physiological processes in the brain. We present here the first crystal structure of human MGL in its apo form and in complex with the covalent inhibitor SAR629. MGL shares the classic fold of the alpha/beta hydrolase family but depicts an unusually large hydrophobic occluded tunnel with a highly flexible lid at its entry and the catalytic triad buried at its end. Structures reveal the configuration of the catalytic triad and the shape and nature of the binding site of 2-AG. The bound structure of SAR629 highlights the key interactions for productive binding with MGL. The shape of the tunnel suggests a high druggability of the protein and provides an attractive template for drug discovery.

Plasma proteasome level is a reliable early marker of malignant transformation of liver cirrhosis.

BACKGROUND: Proteasomes are the main non-lysosomal proteolytic structures which regulate crucial cellular processes. Circulating proteasome levels can be measured using an ELISA test and can be considered as a tumour marker in several types of malignancy. Given that there is no sensitive marker of hepatocellular carcinoma (HCC) in patients with cirrhosis, we measured plasma proteasome levels in 83 patients with cirrhosis (33 without HCC, 50 with HCC) and 40 controls. METHODS AND RESULTS: Patients with HCC were sub-classified into three groups according to tumour mass. alpha-Fetoprotein (AFP) was also measured. Plasma proteasome levels were significantly higher in patients with HCC compared to controls (4841 (SEM 613) ng/ml vs 2534 (SEM 187) ng/ml; p<0.001) and compared to patients with cirrhosis without HCC (2077 (SEM 112) ng/ml; p<0.001). This difference remained significant when the subgroup of patients with low tumour mass (proteasome level 3970 (SEM 310) ng/ml, p<0.001) was compared to controls and patients with cirrhosis without HCC. Plasma proteasome levels were independent of the cause of cirrhosis and were weakly correlated with AFP levels. With a cut-off of 2900 ng/ml, diagnostic specificity for HCC was 97% with a sensitivity of 72%, better than results obtained with AFP. Diagnostic relevance of plasma proteasome measurement was also effective in low tumour mass patients (sensitivity 76.2% vs 57.1% for AFP). CONCLUSION: The plasma proteasome level is a reliable marker of malignant transformation in patients with cirrhosis, even when there is a low tumour mass.

High plasma proteasome levels are detected in patients with metastatic malignant melanoma.

BACKGROUND: Proteasomes, nonlysosomal proteolytic structures, are implicated in cell growth and differentiation. An abnormal expression has been described in haematopoietic malignancies and in some solid tumours. OBJECTIVES: To study the plasma proteasome levels in patients with malignant melanoma (MM) using an enzyme-linked immunosorbent assay (ELISA) technique, and to compare them with the values obtained in a normal population and in patients with severe psoriasis or chronic idiopathic urticaria (CIU). METHODS: Plasma proteasome level was measured using a sandwich ELISA test in normal donors (n = 14), and in patients with stage I/II (n = 13), stage III (n = 6) and stage IV (n = 10) MM, severe psoriasis (n = 13) and CIU (n = 6). Tissue proteasome expression was also detected by immunohistology using a monoclonal antibody in paraffin-embedded samples of normal tissue, psoriasis skin and MM. RESULTS: In normal donors, mean +/- SEM plasma proteasome concentration was 2138 +/- 221 ng mL(-1). Patients with stages III and IV MM exhibited a significantly higher value (3373 +/- 470 ng mL(-1) and 8931 +/- 1232 ng mL(-1), respectively). Values in patients with stage I/II MM and CIU were not significantly different from those in normal volunteers. Patients with severe psoriasis also exhibited increased values (3398 +/- 374 ng mL(-1)) but to a lesser extent than in patients with stage IV MM. There was a significant correlation of proteasome levels with serum lactate dehydrogenase in the MM group. Tissue expression as demonstrated by immunohistochemistry paralleled these findings. The strongest expression was seen on MM slides and to a lesser extent in psoriasis samples, the weakest expression being observed in normal skin. CONCLUSIONS: Proteasomes are strongly expressed in cutaneous MM; high levels of circulating proteasomes are detected in patients with metastatic MM with a high melanoma burden, and at a lesser extent in psoriatic patients, which suggests proteasomes represent a marker more of nonspecific inflammation than of early cancer.