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Integrating new technologies such as Virtual Reality (VR) can contribute to increasing efficiency in several areas relevant to society. VR can be applied in various contexts and has the potential to improve mnemonic processes and memory performance. However, the specific conditions under which VR is more beneficial than conventional learning methods remain unclear. To further investigate the value of VR for mnemonic processing, participants performed a memory task under three different conditions. For that task, they were presented with rules regarding the spatial arrangement of building blocks with a written text or a video in 2D on a screen or in 3D/360° with a head-mounted display. Following the learning session, memory performance was measured by a recognition test involving a multiple-choice questionnaire, in which participants had to mark the correct arrangement of building blocks, and a construction test, in which they had to arrange five different building blocks according to the rules learned. Additionally, participants had to arrange 38 building blocks according to the rules in a free recall test the following day. Surprisingly, results revealed no superiority effect for learning in VR. Instead, learning the rules with the text yielded the best memory performance results, indicating that prior experience with conventional learning methods facilitates declarative knowledge acquisition. Considering previous findings regarding cognitive processing in VR, our results suggest that in passive learning, processing the more salient and personally relevant virtual stimuli in the surrounding VR environment requires more attentional resources. Therefore, VR impairs focusing on the relevant declarative information and impedes the transfer of the learned knowledge to different contexts. When considering to implement VR, the value to the particular domain and specific learning task should be taken into consideration: For learning basic declarative information without actively involving the students, conventional learning methods seem sufficient and more efficient for mnemonic processing compared to new technologies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Johnsdorf, Pham, Schmidt, Truong, Wohnig, Kisker, Gruber and Schöne.)

Purpose: Whether triplet chemotherapy is superior to doublet chemotherapy in advanced biliary tract cancer (BTC) is unknown., Methods: In this open-label, randomized phase II-III study, patients with locally advanced or metastatic BTC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive oxaliplatin, irinotecan, and infusional fluorouracil (mFOLFIRINOX), or cisplatin and gemcitabine (CISGEM) for a maximum of 6 months. We report the results of the phase II part, where the primary end point was the 6-month progression-free survival (PFS) rate among the patients who received at least one dose of treatment (modified intention-to-treat population) according to Response Evaluation Criteria in Solid Tumors version 1.1 (statistical assumptions: 6-month PFS rate ≥ 59%, 73% expected)., Results: A total of 191 patients (modified intention-to-treat population, 185: mFOLFIRINOX, 92; CISGEM, 93) were randomly assigned in 43 French centers. After a median follow-up of 21 months, the 6-month PFS rate was 44.6% (90% CI, 35.7 to 53.7) in the mFOLFIRINOX arm and 47.3% (90% CI, 38.4 to 56.3) in the CISGEM arm. Median PFS was 6.2 months (95% CI, 5.5 to 7.8) in the mFOLFIRINOX arm and 7.4 months (95% CI, 5.6 to 8.7) in the CISGEM arm. Median overall survival was 11.7 months (95% CI, 9.5 to 14.2) in the mFOLFIRINOX arm and 13.8 months (95% CI, 10.9 to 16.1) in the CISGEM arm. Adverse events ≥ grade 3 occurred in 72.8% of patients in the mFOLFIRINOX arm and 72.0% of patients in the CISGEM arm (toxic deaths: mFOLFIRINOX arm, two; CISGEM arm, one)., Conclusion: mFOLFIRINOX triplet chemotherapy did not meet the primary study end point. CISGEM doublet chemotherapy remains the first-line standard in advanced BTC., Competing Interests: Jean marc PhelipHonoraria: Merck Serono, Roche, Sanofi, Amgen, Lilly, Servier, BayerConsulting or Advisory Role: Roche, Merck Serono, Amgen, Servier, Bayer, SanofiResearch Funding: Roche, Merck SeronoTravel, Accommodations, Expenses: Roche, Merck Serono, Bayer, Servier, Sanofi Jérôme DesrameExpert Testimony: RocheTravel, Accommodations, Expenses: Hospira Julien EdelineConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Bayer, Ipsen, AstraZeneca, MSD, AstraZeneca, Eisai, Boston Scientific, AstraZeneca, Roche, Basilea, AstraZeneca, Merck SeronoResearch Funding: Bristol Myers Squibb, BeigeneTravel, Accommodations, Expenses: Amgen, Bristol Myers Squibb, Roche Eric TerrebonneConsulting or Advisory Role: Ipsen, Servier Pierre MichelHonoraria: Bayer, Servier Laetitia DahanHonoraria: Amgen, BMS, Servier, Oseus, Mylan Vincent BourgeoisConsulting or Advisory Role: ServierTravel, Accommodations, Expenses: Servier, Sanofi Faiza Khemissa AkouzLeadership: Bayer, SanofiTravel, Accommodations, Expenses: Sanofi, Ipsen, Servier, Roche Emilie SoularueConsulting or Advisory Role: ServierSpeakers' Bureau: BMSTravel, Accommodations, Expenses: Servier Yann MolinConsulting or Advisory Role: Janssen Oncology Thierry LecomteConsulting or Advisory Role: Sanofi, Merck Serono, Servier, Amgen, Sanofi, Amgen, Ipsen, Pierre FabreTravel, Accommodations, Expenses: Ipsen, Servier/Pfizer François GhiringhelliHonoraria: RocheTravel, Accommodations, Expenses: Amgen, Roche/Genentech Romain CoriatConsulting or Advisory Role: BayerSpeakers' Bureau: Novartis/Ipsen, Bayer, AmgenResearch Funding: IpsenTravel, Accommodations, Expenses: Pierre Fabre, Amgen Cindy NeuzilletHonoraria: Servier, Roche, AstraZeneca, Bristol Myers Squibb, Amgen, Merck¸ MSD Oncology, Novartis, Pierre Fabre, Incyte, Mylan, Baxter, Fresenius Kabi, NutriciaResearch Funding: Roche, AstraZeneca, OSE ImmunotherapeuticsTravel, Accommodations, Expenses: MSD Oncology, Merck, Amgen, Mylan David MalkaHonoraria: Roche, Bayer, Servier, Sanofi, HalioDx, Pierre Fabre, Viatris, Bristol Myers Squibb, MSD Oncology, LEO PharmaConsulting or Advisory Role: Roche, Sanofi, Merck Serono, MSD, Servier, Bayer, Incyte, Amgen, HalioDx, Agios, Bristol Myers SquibTravel, Accommodations, Expenses: Roche, Bayer, Sanofi, Merck Serono, Servier, AmgenNo other potential conflicts of interest were reported.

Natural Killer (NK) cells control metastatic dissemination of murine tumors and are an important prognostic factor in several human malignancies. However, tumor cells hijack many of the NK cell functional features compromising their tumoricidal activity. Here, we show a deleterious role of the TNFα/TNFR2/BIRC3/TRAF1 signaling cascade in NK cells from the tumor microenvironment (TME). TNFα induces BIRC3/cIAP2 transcripts and reduces NKp46/NCR1 transcription and surface expression on NK cells, promoting metastases dissemination in mice and poor prognosis in GIST patients. NKp30 engagement, by promoting the release of TNFα, also contributes to BIRC3 upregulation, and more so in patients expressing predominantly NKp30C isoforms. These findings reveal that in the absence of IL-12 or a Th1-geared TME, TNFα can be considered as a negative regulatory cytokine for innate effectors.

Ultrafiltration (UF) membrane fouling caused by terrestrial input of dissolved organic matter (DOM), especially during high flood periods, is poorly understood. In this study, we examined the fouling characteristics of three different terrestrial humic substances (HS) on regenerated cellulose (RC) UF membranes with the pore sizes of 30 k-3 kDa via conventional bulk HS measurements as well as an advanced fluorescence spectroscopy. The fluorescence excitation-emission matrix coupled with parallel factor analysis (EEM-PARAFAC) identified one protein-like (C1) and three humic-like fluorescent components (C2-C4) from soil and leaf-derived HS. The fate of the different fluorescent components was individually tracked for the UF processes. The higher removal rates were found generally on the order of high molecular weight (HMW) C1 to smaller sized humic-like components (C4 > C3 > C2) regardless of the HS sources, implying the importance of HS molecular sizes on the UF operation. Among the humic-like components, C2 was the most associated with irreversible fouling, while other two humic-like components contributed more to reversible fouling. For soil-derived HS, C4 can be suggested as a good surrogate for membrane fouling, as evidenced by the highest correlation between the removal rates and the total fouling indices among the tested HS variables including conventional bulk parameters. Our study demonstrated a promising application of EEM-PARAFAC for probing membrane fouling of terrestrial DOM, which provided additional insight into the fate of different fluorescent components on the UF processes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In this study, we successfully tracked the dynamic changes in different constitutes of bound extracellular polymeric substances (bEPS), soluble microbial products (SMP), and permeate during the operation of bench scale membrane bioreactors (MBRs) via fluorescence excitation-emission matrix (EEM) combined with parallel factor analysis (PARAFAC). Three fluorescent groups were identified, including two protein-like (tryptophan-like C1 and tyrosine-like C2) and one microbial humic-like components (C3). In bEPS, protein-like components were consistently more dominant than C3 during the MBR operation, while their relative abundance in SMP depended on aeration intensities. C1 of bEPS exhibited a linear correlation (R(2)=0.738; p<0.01) with bEPS amounts in sludge, and C2 was closely related to the stability of sludge. The protein-like components were more greatly responsible for membrane fouling. Our study suggests that EEM-PARAFAC can be a promising monitoring tool to provide further insight into process evaluation and membrane fouling during MBR operation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Herein, we report the enantioselective synthesis of a functionalized aza-octahydropentalene and its elaboration to a model tetracyclic core structure of calyciphylline B-type alkaloids.

Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B-type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1-aza-perhydrocyclopentalene core, representing rings A and E of all calyciphylline B-type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4-conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2-carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this study, five different dissolved organic matter (DOM) fractions, defined based on a size exclusion chromatography with simultaneous detection of organic carbon (OCD) and ultraviolet (UVD), were quantitatively tracked with a treatment train of coagulation/flocculation-sand filtration-ozonation-granular activated carbon (GAC) filtration in a full-scale advanced drinking water treatment plant (DWTP). Five DOM samples including raw water were taken after each treatment process in the DWTP every month over the period of three years. A higher abundance of biopolymer (BP) fraction was found in the raw water during spring and winter than in the other seasons, suggesting an influence of algal bloom and/or meltwater on DOM composition. The greater extent of removal was observed upon the coagulation/flocculation for high-molecular-weight fractions including BP and humic substances (HS) and aromatic moieties, while lower sized fractions were preferentially removed by the GAC filtration. Ozone treatment produced the fraction of low-molecular-weight neutrals probably resulting from the breakdown of double-bonded carbon structures by ozone oxidation. Coagulation/flocculation was the only process that revealed significant effects of influent DOM composition on the treatment efficiency, as revealed by a high correlation between the DOM removal rate and the relative abundance of HS for the raw water. Our study demonstrated that SEC-OCD-UVD was successful in monitoring size-based DOM composition for the advanced DWTP, providing an insight into optimizing the treatment options and the operational conditions for the removal of particular fractions within the bulk DOM.

Pd(II)-catalyzed alkene aminopalladation and allylic C-H activation are two competing reaction sequences sharing the same reaction conditions. This study aimed at understanding the factors that bias one or the other path in the intramolecular oxidative cyclization of two types of N-tosyl amidoalkenes. The results obtained are in accord with the initial generation of a high-energy cyclic (5- or 6-membered) aminopalladated intermediate. However, this latter species can evolve only if the following specific conditions are met: the availability of distocyclic β-H elimination pathway, the presence of a strong terminal oxidant, or the availability of a carbopalladation pathway. Conversely, the cyclic alkylpalladium complex is only a latent species in equilibrium with the initial substrate and cannot evolve. Such a reactivity hurdle leaves the way open for alternative reactivities such as allylic C-H activation of the olefinic substrate to generate a η(3)-allyl complex followed by its interception by the nitrogen nucleophile, [3,3]-sigmatropic rearrangement, or decomposition. This study proposes a unifying mechanistic picture that connects these competing mechanisms., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Parasitic infections recognized as neglected tropical diseases are a source of concern for several regions of the world. Aminoglycosides are potent antimicrobial agents that have been extensively studied by biochemical and structural studies in prokaryotes. However, the molecular mechanism of their potential antiprotozoal activity is less well understood. In the present study, we have examined the in vitro inhibitory activities of some aminoglycosides with a 6'-hydroxy group on ring I and highlight that one of them, 6'-hydroxysisomicin, exhibits promising activity against a broad range of protozoan parasites. Furthermore, we have conducted X-ray analyses of 6'-hydroxysisomicin bound to the target ribosomal RNA A-sites in order to understand the mechanisms of both its antibacterial and antiprotozoal activities at the molecular level. The unsaturated ring I of 6'-hydroxysisomicin can directly stack on G1491, which is highly conserved in bacterial and protozoal species, through π-π interaction and fits closer to the guanidine base than the typically saturated and hydroxylated ring I of other structurally related aminoglycosides. Consequently, the compound adopts a lower energy conformation within the bacterial and protozoal A-sites and makes pseudo pairs to either A or G at position 1408. The A-site-selective binding mode strongly suggests that 6'-hydroxysisomicin is a potential lead for the design of next-generation aminoglycosides targeting a wide variety of infectious diseases., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

There is accumulating evidence that leptin may be directly involved in pre-implantation embryonic development, however, it is unclear whether there is a concentration and stage-dependent regulatory pattern. In this study, the addition of 10 ng/ml human recombinant leptin to the culture medium significantly increased the percentage of two-cell mouse embryos that developed into blastocysts and hatched blastocysts, whereas in the presence of 100 ng/ml leptin, the development rate was significantly inhibited. The total cell numbers in the hatched blastocysts were significantly higher in the presence of 10 ng/ml leptin compared with controls and higher concentrations. The differential sensitivity to leptin was found to vary among embryos at different stages of development. Supplementation of leptin (10 ng/ml) to culture medium at two- to eight-cell stages resulted in a consistent stimulatory effect on embryo development. Most interestingly, the inhibitory effect of high leptin concentration (100 ng/ml) on embryo development was diminished when it was added to the culture medium at the eight-cell stage of development. The concentration-dependent regulation pattern was confirmed using sheep embryos, under similar conditions although sheep embryos appeared to be more sensitive in responding to leptin. Having established the effect of exogenous leptin on embryo development, the expression pattern of leptin and its receptors were also investigated. Leptin mRNA was not detected in mouse two-, four-, eight-cell and blastocyst stage embryos, whereas three isoforms of leptin receptor (Ob-Ra, Ob-Rb and Ob-Re) were identified in these cells, indicating that leptin is likely to modulate embryo development via a paracrine signalling system.

The sigma1 receptor is a unique intracellular receptor whose activation results in an efficient modulation of several neurotransmitter responses. Its role as a target for the rapid nongenomic effects of neuro(active)steroids and the age-related diminutions in steroid levels suggested that targeting the sigma1 receptor might allow alleviation of age-related neuronal dysfunctions. We examined here the expression and behavioral efficacy of sigma1 receptors in the senescence-accelerated (SAM) mouse model. The sigma1 receptor mRNA expression was measured by using comparative RT-PCR in the olfactory bulb, hippocampus, hypothalamus, cortex, or cerebellum of senescence-prone SAMP/8 and senescence-resistant SAMR/1 control animals. No difference was observed between substrains in 6-, 9-, and 12-month-old (m.o.) mice. The sigma1 protein expression was analyzed by using immunohistochemical techniques. Labeling was intense in the olfactory bulb, hippocampus, hypothalamus, and midbrain of both SAMR/1 and SAMP/8 mice, and the distribution appeared unchanged in 6-, 9-, and 12-m.o. animals. The receptor's in vivo availability was examined by using in vivo [3H](+)-SKF-10,047 binding. No age-related difference was observed in the olfactory bulb, hippocampus, hypothalamus, cortex, cerebellum, and brainstem of 6- or 12-m.o. SAMR/1 or SAMP/8 mice. The antidepressant efficacy of the selective agonist igmesine was examined in the forced-swimming test. The compound decreased significantly the immobility duration at 60 mg/kg in 6- and 12-m.o. SAMR/1 and in 6-m.o. SAMP/8 mice. In 12-m.o. SAMP/8 mice, the drug efficacy was facilitated; a significant effect was measured at 30 mg/kg. Decreased neurosteroid levels, particularly of progesterone, were seen in 12-m.o. SAMP/8 mice that might explain the enhanced efficacy of igmesine. Preserved sigma1 receptor expression and enhanced behavioral efficacy of sigma1 agonists were measured in SAM animals, confirming the therapeutic opportunities for selective ligands against age-related mood disorders., (Copyright (c) 2005 Wiley-Liss, Inc.)

The sigma(1) (sigma(1)) receptor represents a unique intracellular neuronal protein modulating several neurotransmitter responses with relevant effects on cognitive functions. We examined here its expression and behavioral efficacy during aging. The sigma(1) receptor expression was examined in young (2 months old) and aged (24 months old) C57BL/6 mouse brain using comparative RT-PCR and immunohistochemistry. The promnesic effect of PRE-084, a selective sigma(1) agonist, was assessed using a water-maze procedure. The sigma(1) mRNA expression was not affected during aging in the olfactory bulb, hippocampus, hypothalamus, cortex or cerebellum. The sigma(1) immunolabeling was intense in the olfactory bulb, hippocampus, hypothalamus and midbrain of the young mouse and the distribution appeared unchanged in the aged. The subcellular localization was similar in aged and younger animals, the protein being present on nuclear, mitochondrial, endoplasmic reticular and plasmic membranes. At the behavioral level, aged C57BL/6 mice showed deficits in the invisible platform learning, but not when the platform was visible. Animals subjected to a transfer test under repeated treatment with saline or PRE-084 significantly learned the new platform location. This study shows that sigma(1) receptor expression is preserved in aged animals and demonstrates the efficacy of a selective sigma(1) agonist against age-related memory deficits. Targeting this unique receptor may offer an original drug strategy during aging.

The sigma(1) (sigma(1)) receptor exerts a potent neuromodulatory role in the brain with relevant consequences in memory processes, response to stress, depression and pharmacodependence. Its precise endogenous ligand is not yet identified but the sigma(1) receptor appears to be one target for the nongenomic rapid effects of neuroactive steroids in the brain. The aim of the present study was to establish whether differences in sigma(1) receptor-mediated behaviours could be observed among mouse strains, in relation with differences in either sigma(1) receptor expression or steroid levels. The sigma(1)-receptor immunohistochemical distribution appeared similar between Swiss and C57BL/6 strains in all the brain structures examined. The levels of in vivo [(3)H](+)-SKF-10 047 binding to sigma(1) receptors were lower in Swiss than in C57BL/6. Adrenalectomy/castration significantly increased [(3)H](+)-SKF-10 047 binding only in Swiss. The behavioural efficacy of the selective sigma( 1) agonists igmesine and PRE-084 -- reversion of the scopolamine-induced amnesia in the passive avoidance test; diminution of the immobility duration in the forced swimming test -- were significantly higher in C57BL/6 than in Swiss. Steroid levels were measured in the brain in basal conditions and after stress. C57BL/6 mice presented in both conditions, the lowest progesterone levels, this steroid acting as an endogenous sigma(1) antagonist. Collectively, the results suggested that strain differences in neuroactive steroid and particularly, progesterone, biosynthesis and sensitivity may contribute to the differential behavioural efficacy of sigma(1)-receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine-induced reward properties, known to critically involve the sigma(1) receptor.

The involvement of the sigma(1) receptor on the rewarding effects of cocaine was examined using the conditioned place preference (CPP) procedure in C57BL/6 mice. Acquisition or expression of cocaine (20 mg/kg i.p.)-induced CPP was significantly decreased by pre-treatment with the selective sigma(1) receptor antagonists N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) or N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047), 1-10 mg/kg, i.p. The sigma(1) receptor agonists igmesine or 2-(4-morpholinoethyl-1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) failed to induce CPP when injected alone. Moreover, the CPP induced by N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP), a selective dopamine reuptake inhibitor, was blocked by treatments with the sigma(1) receptor antagonists as was similarly observed with cocaine. In addition, the repetitive treatment with cocaine during conditioning increased sigma(1) receptor mRNA expression in the nucleus accumbens, but not in the caudate putamen, prefrontal cortex or cerebellum. These data show that the sigma(1) receptor is not only necessary for acquisition of the cocaine-induced CPP, but that it is also implicated in its expression, confirming that activation of the sigma(1) receptor is induced during cocaine's early effects. The sigma(1) receptor is activated consequently to dopamine reuptake blockade and is not sufficient to induce CPP by itself. The mechanism of the sigma(1) receptor involvement in CPP and the selectivity toward the CPP-inducing drug remains however to be determined. These results show that strategies targeting the sigma(1) receptor with selective antagonists may allow effective attenuation of cocaine's rewarding properties and, in turn, offer new treatment strategies against drug addiction.