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Many industrial applications require the displacement of liquid-filled containers on planar paths (namely, paths on a horizontal plane), by means of linear transport systems or serial robots. The movement of the liquid inside the container, known as sloshing, is usually undesired, thus there is the necessity to keep under control the peaks that the liquid free-surface exhibits during motion. This paper aims at validating a model for estimating the liquid sloshing height, taking into account 2-dimensional motions of a cylindrical container occurring on a horizontal plane, with accelerations up to 9.5 m/s2. This model can be exploited for assessment or optimization purposes. Experiments performed with a robot following three paths, each one of them with different motion profiles, are described. Comparisons between experimental results and model predictions are provided and discussed.Finally, the previous formulation is extended in order to take into account the addition of a vertical acceleration, up to 5 m/s2. The resulting 3-dimensional motions are experimentally validated to prove the effectiveness of the extended technique.

Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes and correlates with altered alternative splicing patterns of 462 genes implicated in ‘regulation of RNA splicing’ and ‘mRNA catabolic process’. Mass spectrometry analysis uncovered a novel interaction between CHD8 and the splicing regulator heterogeneous nuclear ribonucleoprotein L (hnRNPL), providing the first mechanistic insights to explain the CHD8 suppression-derived splicing phenotype, partly implicating SETD2, a H3K36me3 methyltransferase. In summary, our results point toward broad molecular consequences of CHD8 suppression, entailing altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD.

Compounds featuring a 1,2,4-oxadiazole core have been recently identified as a new chemotype of farnesoid X receptor (FXR) antagonists. With the aim to expand this class of compounds and to understand the building blocks necessary to maintain the antagonistic activity, we describe herein the synthesis, the pharmacological evaluation, and the in vitro pharmacokinetic properties of a novel series of 1,2,4-oxadiazole derivatives decorated on the nitrogen of the piperidine ring with different N-alkyl and N-aryl side chains. In vitro pharmacological evaluation showed compounds 5 and 11 as the first examples of nonsteroidal dual FXR/Pregnane X receptor (PXR) modulators. In HepG2 cells, these compounds modulated PXR- and FXR-regulated genes, resulting in interesting leads in the treatment of inflammatory disorders. Moreover, molecular docking studies supported the experimental results, disclosing the ligand binding mode and allowing rationalization of the activities of compounds 5 and 11.

Over recent years, αvβ6 and αvβ8 Arg-Gly-Asp (RGD) integrins have risen to prominence as interchangeable co-receptors for the cellular entry of herpes simplex virus-1 (HSV-1). In fact, the employment of subtype-specific integrin-neutralizing antibodies or gene-silencing siRNAs has emerged as a valuable strategy for impairing HSV infectivity. Here, we shift the focus to a more affordable pharmaceutical approach based on small RGD-containing cyclic pentapeptides. Starting from our recently developed αvβ6-preferential peptide [RGD-Chg-E]-CONH2 (1), a small library of N-methylated derivatives (2–6) was indeed synthesized in the attempt to increase its affinity toward αvβ8. Among the novel compounds, [RGD-Chg-(NMe)E]-CONH2 (6) turned out to be a potent αvβ6/αvβ8 binder and a promising inhibitor of HSV entry through an integrin-dependent mechanism. Furthermore, the renewed selectivity profile of 6 was fully rationalized by a NMR/molecular modeling combined approach, providing novel valuable hints for the design of RGD integrin ligands with the desired specificity profile.

αv β6 Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-β). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with αv β6 integrin-dependent TGF-β dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the αv β6 -specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH2 ) to enhance αv β6 integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17)3 showed a 28-fold higher αv β6 affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC50 of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC50 -based selectivity over the related integrin αv β8 (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with H2009 tumor-bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17)3 holds promise for improved clinical PET diagnostics of carcinomas and fibrosis.

Supplementary Figure S4. PDGFRbeta identifies vascular lacunae in TNBC tissues

Supplementary Figure legends (S1-S4)

MiR-9 regulates PDGFRbeta expression in TNBC cell lines

Organization of cancer cells into endothelial-like cell-lined structures to support neovascularization and to fuel solid tumors is a hallmark of progression and poor outcome. In triple-negative breast cancer (TNBC), PDGFRβ has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of miRNAs as a therapeutic approach to inhibit PDGFRβ-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted and inhibited, respectively, the formation of vascular-like structures in vitro. Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRβ signaling, promoted significant vascular sprouting of TNBC cells, in part, by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRβ through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA-MB-231–stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, IHC and immunofluorescence analyses in TNBC specimens indicated that PDGFRβ expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRβ, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR-200 to inhibit the process of vascular lacunae formation in TNBC. Cancer Res; 76(18); 5562–72. ©2016 AACR.

MiR-200 family inhibits tube formation ability through PDGFRbeta repression

The file contains all the supplementary tables (S1-S4): - Supplementary Table S1. Clinicopathologic features of 78 breast cancer patients (set 1) and 85 TNBC (set 2). - Supplementary Table S2. Relation between miR-9 expression and clinicopathologic characteristics in human breast cancer. - Supplementary Table S3. Top 40 genes predicted as miR-9 target and statistically significant down-modulated in basal versus luminal breast cancer. - Supplementary Table S4. Relation between clinicopathologic characteristics and miR-9 and miR-200c in TNBC human tissues.

ARLTS1 is a tumor suppressor gene initially described as a low-penetrance cancer gene: a truncated Trp149Stop (MUT) polymorphism is associated with general familial cancer aggregation and, particularly, high-risk familial breast cancer. DNA hypermethylation has been identified as a mechanism of ARLTS1 expression down-regulation in lung carcinomas and B-cell chronic lymphocytic leukemia. We found that, in the majority of ovarian carcinomas (61.5%) and in a significant proportion of ovarian and breast cancer cell lines (45%), ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After ARLTS1 restoration by adenoviral transduction, only the negative TOV-112 and the homozygously mutated (MUT) MCF7 cells, but not the OV-90 cells expressing a normal ARLTS1 product, underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the tumorigenic potential of TOV-112 in nude mice. On the contrary, the ARLTS1-MUT induced significantly lower levels of apoptosis in infected cells and reduced in vivo tumorigenesis only partially, supporting the hypothesis that Trp149Stop polymorphism is retained in the general population and predisposes to cancer because of a reduction, but not full loss, of normal ARLTS1 function. (Cancer Res 2006; 66(21): 10287-91)

Supplementary Figure 3 from Alterations of the Tumor Suppressor Gene ARLTS1 in Ovarian Cancer

Supplementary Figure 5 from microRNA-205 Regulates HER3 in Human Breast Cancer

Supplementary Figure 2 from microRNA-205 Regulates HER3 in Human Breast Cancer

Supplementary Table 5 from MicroRNA Signatures in Human Ovarian Cancer

Supplementary Figure 3 from microRNA-205 Regulates HER3 in Human Breast Cancer

Supplementary Figure 1 from Alterations of the Tumor Suppressor Gene ARLTS1 in Ovarian Cancer

Supplementary Table 3 from MicroRNA Signatures in Human Ovarian Cancer

Supplementary Figure 2 from Alterations of the Tumor Suppressor Gene ARLTS1 in Ovarian Cancer

Supplementary Table 2 from MicroRNA Signatures in Human Ovarian Cancer

Supplementary Table 1 from Alterations of the Tumor Suppressor Gene ARLTS1 in Ovarian Cancer

Supplementary Table 1 from MicroRNA Signatures in Human Ovarian Cancer

Epithelial ovarian cancer (EOC) is the sixth most common cancer in women worldwide and, despite advances in detection and therapies, it still represents the most lethal gynecologic malignancy in the industrialized countries. Unfortunately, still relatively little is known about the molecular events that lead to the development of this highly aggressive disease. The relatively recent discovery of microRNAs (miRNA), a class of small noncoding RNAs targeting multiple mRNAs and triggering translation repression and/or RNA degradation, has revealed the existence of a new level of gene expression regulation. Multiple studies involving various types of human cancers proved that miRNAs have a causal role in tumorigenesis. Here we show that, in comparison to normal ovary, miRNAs are aberrantly expressed in human ovarian cancer. The overall miRNA expression could clearly separate normal versus cancer tissues. The most significantly overexpressed miRNAs were miR-200a, miR-141, miR-200c, and miR-200b, whereas miR-199a, miR-140, miR-145, and miR-125b1 were among the most down-modulated miRNAs. We could also identify miRNAs whose expression was correlated with specific ovarian cancer biopathologic features, such as histotype, lymphovascular and organ invasion, and involvement of ovarian surface. Moreover, the levels of miR-21, miR-203, and miR-205, up-modulated in ovarian carcinomas compared with normal tissues, were significantly increased after 5-aza-2′-deoxycytidine demethylating treatment of OVCAR3 cells, suggesting that the DNA hypomethylation could be the mechanism responsible for their overexpression. Our results indicate that miRNAs might play a role in the pathogenesis of human EOC and identify altered miRNA gene methylation as a possible epigenetic mechanism involved in their aberrant expression. [Cancer Res 2007;67(18):8699–707]

Supplementary Table 4 from MicroRNA Signatures in Human Ovarian Cancer

Supplementary Figure 2 from MicroRNA Signatures in Human Ovarian Cancer

Supplementary Figure 1 from microRNA-205 Regulates HER3 in Human Breast Cancer

Supplementary Figure 4 from microRNA-205 Regulates HER3 in Human Breast Cancer

sSupplementary Legends for Figures 1-5 from microRNA-205 Regulates HER3 in Human Breast Cancer

An increasing amount of experimental evidence shows that microRNAs can have a causal role in breast cancer tumorigenesis as a novel class of oncogenes or tumor suppressor genes, depending on the targets they regulate. HER2 overexpression is a hallmark of a particularly aggressive subset of breast tumors, and its activation is strictly dependent on the trans-interaction with other members of HER family; in particular, the activation of the PI3K/Akt survival pathway, so critically important in tumorigenesis, is predominantly driven through phosphorylation of the kinase-inactive member HER3. Here, we show that miR-205, down-modulated in breast tumors compared with normal breast tissue, directly targets HER3 receptor, and inhibits the activation of the downstream mediator Akt. The reintroduction of miR-205 in SKBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity. Our data describe miR-205 as a new oncosuppressor gene in breast cancer, able to interfere with the proliferative pathway mediated by HER receptor family. Our study also provides experimental evidence suggesting that miR-205 can improve the responsiveness to specific anticancer therapies. [Cancer Res 2009;69(6):2195–200]

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the β-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low μM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics.

Carbon fusion reactions $$^{12}$$ 12 C($$^{12}$$ 12 C,p)$$^{23}$$ 23 Na and $$^{12}$$ 12 C($$^{12}$$ 12 C,$$\alpha $$ α )$$^{20}$$ 20 Ne play a key role in the evolution of massive stars and in explosive scenarios such as type-Ia supernovae and super-bursts in binary stars. A direct determination of their cross sections is extremely challenging and discrepancies exist between different data sets in the literature. Here we report the results of a direct measurement performed at the CIRCE Tandem Accelerator Laboratory in Caserta (Italy), using $$\varDelta E-E$$ Δ E - E detectors for unambiguous charge identification. Cross sections were measured in the energy range $$E_{\mathrm{c.m.}} =2.51{-}4.36$$ E c . m . = 2.51 - 4.36 MeV with energy steps between 10 and 25 keV in the centre of mass. To our knowledge these represent the finest energy steps to date. Results are presented in the form of partial and summed astrophysical $${\tilde{S}}$$ S ~ -factors for individual proton- and $$\alpha $$ α -particle channels. Branching ratios of individual proton- and $$\alpha $$ α -particle groups were found to vary significantly with energy. Angular distributions, albeit limited to three angles, were also found to be non-isotropic, which could be a potential explanation for the discrepancies observed among different data sets. Further efforts are ongoing to extend measurements to lower energies.

The re-entry of a vehicle into Earth's atmosphere either from near-Earth orbit or from interplanetary trajectories is the most critical phases of a space mission for materials, since space capsules and spacecraft surfaces are brought to relatively high temperatures (>2000 °C) and are subject to the high thermal fluxes. The most complex requirements of the on-ground CIRA hypersonic Plasma Wind Tunnel (PWT) test campaigns are to measure and monitor the high heat fluxes, the correlated surface Recession Rate and Surface Temperatures affecting the behavior of Thermal Protection System (TPS) materials which makes up the surface and sub-surface components of the spacecraft's outer layer. For these tests, the recession rate will be obtained by Surface Layer Implantation (SLI), monitored by the gamma ray emission from 7Be implanted into the test material, and the surface temperature by Dual Color free emissivity Infrared Thermography (DCIT). So the first purpose of the paper, in the recession rate determination, is to present the γ-ray detection efficiency of a LaBr3(Ce) crystal by GEANT4 simulation using the radioactive ions, to be implanted by means of the CIRCE accelerator, and the use of γ-rays to monitor their removal during the ablation process. At the same time, for temperature determination, is to evaluate the possibility of carrying out free emissivity temperature measurements in unsteady conditions. On the basis of the results, possible validation tests are outlined, through the use of the intense radioactive 7Be beam available at the 3MV Pelletron tandem accelerator of the CIRCE Laboratory and the GHIBLI-PWT facility at CIRA, to present the combined novel, contactless and non-intrusive diagnostics for the simultaneous recession rate and temperature determinations.

Integrins play important roles in physiological and pathophysiological processes. Among the RGD-recognizing integrin subtypes, the αvβ8 receptor is emerging as an attractive target because of its involvement in various illnesses, such as autoimmune diseases, viral infections, and cancer. However, its functions have, so far, not been investigated in living subjects mainly because of the lack of a selective αvβ8 ligand. Here, we report the design and potential medical applications of a cyclic octapeptide as the first highly selective small-molecule ligand for αvβ8. Remarkably, this compound displays low nanomolar αvβ8 binding affinity and a strong discriminating power of at least 2 orders of magnitude versus other RGD-recognizing integrins. Peptide functionalization with fluorescent or radioactive labels enables the selective imaging of αvβ8-positive cells and tissues. This new probe will pave the way for detailed characterization of the distinct (patho)physiological role of this relatively unexplored integrin, providing a basis to fully exploit the potential of αvβ8 as a target for molecular diagnostics and personalized therapy regimens.

Mutations in the

When considering industrial applications in which liquid-filled containers are transported by a robot, the performed motions can cause undesired liquid stirring inside the container (also known as liquid sloshing), especially when the robot end-effector reaches high accelerations. The use of a simple sloshing-dynamics prediction model can be used for constrained-optimization purposes. The aim of this work is the time-optimal trajectory planning of an industrial robot carrying a cylindrical container filled with liquid, imposing limits on the liquid's sloshing for 1D and 2D planar motions of the container. Experimental tests taking into account three different paths are described, considering both non-optimized and optimized motions. Results from the experiments are illustrated and discussed, thus proving the effectiveness of the optimization.

This paper investigates the use of smartphone in older people everyday life and it is based on an empirical research involving 30 Italian smartphone users aged 62–76. The research drawn on the anal...

Il presente lavoro rappresenta un pretesto per attivare una riflessione sulla genitorialità e le pratiche diparentingnelle scuole. A tale scopo è stata effettuata nel 2017 una ricerca di tipo esplorativo, che ha visto il coinvolgimento dei genitori di studenti di una Scuola Superiore della provincia di Salerno. Lo studio ha permesso di rilevare alcune dimensioni delparentingquali: ilcoinvolgimentogenitoriale nelle attività̀ del proprio figlio, ilparenting positivo, lasupervisionedel proprio figlio, il tipo didisciplinae dipunizioniutilizzate dai genitori, cercando inoltre di evidenziare eventuali differenze tra padri e madri. Come strumento è stato utilizzato l’Alabama Parenting Questionnaire (APQ), un questionario di autovalutazione delle pratiche educative dei genitori. L’APQ raccoglie le stime del genitore sulla frequenza dei comportamenti educativi nel corso delle interazioni ordinarie con il proprio figlio. Esso è tra gli strumenti diassessmentpiù utilizzati per rilevare le dimensioni delparentingmaggiormente correlate al mantenimento dei problemi comportamentali nell’infanzia e nell’adolescenza. I risultati mostrano un elevatocoinvolgimento del genitore nella vita del proprio figlio e utilizzo di pratiche diparenting positivoemonitoringadeguato; ladisciplinarisulta “quasi mai” incoerente e lapunizione fisica“quasi mai” utilizzata. Le madri hanno mostrato, rispetto ai padri, maggiorecoinvolgimentonella vita dei propri figli e livelli diparenting positivopiù alti. Esse inoltre fanno registrare una elevata supervisione sulla condotta del proprio figlio e una maggiore inclinazione all’utilizzo dipratiche disciplinari alternativea quella fisica.

Background: Current Rehabilitation in the Home (RITH) programs provide rehabilitation for people with a variety of conditions, yet little evidence is available to guide admission criteria. The primary aim of this cross-sectional study was to profile patients admitted to a non-condition specific RITH program. The secondary aim was to explore factors influencing program outcomes.Methods: This retrospective audit utilised a two-year dataset collected from patients, aged ≥60 years, admitted under a RITH program. Clinical information such as age, sex, hospital utilisation, past medical history, functional and social status were collected to profile the patients. Outcomes such as length of stay, FIM change and hospital representations were used to determine success in the program. A regression analysis was conducted to determined variables that were independently related to the outcome.Results: Among the 202 patients included, patients were on average 78 years of age, living with three comorbid conditions, and have an average stay of 29 days in hospital prior to rehabilitation. The presence of home modifications was found to be an independent factor that correlated with RITH length of stay, FIM change scores and hospital readmissions. In addition, factors such as age, comorbidities, acute hospital length of stay and carer status were shown to correlate with at least two out of three of the outcomes. Conclusions: This study suggest that commonly collected information such as age, acute hospital length of stay, presence of home modifications and carer status may be used to better identify suitable patients for a non-condition specific RITH program. Trial registration: This study was approved through SWSLHD’s Human Research Ethics Committee (approval number: CT06_2019).

Telomerase activity has been regarded as a critical step in cellular immortalization and carcinogenesis and because of this, regulation of telomerase represents an attractive target for anti-tumor specific therapeutics. Recently, one avenue of cancer research focuses on antisense strategy to target the oncogenes or cancer driver genes, in a sequence specific fashion to down-regulate the expression of the target gene. The protein catalytic subunit, human telomerase reverse transcriptase (hTERT) and the template RNA component (hTERC) are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the gene expression of hTERT or the hTERC of the telomerase enzymatic complex. The present study showed that phosphorothioate antisense oligonucleotide (sASO)-nuclear localization signal (NLS) peptide conjugates targeting hTERC could inhibit telomerase activity very efficiently at 5 μM concentration but less efficiently at 1 μM concentration. On the other hand, siRNA targeting hTERT mRNA could strongly suppress hTERT expression at 200 nM concentration. It was also revealed that siRNA targeting hTERT could induce telomere attrition and then irreversible arrest of proliferation of cancer cells.

12C fusion reactions are among the most important in stellar evolution since they determine the destiny of massive stars. Over the past fifty years, massive efforts have been done to measure these reactions at low energies. However, existing data present several discrepancies between sets and large uncertainties specially at the lowest energies. Factors such as beam/environmental backgrounds, extremely low cross sections and insufficient knowledge of the reaction mechanism contribute to these problems. Recently, the ERNA collaboration measured the 12C+12C reactions at Ec.m. = 2.51 - 4.36 MeV with energy steps between 10 and 25 keV in the centre of mass. Representing the smallest energy steps to date. In these measurements, beam induced background was minimised and S-factors for the proton and alpha channels were calculated. Results indicate that a possible explanation for the discrepancies between data sets is the wrongly assumed constant branching ratios and isotropical angular distributions. Given the excellent performance of the detectors for low energy measurements, a collaboration with the LUNA group (LNGS) has started. Background measurements underground are being performed and results indicate it could be possible to measure the 12C+12C reactions directly into the Gamow Window.