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Students and instructors bring varying levels of experience and expectations to online learning. This became even more apparent in March 2020 when the pandemic disrupted face-to-face instruction and required rapid conversion to remote teaching. In this study, mixed methods were used to understand how students perceived these instructional changes and to examine the effects of remote learning on their approach to subsequent coursework and faculty interactions. First, open-ended survey data collected from students enrolled in a summer 2020 nonmajors asynchronous laboratory course were analyzed to learn more about students' spring 2020 remote learning experiences. The questions directly addressed remote learning experiences and emphasized study strategies learned, faculty communication modes, and students' perceived ability at taking online courses. Second, four consecutive years of survey data--including both Likert-type scale surveys and open-ended questions--were analyzed to identify core themes and to measure variations between cohorts. These data present a unique opportunity in that they allow for critical analyses and document differences in online learning experiences for student cohorts pre- (2017-2019) and post- (2020) the COVID-19 disruption. The findings from the survey data can be used to inform how faculty may better focus their teaching efforts while promoting student learning and engagement during a time of continued teaching disruption and uncertainty. The overall results of this study are applicable to all levels of chemistry courses. In addition, the established nonmajors online laboratory course model presented in this study provides a strong example for others who are developing new online or hybrid chemistry courses.

This case report concerns a 48-year-old man with a history of ischemic stroke at the age of 41 who reported cardiac hypertrophy, registered in his twenties when explained by increased physical activity. Family history was positive for a mother with permanent atrial fibrillation from her mid-thirties. At the age of 44, he had a first episode of persistent atrial fibrillation, accompanied by left atrial thrombosis while on a direct oral anticoagulant. He presented at our clinic at the age of 45 with another episode of persistent atrial fibrillation and decompensated heart failure. Echocardiography revealed a dilated left atrium, reduced left ventricular ejection fraction, and an asymmetric left ventricular hypertrophy. Cardiac magnetic resonance was positive for a cardiomyopathy with diffuse fibrosis, while slow-flow phenomenon was present on coronary angiography. Genetic testing by whole-exome sequencing revealed three variants in the patient, c.309C > A, p.His103Gln in the ACTC1 gene, c.116T > G, p.Leu39Ter in the PLN gene, and c.5827C > T, p.His1943Tyr in the SCN5A gene, the first two associated with hypertrophic cardiomyopathy and the latter possibly with familial atrial fibrillation. This case illustrates the need for advanced diagnostics in unexplained left ventricular hypertrophy, as hypertrophic cardiomyopathy is often overlooked, leading to potentially debilitating health consequences.

Currently, one of the most important challenges for the conservation of stone artworks is the removal of metal corrosion products on their surfaces. Traditional cleaning methods, which typically involve the application of aqueous solutions containing chelating agents capable of complexing these metal ions, have shown some weaknesses. These weaknesses become apparent when such methods are applied to statues and other vertical surfaces or when aiming to limit the cleaning process to a specific area with controlled application times. Furthermore, the porosity of the stone surface plays a role concerning the cleaning efficiency. To address these issues, chelating agents can be incorporated into gel-like materials. This study is a proof of concept to evaluate the cleaning efficacy of various gel formulations composed of polyvinyl alcohol (PVA), borax (B), and agarose (AG), loaded with two chelators: ethylenediaminetetraacetic acid (EDTA) and potassium sodium tartrate (PST or Rochelle salt). Three types of carbonate stones (travertine, Lecce stone, and Carrara marble) characterized by different porosities were artificially stained with copper sulphates and treated with the different PVA-B-AG formulations. The effectiveness of the treatment was directly monitored on the stones using a multi-technique approach that included scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS) and non-invasive portable nuclear magnetic resonance (NMR). Additionally, the rheological properties of the gels were investigated, and the Fourier transform infrared attenuated total reflection spectroscopy (FTIR ATR) was used to analyse the chemical structure of the gel before and after treatment, aiming to understand the changes induced by the cleaning process.

The identification of targets whose inactivation increases the activity of antibiotics helps to fight antibiotic resistance. Previous work showed that a transposon-insertion mutant in the gene PA14_27940 increases Pseudomonas aeruginosa susceptibility to aminoglycosides. Since polar effects may affect the phenotype, in the present work, we generated an in-frame PA14_27940 deletion mutant. A PA14_27940 deletion increased the susceptibility to aminoglycosides, tetracycline, tigecycline, erythromycin and fosfomycin. Excepting fosfomycin, the other antibiotics are inducers of the MexXY efflux pump. MexXY induction is required for P. aeruginosa resistance to these antibiotics, which is post-transcriptionally regulated by the anti-repressor ArmZ. Although mexXY is inducible by tobramycin in ΔPA14_27940, the induction level is lower than in the parental PA14 strain. Additionally, armZ is induced by tobramycin in PA14 and not in ΔPA14_27940, supporting that ΔPA14_27940 presents an ArmZ-mediated defect in mexXY induction. For its part, hypersusceptibility to fosfomycin may be due to a reduced expression of nagZ and agmK, which encode enzymes of the peptidoglycan recycling pathway. ΔPA14_27940 also presents defects in motility, an element with relevance in P. aeruginosa’s virulence. Overall, our results support that PA14_27940 is a good target for the search of adjuvants that will increase the activity of antibiotics and reduce the virulence of P. aeruginosa.

Small cell lung cancer (SCLC) has been historically considered a homogeneous disease and thus approached as a single entity when it comes to clinical studies design and new treatments developments. However, increasing knowledge in the genetic and molecular landscape of this disease challenges this concept, opening the possibility that different subtypes might show differential vulnerability to treatments. In this narrative review, we gather the most relevant advances in genetic and molecular characterization of SCLC, focusing on how these discoveries may be used to design the path for a personalized treatment approach. Indeed, we discuss the new classification based on differential protein expression, the prevalence and significance of oncogenic drivers (e.g., EGFR mutations and ALK rearrangements) in SCLC, the genetic characteristics of SCLC in patients with no smoking history, and the existing evidence supporting the use of liquid biopsy for capturing the heterogeneity of the disease. We use the keywords “small cell lung cancer”, “SCLC”, “EGFR”, “ALK”, “histological transformation”, and “transcriptional factors” to identify original research manuscripts, clinical trials, case reports, and case series from PubMed.

Helicobacter pylori is a leading cause of chronic gastric inflammation, generally associated with gastritis and adenocarcinoma. Activation of the NF-κB pathway mainly contributes to the inflammatory phenotype observed in H. pylori infection in humans and experimental models. Since the gastric epithelium undergoes rapid turnover, inflammation and pathogenicity of H. pylori result from early phase and chronically activated pathways. In the present study we investigated the early host response to H. pylori in non-tumoral human gastric epithelial cells (GES-1). To dissect the pathogen-specific mechanisms we also examined the response to tumor necrosis factor (TNF), a prototypical cytokine. By analyzing the activation state of NF-κB signaling, cytokine expression and secretion, and the transcriptome, we found that the inflammatory response of GES-1 cells to H. pylori and TNF results from activation of multiple pathways and transcription factors, e.g., NF-κB and CCAAT/enhancer-binding proteins (CEBPs). By comparing the transcriptomic profiles, we found that H. pylori infection induces a less potent inflammatory response than TNF but affects gene transcription to a greater extent by specifically inducing transcription factors such as CEBPβ and numerous zinc finger proteins. Our study provides insights on the cellular pathways modulated by H. pylori in non-tumoral human gastric cells unveiling new potential targets.

By virtue of their unique physicochemical properties, gold nanoparticles (AuNPs) have gained significant interest in a broad range of biomedical applications such as sensors, diagnosis, and therapy. AuNPs are generally synthesized via different conventional physical and chemical methods, which often use harmful chemicals that induce health hazards and pollute the environment. To overcome these issues, green synthesis techniques have evolved as alternative and eco-friendly approaches to the synthesis of environmentally safe and less-expensive nanoparticles using naturally available metabolites from plants and microorganisms such as bacteria, fungi, and algae. This review provides an overview of the advances in the synthesis of AuNPs using different biological resources with examples, and their profound applications in biomedicine. A special focus on the biosynthesis of AuNPs using different medicinal plants and their multifunctional applications in antibacterial, anti-inflammatory, and immune responses are featured. Additionally, the applications of AuNPs in cancer theranostics, including contrast imaging, drug delivery, hyperthermia, and cancer therapeutics, are comprehensively discussed. Moreover, this review will shed light on the importance of the green synthesis approach, and discuss the advantages, challenges, and prospects in this field.

The conjugation of photosensitizer with collagen seems to be a very promising approach for innovative topical photodynamic therapy (PDT). The study aims to evaluate the effects of bovine collagen hydrolysate (Clg) on the properties of gallium (III) phthalocyanine (GaPc) on pigmented melanoma. The interaction of GaPc with Clg to form a conjugate (GaPc-Clg) showed a reduction of the intensive absorption Q-band (681 nm) with a blue shift of the maximum (678 nm) and a loss of shape of the UV-band (354 nm). The fluorescence of GaPc, with a strong emission peak at 694 nm was blue shifted due to the conjugation which lower intensity owing to reduce quantum yield (0.012 vs. 0.23, GaPc). The photo- and dark cytotoxicity of GaPc, Glg and GaPc-Clg on pigmented melanoma cells (SH-4) and two normal cell lines (BJ and HaCaT) showed a slight decrease of cytotoxicity for a conjugate, with low selectivity index (0.71 vs. 1.49 for GaPc). The present study suggests that the ability of collagen hydrolysate to form gels minimizes the high dark toxicity of GaPc. Collagen used for conjugation of a photosensitizer might be an essential step in advanced topical PDT.

Gold nanoparticles (AuNPs) are promising candidates in various biomedical applications such as sensors, imaging, and cancer therapy. Understanding the influence of AuNPs on lipid membranes is important to assure their safety in the biological environment and to improve their scope in nanomedicine. In this regard, the present study aimed to analyze the effects of different concentrations (0.5, 1, and 2 wt.%) of dodecanethiol functionalized hydrophobic AuNPs on the structure and fluidity of zwitterionic 1-stearoyl-2-oleoyl-sn-glycerol-3-phosphocholine (SOPC) lipid bilayer membranes using Fourier-transform infrared (FTIR) spectroscopy and fluorescent spectroscopy. The size of AuNPs was found to be 2.2 ± 1.1 nm using transmission electron microscopy. FTIR results have shown that the AuNPs induced a slight shift in methylene stretching bands, while the band positions of carbonyl and phosphate group stretching were unaffected. Temperature-dependent fluorescent anisotropy measurements showed that the incorporation of AuNPs up to 2 wt.% did not affect the lipid order in membranes. Overall, these results indicate that the hydrophobic AuNPs in the studied concentration did not cause any significant alterations in the structure and membrane fluidity, which suggests the suitability of these particles to form liposome–AuNP hybrids for diverse biomedical applications including drug delivery and therapy.

Non-small-cell lung cancer (NSCLC) is the major cause of cancer-related deaths worldwide, due to its high incidence and mortality [...]

The pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) is multifactorial and there is a substantial consensus on the role of antiresorptive drugs (ARDs), including bisphosphonates (BPs) and denosumab (Dmab), as one of the main determinants. The time exposure, cumulative dose and administration intensity of these drugs are critical parameters to be considered in the treatment of patients, as cancer patients show the highest incidence of MRONJ. BPs and Dmab have distinct mechanisms of action on bone, but they also exert different effects on immune subsets which interact with bone cells, thus contributing to the onset of MRONJ. Here, we summarized the main effects of ARDs on the different immune cell subsets, which consequently affect bone cells, particularly osteoclasts and osteoblasts. Data from animal models and MRONJ patients showed a deep interference of ARDs in modulating immune cells, even though a large part of the literature concerns the effects of BPs and there is a lack of data on Dmab, demonstrating the need to further studies.

Understanding the consequences in bacterial physiology of the acquisition of drug resistance is needed to identify and exploit the weaknesses derived from it. One of them is collateral sensitivity, a potentially exploitable phenotype that, unfortunately, is not always conserved among different isolates. The identification of robust, conserved collateral sensitivity patterns is then relevant for the translation of this knowledge into clinical practice. We have previously identified a robust fosfomycin collateral sensitivity pattern of Pseudomonas aeruginosa that emerged in different tobramycin-resistant clones. To go one step further, here, we studied if the acquisition of resistance to tobramycin is associated with robust collateral sensitivity to fosfomycin among P. aeruginosa isolates. To that aim, we analyzed, using adaptive laboratory evolution approaches, 23 different clinical isolates of P. aeruginosa presenting diverse mutational resistomes. Nine of them showed collateral sensitivity to fosfomycin, indicating that this phenotype is contingent on the genetic background. Interestingly, collateral sensitivity to fosfomycin was linked to a larger increase in tobramycin minimal inhibitory concentration. Further, we unveiled that fosA low expression, rendering a higher intracellular accumulation of fosfomycin, and a reduction in the expression of the P. aeruginosa alternative peptidoglycan-recycling pathway enzymes, might be on the basis of the collateral sensitivity phenotype.

Chemosensory pathways and two-component systems are important bacterial signal transduction systems. In the human pathogen Pseudomonas aeruginosa, these systems control many virulence traits. Previous studies showed that inorganic phosphate (Pi) deficiency induces virulence. We report here the abundance of chemosensory and two-component signaling proteins of P. aeruginosa grown in Pi deficient and sufficient media. The cellular abundance of chemoreceptors differed greatly, since a 2400-fold difference between the most and least abundant receptors was observed. For many chemoreceptors, their amount varied with the growth condition. The amount of chemoreceptors did not correlate with the magnitude of chemotaxis to their cognate chemoeffectors. Of the four chemosensory pathways, proteins of the Che chemotaxis pathway were most abundant and showed little variation in different growth conditions. The abundance of chemoreceptors and solute binding proteins indicates a sensing preference for amino acids and polyamines. There was an excess of response regulators over sensor histidine kinases in two-component systems. In contrast, ratios of the response regulators CheY and CheB to the histidine kinase CheA of the Che pathway were all below 1, indicative of different signaling mechanisms. This study will serve as a reference for exploring sensing preferences and signaling mechanisms of other bacteria.

We have derived values of the ultraviolet index (UVI) at solar noon using the Tropospheric Ultraviolet Model (TUV) driven by ozone, temperature and aerosol fields from climate simulations of the first phase of the Chemistry-Climate Model Initiative (CCMI-1). Since clouds remain one of the largest uncertainties in climate projections, we simulated only the clear-sky UVI. We compared the modelled UVI climatologies against present-day climatological values of UVI derived from both satellite data (the OMI-Aura OMUVBd product) and ground-based measurements (from the NDACC network). Depending on the region, relative differences between the UVI obtained from CCMI/TUV calculations and the ground-based measurements ranged between −5.9 % and 10.6 %. We then calculated the UVI evolution throughout the 21st century for the four Representative Concentration Pathways (RCPs 2.6, 4.5, 6.0 and 8.5). Compared to 1960s values, we found an average increase in the UVI in 2100 (of 2 %–4 %) in the tropical belt (30∘ N–30∘ S). For the mid-latitudes, we observed a 1.8 % to 3.4 % increase in the Southern Hemisphere for RCPs 2.6, 4.5 and 6.0 and found a 2.3 % decrease in RCP 8.5. Higher increases in UVI are projected in the Northern Hemisphere except for RCP 8.5. At high latitudes, ozone recovery is well identified and induces a complete return of mean UVI levels to 1960 values for RCP 8.5 in the Southern Hemisphere. In the Northern Hemisphere, UVI levels in 2100 are higher by 0.5 % to 5.5 % for RCPs 2.6, 4.5 and 6.0 and they are lower by 7.9 % for RCP 8.5. We analysed the impacts of greenhouse gases (GHGs) and ozone-depleting substances (ODSs) on UVI from 1960 by comparing CCMI sensitivity simulations (1960–2100) with fixed GHGs or ODSs at their respective 1960 levels. As expected with ODS fixed at their 1960 levels, there is no large decrease in ozone levels and consequently no sudden increase in UVI levels. With fixed GHG, we observed a delayed return of ozone to 1960 values, with a corresponding pattern of change observed on UVI, and looking at the UVI difference between 2090s values and 1960s values, we found an 8 % increase in the tropical belt during the summer of each hemisphere. Finally we show that, while in the Southern Hemisphere the UVI is mainly driven by total ozone column, in the Northern Hemisphere both total ozone column and aerosol optical depth drive UVI levels, with aerosol optical depth having twice as much influence on the UVI as total ozone column does.

In the fight against prostate cancer (PCa), TRPM8 is one of the most promising clinical targets. Indeed, several studies have highlighted that TRPM8 involvement is key in PCa progression because of its impact on cell proliferation, viability, and migration. However, data from the literature are somewhat contradictory regarding the precise role of TRPM8 in prostatic carcinogenesis and are mostly based on in vitro studies. The purpose of this study was to clarify the role played by TRPM8 in PCa progression. We used a prostate orthotopic xenograft mouse model to show that TRPM8 overexpression dramatically limited tumor growth and metastasis dissemination in vivo. Mechanistically, our in vitro data revealed that TRPM8 inhibited tumor growth by affecting the cell proliferation and clonogenic properties of PCa cells. Moreover, TRPM8 impacted metastatic dissemination mainly by impairing cytoskeleton dynamics and focal adhesion formation through the inhibition of the Cdc42, Rac1, ERK, and FAK pathways. Lastly, we proved the in vivo efficiency of a new tool based on lipid nanocapsules containing WS12 in limiting the TRPM8–positive cells’ dissemination at metastatic sites. Our work strongly supports the protective role of TRPM8 on PCa progression, providing new insights into the potential application of TRPM8 as a therapeutic target in PCa treatment.

Adenosinergic signaling is an important regulator of tissue homeostasis and extracellular accumulation of adenosine (Ado) and is associated with different pathologies, such as cancer. In non-small-cell lung cancer (NSCLC), a subset of CD133/CXCR4+ cancer stem cell (CSCs) has been demonstrated to initiate bone metastases. Here we investigated how NSCLC CSCs interact with osteoclasts (OCs) and osteoblasts (OBs) by modulating Ado production and OC activity. We proved that CSC-spheres, generated in vitro from NSCLC cell lines, express CD38, PC-1, and CD73, enzymes of the non-canonical adenosinergic pathway, produce high level of Ado, and down-regulate A1R and A3R inhibitory receptors, while expressing A2AR and A2BR. To address the Ado role and modulation of the in-bone pre-metastatic niche, we performed co-cultures of CSC-spheres with OCs and OBs cells. Firstly, we verified that active OCs do not activate non-canonical the adenosinergic pathway, conversely to OBs. OCs co-cultured with CSC-spheres increase Ado production that is related to the OC resorption activity and contributes to T-cell suppression. Finally, we proved the efficacy of anti-CD73 agents in blocking NSCLC cell migration. Overall, we assessed the importance of adenosinergic signaling in the interaction between CSCs and OCs at the pre-metastatic niche, with therapeutic implications related to Ado production.

Sulfate geoengineering (SG), made by sustained injection of SO2 in the tropical lower stratosphere, may impact the CH4 abundance through several photochemical mechanisms affecting tropospheric OH and hence the methane lifetime. (a) The reflection of incoming solar radiation increases the planetary albedo and cools the surface, with a tropospheric H2O decrease. (b) The tropospheric UV budget is upset by the additional aerosol scattering and stratospheric ozone changes: the net effect is meridionally not uniform, with a net decrease in the tropics, thus producing less tropospheric O(1D). (c) The extratropical downwelling motion from the lower stratosphere tends to increase the sulfate aerosol surface area density available for heterogeneous chemical reactions in the mid-to-upper troposphere, thus reducing the amount of NOx and O3 production. (d) The tropical lower stratosphere is warmed by solar and planetary radiation absorption by the aerosols. The heating rate perturbation is highly latitude dependent, producing a stronger meridional component of the Brewer–Dobson circulation. The net effect on tropospheric OH due to the enhanced stratosphere–troposphere exchange may be positive or negative depending on the net result of different superimposed species perturbations (CH4, NOy, O3, SO4) in the extratropical upper troposphere and lower stratosphere (UTLS). In addition, the atmospheric stabilization resulting from the tropospheric cooling and lower stratospheric warming favors an additional decrease of the UTLS extratropical CH4 by lowering the horizontal eddy mixing. Two climate–chemistry coupled models are used to explore the above radiative, chemical and dynamical mechanisms affecting CH4 transport and lifetime (ULAQ-CCM and GEOSCCM). The CH4 lifetime may become significantly longer (by approximately 16 %) with a sustained injection of 8 Tg-SO2 yr−1 starting in the year 2020, which implies an increase of tropospheric CH4 (200 ppbv) and a positive indirect radiative forcing of sulfate geoengineering due to CH4 changes (+0.10 W m−2 in the 2040–2049 decade and +0.15 W m−2 in the 2060–2069 decade).

Reconstruction of bony defects is challenging when conventional grafting methods are used because of their intrinsic limitations (biological cost and/or biological properties). Bone regeneration techniques are rapidly evolving since the introduction of three-dimensional (3D) bioprinting. Bone tissue engineering is a branch of regenerative medicine that aims to find new solutions to treat bone defects, which can be repaired by 3D printed living tissues. Its aim is to overcome the limitations of conventional treatment options by improving osteoinduction and osteoconduction. Several techniques of bone bioprinting have been developed: inkjet, extrusion, and light-based 3D printers are nowadays available. Bioinks, i.e., the printing materials, also presented an evolution over the years. It seems that these new technologies might be extremely promising for bone regeneration. The purpose of the present review is to give a comprehensive summary of the past, the present, and future developments of bone bioprinting and bioinks, focusing the attention on crucial aspects of bone bioprinting such as selecting cell sources and attaining a viable vascularization within the newly printed bone. The main bioprinters currently available on the market and their characteristics have been taken into consideration, as well.

Background: Attaining an effective mucosal attachment to the transmucosal part of the implant could protect the peri-implant bone. Aim: To evaluate if chair side surface treatments (plasma of Argon and ultraviolet light) may affect fibroblast adhesion on different titanium surfaces designed for soft tissue healing. Methods: Grade 5 titanium discs with four different surface topographies were subdivided into 3 groups: argon-plasma; ultraviolet light, and no treatment. Cell morphology and adhesion tests were performed at 20 min, 24 h, and 72 h. Results: Qualitative observation of the surfaces performed at the SEM was in accordance with the anticipated features. Roughness values ranged from smooth (MAC Sa = 0.2) to very rough (XA Sa = 21). At 20 min, all the untreated surfaces presented hemispherical cells with reduced filopodia, while the cells on treated samples were more spread with broad lamellipodia. However, these differences in spreading behavior disappeared at 24 h and 72 h. Argon-plasma, but not UV, significantly increased the number of fibroblasts independently of the surface type but only at 20 min. Statistically, there was no surface in combination with a treatment that favored a greater cellular adhesion. Conclusions: Data showed potential biological benefits of treating implant abutment surfaces with the plasma of argon in relation to early-stage cell adhesion.

In this study we examine the performance of 31 global model radiative transfer schemes in cloud-free conditions with prescribed gaseous absorbers and no aerosols (Rayleigh atmosphere), with prescribed scattering-only aerosols, and with more absorbing aerosols. Results are compared to benchmark results from high-resolution, multi-angular line-by-line radiation models. For purely scattering aerosols, model bias relative to the line-by-line models in the top-of-the atmosphere aerosol radiative forcing ranges from roughly −10 to 20%, with over- and underestimates of radiative cooling at lower and higher solar zenith angle, respectively. Inter-model diversity (relative standard deviation) increases from ~10 to 15% as solar zenith angle decreases. Inter-model diversity in atmospheric and surface forcing decreases with increased aerosol absorption, indicating that the treatment of multiple-scattering is more variable than aerosol absorption in the models considered. Aerosol radiative forcing results from multi-stream models are generally in better agreement with the line-by-line results than the simpler two-stream schemes. Considering radiative fluxes, model performance is generally the same or slightly better than results from previous radiation scheme intercomparisons. However, the inter-model diversity in aerosol radiative forcing remains large, primarily as a result of the treatment of multiple-scattering. Results indicate that global models that estimate aerosol radiative forcing with two-stream radiation schemes may be subject to persistent biases introduced by these schemes, particularly for regional aerosol forcing.

The rapid development and application of nanotechnology to biological interfaces has impacted the bone implant field, allowing researchers to finely modulate the interface between biomaterials and recipient tissues. In the present study, oxidative anodization was exploited to generate two alumina surfaces with different pore diameters. The former displayed surface pores in the mean range of 16–30 nm, while in the latter pores varied from to 65 to 89 nm. The samples were characterized by Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive X-ray spectroscopy (EDX) analysis prior to being tested with pre-osteoblastic MC3T3-E1 cells. In vitro cell response was studied in terms of early cell adhesion, viability, and morphology, including focal adhesion quantification. Both the alumina samples promoted higher cell adhesion and viability than the control condition represented by the standard culture dish plastic. Osteogenic differentiation was assessed through alkaline phosphatase activity and extracellular calcium deposition, and it was found that of the two nano-surfaces, one was more efficient than the other. By comparing for the first time two nano-porous alumina surfaces with different pore diameters, our data supported the role of nano-topography in inducing cell response. Modulating a simple aspect of surface texture may become an attractive route for guiding bone healing and regeneration around implantable metals.

Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma cfDNA quantification was performed by quantitative PCR (qPCR) whereas CTCs were isolated by the ScreenCell Cyto (ScreenCell, Paris, France) device and enumerated according to malignant features. Patients with baseline cfDNA higher than the median value (96.3 hTERT copy number) had a significantly worse overall survival (OS) and double the risk of death (hazard ratio (HR): 2.14; 95% confidence limits (CL) = 1.24–3.68; p-value = 0.006). Conversely, an inverse relationship between CTC median baseline number (6 CTC/3 mL of blood) and OS was observed. In addition, we found that in patients reporting stable disease (SD), the baseline cfDNA and CTCs were able to discriminate patients at high risk of poor survival. cfDNA demonstrated a more reliable biomarker than CTCs in the overall population. In the subgroup of SD patients, both biomarkers identified patients at high risk of poor prognosis who might deserve additional/alternative therapeutic interventions.

Transport codes are frequently used for describing fusion plasmas with the aim to prepare tokamak operations. Considering novel codes, such as SolEdge3X-HDG, synthetic diagnostics are a common technique used to validate new models and confront them with experimental data. The purpose of this study is to develop a set of synthetic diagnostics, starting from bolometer and visible cameras for the WEST tokamak, in order to compare the code results with the experimental data. This research is done in the framework of Raysect and Cherab Python libraries. This allows us to process various synthetic diagnostics in the same fashion in terms of 3D ray tracing with volume emitters developed specifically for fusion plasmas. We were able to implement the WEST tokamak model and the design of bolometer and visible cameras. Synthetic signals, based on full-discharge WEST plasma simulation, were used for to compare the SolEdge3X-HDG output plasma with experimental data. The study also considers the optical properties of the plasma-facing components (PFCs) and their influence on the performance of diagnostics. The paper shows a unified approach to synthetic diagnostic design, which will be further extended to cover the remaining diagnostics on the WEST tokamak.

Aside from the direct surface cooling that sulfate geoengineering (SG) would produce, investigations of the possible side effects of this method are still ongoing, such as the exploration of the effect that SG may have on upper tropospheric cirrus cloudiness. The goal of the present study is to better understand the SG thermodynamical effects on the freezing mechanisms leading to ice particle formation. This is undertaken by comparing SG model simulations against a Representative Concentration Pathway 4.5 (RCP4.5) reference case. In the first case, the aerosol-driven surface cooling is included and coupled to the stratospheric warming resulting from the aerosol absorption of terrestrial and solar near-infrared radiation. In a second SG perturbed case, the surface temperatures are kept unchanged with respect to the reference RCP4.5 case. When combined, surface cooling and lower stratospheric warming tend to stabilize the atmosphere, which decreases the turbulence and updraft velocities (−10 % in our modeling study). The net effect is an induced cirrus thinning, which may then produce a significant indirect negative radiative forcing (RF). This RF would go in the same direction as the direct effect of solar radiation scattering by aerosols, and would consequently influence the amount of sulfur needed to counteract the positive RF due to greenhouse gases. In our study, given an 8 Tg-SO2 yr−1 equatorial injection into the lower stratosphere, an all-sky net tropopause RF of −1.46 W m−2 is calculated, of which −0.3 W m−2 (20 %) is from the indirect effect on cirrus thinning (6 % reduction in ice optical depth). When surface cooling is ignored, the ice optical depth reduction is lowered to 3 %, with an all-sky net tropopause RF of −1.4 W m−2, of which −0.14 W m−2 (10 %) is from cirrus thinning. Relative to the clear-sky net tropopause RF due to SG aerosols (−2.1 W m−2), the cumulative effect of the background clouds and cirrus thinning accounts for +0.6 W m−2, due to the partial compensation of large positive shortwave (+1.6 W m−2) and negative longwave adjustments (−1.0 W m−2). When surface cooling is ignored, the net cloud adjustment becomes +0.8 W m−2, with the shortwave contribution (+1.5 W m−2) almost twice as much as that of the longwave (−0.7 W m−2). This highlights the importance of including all of the dynamical feedbacks of SG aerosols.

Bacterial leaf scorch (BLS), caused by Xylella fastidiosa (Xf), is a prevalent disease of blueberries in the southeastern United States. Initially, this disease was reported to be caused by X. fastidiosa subsp. multiplex (Xfm). However, a recent survey revealed the presence of another subspecies, X. fastidiosa subsp. fastidiosa (Xff), within naturally infected blueberry plantings in Georgia. Since knowledge regarding the origins of isolates causing Xf outbreaks can impact management recommendations, a routine method for identifying the pathogen at the subspecies level can be beneficial. Several detection strategies are available to identify Xf infection at the subspecies level. However, none of these have been developed for the routine and rapid differentiation of the blueberry-infecting Xf subspecies. Here, we developed two separate straightforward and rapid detection techniques, a cleaved amplified polymorphic sequence (CAPS) marker, and a loop-mediated isothermal amplification (LAMP) assay, targeting the RNA polymerase sigma-70 factor (rpoD) gene sequence of Xfm to discriminate between the two Xf subspecies infecting blueberry. With the CAPS marker, specific detection of Xfm isolates was possible from pure cultures, inoculated greenhouse-grown plant samples, and field infected blueberry samples by restriction digestion of the rpoD gene PCR product (amplified with primers RST31 and RST33) using the BtsI enzyme. The LAMP assay allowed for specific real-time amplification of a 204-bp portion of the XfmrpoD gene from both pure bacterial cultures and infected plant material using the Genie® III system, a result further affirmed by gel electrophoresis and SYBR™ Green I DNA staining for visual observation. These detection strategies have the potential to greatly aid existing diagnostic methods for determining the distribution and prevalence of these Xf subspecies causing bacterial leaf scorch (BLS) in blueberries in the southeastern United States.

Ozone fields simulated for the first phase of the Chemistry-Climate Model Initiative (CCMI-1) will be used as forcing data in the 6th Coupled Model Intercomparison Project. Here we assess, using reference and sensitivity simulations produced for CCMI-1, the suitability of CCMI-1 model results for this process, investigating the degree of consistency amongst models regarding their responses to variations in individual forcings. We consider the influences of methane, nitrous oxide, a combination of chlorinated or brominated ozone-depleting substances, and a combination of carbon dioxide and other greenhouse gases. We find varying degrees of consistency in the models' responses in ozone to these individual forcings, including some considerable disagreement. In particular, the response of total-column ozone to these forcings is less consistent across the multi-model ensemble than profile comparisons. We analyse how stratospheric age of air, a commonly used diagnostic of stratospheric transport, responds to the forcings. For this diagnostic we find some salient differences in model behaviour, which may explain some of the findings for ozone. The findings imply that the ozone fields derived from CCMI-1 are subject to considerable uncertainties regarding the impacts of these anthropogenic forcings. We offer some thoughts on how to best approach the problem of generating a consensus ozone database from a multi-model ensemble such as CCMI-1.

The exploration of planetary surfaces with unmanned wheeled vehicles will require sophisticated software for guidance, navigation and control. Future missions will be designed to study harsh environments that are characterized by rough terrains and extreme conditions. An accurate knowledge of the trajectory of planetary rovers is fundamental to accomplish the scientific goals of these missions. This paper presents a method to improve rover localization through the processing of wheel odometry (WO) and inertial measurement unit (IMU) data only. By accurately defining the dynamic model of both a rover’s wheels and the terrain, we provide a model-based estimate of the wheel slippage to correct the WO measurements. Numerical simulations are carried out to better understand the evolution of the rover’s trajectory across different terrain types and to determine the benefits of the proposed WO correction method.

The use of dental implants has grown over the years and has led to higher success rates. To further enhance surgical outcomes, many research groups and companies have shifted their focus to surfaces roughness, wettability and chemistry. In a recent study a new dry salt bioactivate surface has been described from a chemical and physical point of view. The aim of this study is to evaluate the osteogenic response of pre-osteoblast cell lines to dry bioactivated surface. MC3T3-E1 osteogenic cell lines were cultured on SM (sandblasted and dual acid-etched surface) and HNS (SM surface with dry salts bioactive technology). Cell adhesion assay, proliferation assay and cell morphology were performed. Osteogenic activity was performed using Alizarin Red S and alkaline phosphatase. The results showed that SM surface determines a slighter but significant increase in cell adhesion and proliferation in a shorter time compared to HNS. On the contrary, HNS surface has long and intertwining filopodia that could be a response to surface HNS-topography that results in a higher stage of differentiation. The nature of the HNS surface is more prone to determine massive deposition of calcium minerals. This study is the first investigating the role of this interesting dry-salts bioactive surface during the first phase of healing and its potential biochemical advantage could be validated by future animal studies with the aim of evaluate the rate of bone implant contact in the early stages of healing.

SmartBone® (SB) is a biohybrid bone substitute advantageously proposed as a class III medical device for bone regeneration in reconstructive surgeries (oral, maxillofacial, orthopedic, and oncology). In the present study, a new strategy to improve SB osteoinductivity was developed. SB scaffolds were loaded with lyosecretome, a freeze-dried formulation of mesenchymal stem cell (MSC)-secretome, containing proteins and extracellular vesicles (EVs). Lyosecretome-loaded SB scaffolds (SBlyo) were prepared using an absorption method. A burst release of proteins and EVs (38% and 50% after 30 min, respectively) was observed, and then proteins were released more slowly with respect to EVs, most likely because they more strongly adsorbed onto the SB surface. In vitro tests were conducted using adipose tissue-derived stromal vascular fraction (SVF) plated on SB or SBlyo. After 14 days, significant cell proliferation improvement was observed on SBlyo with respect to SB, where cells filled the cavities between the native trabeculae. On SB, on the other hand, the process was still present, but tissue formation was less organized at 60 days. On both scaffolds, cells differentiated into osteoblasts and were able to mineralize after 60 days. Nonetheless, SBlyo showed a higher expression of osteoblast markers and a higher quantity of newly formed trabeculae than SB alone. The quantification analysis of the newly formed mineralized tissue and the immunohistochemical studies demonstrated that SBlyo induces bone formation more effectively. This osteoinductive effect is likely due to the osteogenic factors present in the lyosecretome, such as fibronectin, alpha-2-macroglobulin, apolipoprotein A, and TGF-β.

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal–epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.

Hypercholesterolemia is one of the major causes of cardiovascular disease, the risk of which is further increased if other forms of dyslipidemia occur. Current therapeutic strategies include changes in lifestyle coupled with drug administration. Statins represent the most common therapeutic approach, but they may be insufficient due to the onset of resistance mechanisms and side effects. Consequently, patients with mild hypercholesterolemia prefer the use of food supplements since these are perceived to be safer. Here, we investigate the phytochemical profile and cholesterol-lowering potential of Protium heptaphyllum gum resin extract (PHE). Chemical characterization via HPLC-APCI-HRMS2 and GC-FID/MS identified 13 compounds mainly belonging to ursane, oleanane, and tirucallane groups. Studies on human hepatocytes have revealed how PHE is able to reduce cholesterol production and regulate the expression of proteins involved in its metabolism. (HMGCR, PCSK9, LDLR, FXR, IDOL, and PPAR). Moreover, measuring the inhibitory activity of PHE against HMGR, moderate inhibition was recorded. Finally, molecular docking studies identified acidic tetra- and pentacyclic triterpenoids as the main compounds responsible for this action. In conclusion, our study demonstrates how PHE may be a useful alternative to contrast hypercholesterolemia, highlighting its potential as a sustainable multitarget natural extract for the nutraceutical industry that is rapidly gaining acceptance as a source of health-promoting compounds.

In recent decades, agriculture has faced the fundamental challenge of needing to increase food production and quality in order to meet the requirements of a growing global population. Similarly, viticulture has also been undergoing change. Several countries are reducing their vineyard areas, and several others are increasing them. In addition, viticulture is moving towards higher altitudes and latitudes due to climate change. Furthermore, global warming is also exacerbating the incidence of fungal diseases in vineyards, forcing farmers to apply agrochemicals to preserve production yields and quality. The repeated application of copper (Cu)-based fungicides in conventional and organic farming has caused a stepwise accumulation of Cu in vineyard soils, posing environmental and toxicological threats. High Cu concentrations in soils can have multiple impacts on agricultural systems. In fact, it can (i) alter the chemical-physical properties of soils, thus compromising their fertility; (ii) induce toxicity phenomena in plants, producing detrimental effects on growth and productivity; and (iii) affect the microbial biodiversity of soils, thereby influencing some microbial-driven soil processes. However, several indirect (e.g., management of rhizosphere processes through intercropping and/or fertilization strategies) and direct (e.g., exploitation of vine resistant genotypes) strategies have been proposed to restrain Cu accumulation in soils. Furthermore, the application of precision and smart viticulture paradigms and their related technologies could allow a timely, localized and balanced distribution of agrochemicals to achieve the required goals. The present review highlights the necessity of applying multidisciplinary approaches to meet the requisites of sustainability demanded of modern viticulture.

O presente trabalho objetivou avaliar os aspectos da dinâmica dos sedimentos finos em suspensão nas bacias dos rios Jundiaí e Capivari (SP), para o entendimento dos processos de erosão mecânica que ocorrem nas duas bacias estudadas, e investigar a origem da matéria orgânica dos sedimentos finos em suspensão utilizando os parâmetros de referências (end-members), a fim de evidenciar a influência das diferentes atividades relacionadas ao uso e ocupação do solo. Foi possível verificar que apesar do tempo de residência e a correlação linear entre o FSS e a vazão dos rios Jundiaí e Capivari serem considerados rios de pequeno porte, o transporte dos sedimentos finos em suspensão demonstrou uma erosão média a alta, respectivamente, associada principalmente ao uso e ocupação de solo existente nas bacias. Utilizando as razões isotópicas (C/N) e o d13C verificou-se que apesar da influência da erosão mecânica nas bacias, as matérias orgânicas, presentes nos sedimentos finos em suspensão, são de esgotos domésticos lançados em ambos os rios sem tratamento prévio.

Aerosols have important impacts on air quality and climate, but the processes affecting their removal from the atmosphere are not fully understood and are poorly constrained by observations. This makes modelled aerosol lifetimes uncertain. In this study, we make use of an observational constraint on aerosol lifetimes provided by radionuclide measurements and investigate the causes of differences within a set of global models. During the Fukushima Dai-Ichi nuclear power plant accident of March 2011, the radioactive isotopes cesium-137 (137Cs) and xenon-133 (133Xe) were released in large quantities. Cesium attached to particles in the ambient air, approximately according to their available aerosol surface area. 137Cs size distribution measurements taken close to the power plant suggested that accumulation-mode (AM) sulfate aerosols were the main carriers of cesium. Hence, 137Cs can be used as a proxy tracer for the AM sulfate aerosol's fate in the atmosphere. In contrast, the noble gas 133Xe behaves almost like a passive transport tracer. Global surface measurements of the two radioactive isotopes taken over several months after the release allow the derivation of a lifetime of the carrier aerosol. We compare this to the lifetimes simulated by 19 different atmospheric transport models initialized with identical emissions of 137Cs that were assigned to an aerosol tracer with each model's default properties of AM sulfate, and 133Xe emissions that were assigned to a passive tracer. We investigate to what extent the modelled sulfate tracer can reproduce the measurements, especially with respect to the observed loss of aerosol mass with time. Modelled 137Cs and 133Xe concentrations sampled at the same location and times as station measurements allow a direct comparison between measured and modelled aerosol lifetime. The e-folding lifetime τe, calculated from station measurement data taken between 2 and 9 weeks after the start of the emissions, is 14.3 days (95 % confidence interval 13.1–15.7 days). The equivalent modelled τe lifetimes have a large spread, varying between 4.8 and 26.7 days with a model median of 9.4 ± 2.3 days, indicating too fast a removal in most models. Because sufficient measurement data were only available from about 2 weeks after the release, the estimated lifetimes apply to aerosols that have undergone long-range transport, i.e. not for freshly emitted aerosol. However, modelled instantaneous lifetimes show that the initial removal in the first 2 weeks was quicker (lifetimes between 1 and 5 days) due to the emissions occurring at low altitudes and co-location of the fresh plume with strong precipitation. Deviations between measured and modelled aerosol lifetimes are largest for the northernmost stations and at later time periods, suggesting that models do not transport enough of the aerosol towards the Arctic. The models underestimate passive tracer (133Xe) concentrations in the Arctic as well but to a smaller extent than for the aerosol (137Cs) tracer. This indicates that in addition to too fast an aerosol removal in the models, errors in simulated atmospheric transport towards the Arctic in most models also contribute to the underestimation of the Arctic aerosol concentrations.

Next-generation sequencing (NGS) is a cost-effective technology capable of screening several genes simultaneously; however, its application in a clinical context requires an established workflow to acquire reliable sequencing results. Here, we report an optimized NGS workflow analyzing 22 lung cancer-related genes to sequence critical samples such as DNA from formalin-fixed paraffin-embedded (FFPE) blocks and circulating free DNA (cfDNA). Snap frozen and matched FFPE gDNA from 12 non-small cell lung cancer (NSCLC) patients, whose gDNA fragmentation status was previously evaluated using a multiplex PCR-based quality control, were successfully sequenced with Ion Torrent PGM™. The robust bioinformatic pipeline allowed us to correctly call both Single Nucleotide Variants (SNVs) and indels with a detection limit of 5%, achieving 100% specificity and 96% sensitivity. This workflow was also validated in 13 FFPE NSCLC biopsies. Furthermore, a specific protocol for low input gDNA capable of producing good sequencing data with high coverage, high uniformity, and a low error rate was also optimized. In conclusion, we demonstrate the feasibility of obtaining gDNA from FFPE samples suitable for NGS by performing appropriate quality controls. The optimized workflow, capable of screening low input gDNA, highlights NGS as a potential tool in the detection, disease monitoring, and treatment of NSCLC.

Targeted next-generation sequencing (NGS) based on molecular tagging technology allowed considerable improvement in the approaches of cell-free DNA (cfDNA) analysis. Previously, we demonstrated the feasibility of the OncomineTM Lung cell-free DNA Assay (OLcfA) NGS panel when applied on plasma samples of post-tyrosine kinase inhibitors (TKIs) non-small cell lung cancer (NSCLC) patients. Here, we explored in detail the coverage metrics and variant calling of the assay and highlighted strengths and challenges by analyzing 92 plasma samples collected from a routine cohort of 76 NSCLC patients. First, performance of OLcfA was assessed using Horizon HD780 reference standards and sensitivity and specificity of 92.5% and 100% reported, respectively. The OLcfA was consequently evaluated in our plasma cohort and NGS technically successful in all 92 sequenced libraries. We demonstrated that initial cfDNA amount correlated positively with library yields (p < 0.0001) and sequencing performance (p < 0.0001). In addition, 0.1% limit of detection could be achieved even when < 10 ng cfDNA was employed. In contrast, the cfDNA amount seems to not affect the EGFR mutational status (p = 0.16). This study demonstrated an optimal performance of the OLcfA on routine plasma samples from NSCLC patients and supports its application in the liquid biopsy practice for cfDNA investigation in precision medicine laboratories.

Para a caracterização físico-química da carga dissolvida dos rios Jundiaí e Capivari, foram quantificadas, durante o período de abril de 2011 a dezembro de 2012, as concentrações dos principais parâmetros físico-quimicos, pH, condutividade elétrica, temperatura, oxigênio dissolvido e demanda bioquímica de oxigênio, associadas às respectivas vazões instantâneas nas águas fluviais dos rios Jundiaí e Capivari, próximos às nascentes e à foz. Foi possível verificar que o pH variou próximo à neutralidade da nascente para a foz dos rios Jundiaí e Capivari, não apresentando padrão de diluição, enquanto a variabilidade da temperatura das águas para ambas as bacias de drenagem foi influenciada principalmente por fatores externos. As concentrações de oxigênio dissolvido e demanda bioquímica de oxigênio nas águas da foz dos rios Jundiaí e Capivari se mostraram em desacordo com os limites de referência estabelecidos pelo CONAMA 375/05, indicando influência antrópica nas áreas próximas às nascentes de ambos os rios estudados e maior antropização na foz do rio Jundiaí em comparação com a foz do rio Capivari. A condutividade elétrica se mostrou elevada na foz dos rios estudados, e sua variabilidade em função da vazão permitiu o ajuste de modelos de potência, evidenciando influência antrópica mais efetiva na bacia do rio Jundiaí, sendo observados também indícios de degradação hídrica nas áreas próximas às nascentes dos rios Jundiaí e Capivari pela variabilidade do oxigênio dissolvido em função da temperatura.