In this article, vibration of viscoelastic axially functionally graded (AFG) moving Rayleigh and Euler–Bernoulli (EB) beams are investigated and compared, aiming at a performance improvement of translating systems. Additionally, a detailed study is performed to elucidate the influence of various factors, such as the rotary inertia factor and axial gradation of material on the stability borders of the system. The material properties of the beam are distributed linearly or exponentially in the longitudinal direction. The Galerkin procedure and eigenvalue analysis are adopted to acquire the natural frequencies, dynamic configuration, and instability thresholds of the system. Furthermore, an exact analytical expression for the critical velocity of the AFG moving Rayleigh beams is presented. The stability maps and critical velocity contours for various material distributions are examined. In the case of variable density and elastic modulus, it is demonstrated that linear and exponential distributions provide a more stable system, respectively. Furthermore, the results revealed that the decrease of density gradient parameter and the increase of the elastic modulus gradient parameter enhance the natural frequencies and enlarge the instability threshold of the system. Hence, the density and elastic modulus gradients play opposite roles in the dynamic behavior of the system. Full article

Synthetic Aperture Radar (SAR) polarimetric datasets are widely used in the detection and classification of urban areas. Most methods used today are based on the decomposition of fully polarimetric SAR data, which allows for the extraction of physical information about the nature of the medium and the application of proper classification methods. According to the theory, the main and predominant backscattering mechanism for buildings is double bounce. However, when analyzing urban environments, the observed predominant backscatter may differ from theory depending on many aspects. In this paper, we analyze fully polarimetric ALOS PALSAR data for various cities located on different continents, proving that the theory does not hold for most cases. There are many factors that have an impact on the detected backscatter mechanism, and the theoretical principle of predominant double bounce in urban areas can be met only under specific conditions. These factors are, among others, the orientation of the buildings, the dimensions of the streets, the type of construction (i.e., numerous planes on the roof), etc. This paper also mentions the canonical example of San Francisco, widely analyzed in the literature, as a case showing the impact of building deorientation on double bounce scattering. This area of interest is also discussed in terms of the impact of SAR data resolution on the detection of specific backscatter mechanisms. The findings of this work are very useful for increasing the awareness of the utilization of classification approaches where only pixels with double bounce backscatter mechanisms are classified as urban areas. Moreover, the article lists factors that should be taken into consideration when performing urban area detection based only on polarimetric data and standard algorithms, such as street and building orientation, building heights, and structures. Full article

Germ cell tumors (GCTs) are the most common solid malignancies found in young men. Although they generally have high cure rates, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin. Additionally, the loss-of-function mutations re-sensitize different tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated ARID1A-deficient GCT cells and demonstrate by mass spectrometry that ARID1A is putatively involved in regulating transcription, DNA repair and the epigenetic landscape via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, ARID1A/ARID1A deficiency or pharmacological inhibition increased the efficacy of romidepsin and considerably sensitized GCT cells, including cisplatin-resistant subclones, towards ATR inhibition. Thus, targeting ARID1A in combination with romidepsin and ATR inhibitors presents as a new putative option to treat GCTs. Full article

Toscana virus (TOSV) is a Phlebovirus in the Phenuiviridae family, order Bunyavirales, found in the countries surrounding the Mediterranean. TOSV is an important cause of seasonal acute meningitis and encephalitis within its range. Here, we determined the full sequence of the TOSV strain 1500590, a lineage A virus obtained from an infected patient (Marseille, 2007) and used this in combination with other sequence information to construct functional cDNA plasmids encoding the viral L, M, and S antigenomic sequences under the control of the T7 RNA promoter to recover recombinant viruses. Importantly, resequencing identified two single nucleotide changes to a TOSV reference genome, which, when corrected, restored functionality to the polymerase L and made it possible to recover infectious recombinant TOSV (rTOSV) from cDNA, as well as establish a minigenome system. Using reverse genetics, we produced an NSs-deletant rTOSV and also obtained viruses expressing reporter genes instead of NSs. The availability of such a system assists investigating questions that require genetic manipulation of the viral genome, such as investigations into replication and tropism, and beyond these fundamental aspects, also the development of novel vaccine design strategies. Full article

We report the synthesis of several related 4-anilinoquinazolines as inhibitors of cardiac troponin I–interacting kinase (TNNi3K). These close structural analogs of 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide (GSK114) provide new understanding of structure–activity relationships between the 4-anilinoquinazoline scaffold and TNNi3K inhibition. Through a small focused library of inhibitors, we observed that the N-methylbenzenesulfonamide was driving the potency in addition to the more traditional quinazoline hinge-binding motif. We also identified a compound devoid of TNNi3K kinase activity due to the addition of a methyl group in the hinge binding region. This compound could serve as a negative control in the study of TNNi3K biology. Small molecule crystal structures of several quinazolines have been solved, supporting observations made about overall conformation and TNNi3K inhibition. Full article

Metal ion elution, including Cr and Ni from dental orthodontic stainless steel, accounts for some allergies. In this study, a self-assembled monolayer (SAM) on a wire surface is proposed for suppressing such elution. This method involves modifying the stainless steel surface using phosphonic acid containing a long alkyl chain. The uncoated and coated wires are immersed in different acidic solutions, and the supernatant is analyzed by inductively coupled plasma mass spectrometry after 1–4 weeks. The results reveal that Cr and Ni ion elution is significantly suppressed by SAM modification. These findings will help in minimizing potential allergens from dental orthodontics. Full article

Previous studies in experimental autoimmune encephalomyelitis (EAE) models have shown that some probiotic bacteria beneficially impact the development of this experimental disease. Here, we tested the therapeutic effect of two commercial multispecies probiotics—Lactibiane iki and Vivomixx—on the clinical outcome of established EAE. Lactibiane iki improves EAE clinical outcome in a dose-dependent manner and decreases central nervous system (CNS) demyelination and inflammation. This clinical improvement is related to the inhibition of pro-inflammatory and the stimulation of immunoregulatory mechanisms in the periphery. Moreover, both probiotics modulate the number and phenotype of dendritic cells (DCs). Specifically, Lactibiane iki promotes an immature, tolerogenic phenotype of DCs that can directly induce immune tolerance in the periphery, while Vivomixx decreases the percentage of DCs expressing co-stimulatory molecules. Finally, gut microbiome analysis reveals an altered microbiome composition related to clinical condition and disease progression. This is the first preclinical assay that demonstrates that a commercial probiotic performs a beneficial and dose-dependent effect in EAE mice and one of the few that demonstrates a therapeutic effect once the experimental disease is established. Because this probiotic is already available for clinical trials, further studies are being planned to explore its therapeutic potential in multiple sclerosis patients. Full article

There are many ways to prepare potatoes that each provide a unique set of sensory properties. However, when conducting a descriptive sensory study, it is important to utilize a cooking method that will highlight, and not distract from, the sensory differences among potato samples due to factors such as variety or growing conditions. This study aimed to determine which of five cooking methods results in the best differentiation among potato varieties to recommend a single method for use in future descriptive sensory studies. Five different potato varieties were each prepared using boiling, mashing, baking, frying, and air frying methods. The samples were provided to six highly trained descriptive panelists and evaluated by consensus using a modified high identity traits (HITs) method. Panelists evaluated the aroma, flavor, and texture to develop a list of up to five total HITs per sample. Additionally, panelists scored each sample for degree of difference (DOD) from the control. Based on the HITs profiles and DOD scores, mashing, baking, and air frying methods were all effective in differentiating the samples. Frying and boiling methods introduced too much variation and are not recommended for sample differentiation. Ultimately, the method chosen for future research would depend on the study objectives. Full article

Since the reform and opening up, a large proportion of the Chinese rural labor force has transferred to urban and non-agricultural industries. Rural labor transfer not only changes the allocation of household labor in agricultural and non-agricultural sectors but also affects the utilization of other agricultural production factors. Based on data from 818 households in three counties in northern Jiangsu province, this paper analyzed the impact of labor migration on farmers’ adoption of cultivated land quality protection (CLQP) behaviors. The survey results showed that farmers’ awareness of CLQP was still very weak, and the proportion of farmers adopting measures such as subsoiling, straw application, cover crops and green manures and the complementary use of organic fertilizers was still relatively low. The empirical results showed that perennial out-migration for work can constrain households’ protective inputs into soil conservation, but part-time farming locally can promote households’ inputs. The results also showed that farmer characteristics, farming conditions and external environment also significantly affected the farmers’ adoption of soil conservation practices. According to these conclusions, this paper puts forward the corresponding policy implications. Full article

Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiophene molecular skeleton, characterized by the presence of a 3′,4′,5′-trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2- or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(3′,4′,5′-trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative 3a and its 6-ethoxycarbonyl homologue 3b as new antiproliferative agents that inhibit cancer cell growth with IC₅₀ values ranging from 1.1 to 4.7 μM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds 3a and 3b were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site. Full article

To the best of our knowledge, a dose-response meta-analysis of the relationship between cardiovascular disease (CVD) and arsenic (As) exposure at drinking water As concentrations lower than the WHO provisional guideline value (10 µg/L) has not been published yet. We conducted a systematic review and meta-analyses to estimate the pooled association between the relative risk of each CVD endpoint and low-level As concentration in drinking water both linearly and non-linearly using a random effects dose-response model. In this study, a significant positive association was found between the risks of most CVD outcomes and drinking water As concentration for both linear and non-linear models (p-value for trend < 0.05). Using the preferred linear model, we found significant increased risks of coronary heart disease (CHD) mortality and CVD mortality as well as combined fatal and non-fatal CHD, CVD, carotid atherosclerosis disease and hypertension in those exposed to drinking water with an As concentration of 10 µg/L compared to the referent (drinking water As concentration of 1 µg/L) population. Notwithstanding limitations included, the observed significant increased risks of CVD endpoints arising from As concentrations in drinking water between 1 µg/L and the 10 µg/L suggests further lowering of this guideline value should be considered. Full article

Retinal homeostasis is under both diurnal and circadian regulation. We sought to investigate the diurnal expression of autophagy proteins in normal rodent retina and to determine if this is impaired in diabetic retinopathy. C57BL/6J mice and Bio-Breeding Zucker (BBZ) rats were maintained under a 12h/12h light/dark cycle and eyes, enucleated over a 24 h period. Eyes were also collected from diabetic mice with two or nine-months duration of type 1 diabetes (T1D) and Bio-Breeding Zucker diabetic rat (BBZDR/wor rats with 4-months duration of type 2 diabetes (T2D). Immunohistochemistry was performed for the autophagy proteins Atg7, Atg9, LC3 and Beclin1. These autophagy proteins (Atgs) were abundantly expressed in neural retina and endothelial cells in both mice and rats. A differential staining pattern was observed across the retinas which demonstrated a distinctive diurnal rhythmicity. All Atgs showed localization to retinal blood vessels with Atg7 being the most highly expressed. Analysis of the immunostaining demonstrated distinctive diurnal rhythmicity, of which Atg9 and LC3 shared a biphasic expression cycle with the highest level at 8:15 am and 8:15 pm. In contrast, Beclin1 revealed a 24-h cycle with the highest level observed at midnight. Atg7 was also on a 24-h cycle with peak expression at 8:15am, coinciding with the first peak expression of Atg9 and LC3. In diabetic animals, there was a dramatic reduction in all four Atgs and the distinctive diurnal rhythmicity of these autophagy proteins was significantly impaired and phase shifted in both T1D and T2D animals. Restoration of diurnal rhythmicity and facilitation of autophagy protein expression may provide new treatment strategies for diabetic retinopathy. Full article

Given the great potential of porous carrier-based drug delivery for stabilising the amorphous form of drugs and enhancing dissolution profiles, this work is focussed on the synthesis and application of carbon onion or onion-like carbon (OLC) as a porous carrier for oral amorphous drug delivery, using paracetamol (PA) and ibuprofen (IBU) as model drugs. Annealing of nanodiamonds at 1100 °C produced OLC with a diamond core that exhibited low cytotoxicity on Caco-2 cells. Solution adsorption followed by centrifugation was used for drug loading and results indicated that the initial concentration of drug in the loading solution needs to be kept below 11.5% PA and 20.7% IBU to achieve complete amorphous loading. Also, no chemical interactions between the drug and OLC could be detected, indicating the safety of loading into OLC without changing the chemical nature of the drug. Drug release was complete in the presence of sodium dodecyl sulphate (SDS) and was faster compared to the pure crystalline drug, indicating the potential of OLC as an amorphous drug carrier. Full article

Acquired Immune Deficiency Syndrome (AIDS) treatment with combination antiretroviral therapy (cART) has improved the life quality of many patients since its implementation. However, resistance mutations and the accumulation of severe side effects associated with cART remain enormous challenges that need to be addressed with the continual design and redesign of anti-HIV drugs. In this review, we focus on the importance of the HIV-1 Gag polyprotein as the master coordinator of HIV-1 assembly and maturation and as an emerging drug target. Due to its multiple roles in the HIV-1 life cycle, the individual Gag domains are attractive but also challenging targets for inhibitor design. However, recent encouraging developments in targeting the Gag domains such as the capsid protein with highly potent and potentially long-acting inhibitors, as well as the exploration and successful targeting of challenging HIV-1 proteins such as the matrix protein, have demonstrated the therapeutic viability of this important protein. Such Gag-directed inhibitors have great potential for combating the AIDS pandemic and to be useful tools to dissect HIV-1 biology. Full article

Inflammatory and oncogenic signaling, both known to challenge genome stability, are key drivers of BCR-ABL-positive chronic myeloid leukemia (CML) and JAK2 V617F-positive chronic myeloproliferative neoplasms (MPNs). Despite similarities in chronic inflammation and oncogene signaling, major differences in disease course exist. Although BCR-ABL has robust transformation potential, JAK2 V617F-positive polycythemia vera (PV) is characterized by a long and stable latent phase. These differences reflect increased genomic instability of BCR-ABL-positive CML, compared to genome-stable PV with rare cytogenetic abnormalities. Recent studies have implicated BCR-ABL in the development of a "mutator" phenotype fueled by high oxidative damage, deficiencies of DNA repair, and defective ATR-Chk1-dependent genome surveillance, providing a fertile ground for variants compromising the ATM-Chk2-p53 axis protecting chronic phase CML from blast crisis. Conversely, PV cells possess multiple JAK2 V617F-dependent protective mechanisms, which ameliorate replication stress, inflammation-mediated oxidative stress and stress-activated protein kinase signaling, all through up-regulation of RECQL5 helicase, reactive oxygen species buffering system, and DUSP1 actions. These attenuators of genome instability then protect myeloproliferative progenitors from DNA damage and create a barrier preventing cellular stress-associated myelofibrosis. Therefore, a better understanding of BCR-ABL and JAK2 V617F roles in the DNA damage response and disease pathophysiology can help to identify potential dependencies exploitable for therapeutic interventions. Full article

The increasing penetration of variable renewable energies (VRE) in the European electricity mix requires flexible energy storage systems (ESS), such as pumped storage hydropower (PSH). Disused mining voids from deep closed mines may be used as subsurface reservoirs of underground pumped-storage hydropower (UPSH) plants. Unlike conventional PSH plants, the air pressure in UPSH plants is variable and it differs from the atmospheric conditions. In this paper, the hydraulic transient process of an UPSH plant operating in pumping mode was investigated and a preliminary thermodynamic analysis of the closed surge tank was carried out. Analytical and CFD three-dimensional numerical simulations based on the volume of fluid (VOF) model with two-phase flow have been performed for analyzing the transient process. In the transient simulation, air and water are considered as ideal gas and compressible liquid, respectively. Different guide vanes closing schemes have been simulated. The obtained results show that the dimensioning of underground reservoir, surge tank, and air ducts is essential for ensuring the hydraulic performance and optimizing the operation of UPSH plants. The static pressure in the air duct, surge tank and lower reservoir reaches -1.6, 112.8 and -4 kPa, respectively, while a heat flux of -80 W was obtained through the surge tank walls. Full article