Fyn-related kinase (FRK), a member of the Src-related tyrosine kinase family, functions as a tumor suppressor in several malignancies. We previously showed that FRK overexpression inhibited the growth of glioma cells. However, it is unknown whether FRK is equally effective against intracranial glioma in vivo, and the mechanism by which FRK influences glioma cell growth remains unclear. In this study, we found that tumor volume was reduced by about one-third in mice with FRK overexpression, which showed improved survival relative to controls. Immunofluorescence analysis revealed that FRK overexpression inhibited glioma cell proliferation and induced their apoptosis. Importantly, in vitro we further found that FRK decreased the expression of integrin subunit β1 (ITGB1) at both the mRNA and protein levels. FRK also inhibited transactivation by ITGB1, resulting in the suppression of its target proteins AKT and focal adhesion kinase (FAK). ITGB1 overexpression promoted glioma cell growth and partially reduced FRK-induced growth suppression. These results indicate that FRK inhibits human glioma growth via regulating ITGB1/FAK signaling and provide a potential therapeutic target for the treatment of glioma.

The objective of this study was to investigate the exact therapeutic effects of Verapamil on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the molecular mechanism involved, through using LPS-induced animal models as well as LPS-stimulated mouse primary peritoneal macrophages models. Our results demonstrated that Verapamil reduced LPS-induced pathological damage of the lung tissue, infiltration of inflammatory cells and the production of IL-1β, TNF-α, and MCP-1 in the serum. The MPO activity, MDA content, lung wet/dry ratio and LDH activity were also attenuated by Verapamil. In addition, Verapamil attenuated LPS-induced inflammatory cytokine production and oxidative stress in primary murine peritoneal macrophages in vitro. Moreover, we confirmed that NF-κB/NLRP3 pathway was involved in the therapeutic effect of Verapamil against LPS-induced injury in vivo and in vitro. In conclusion, these findings indicate that Verapamil has a therapeutic effect on LPS-induced ALI in mice. The mechanism may be related to the inhibition of NF-κB and NLRP3 signaling pathways. Verapamil may be a potential therapeutic agent for the treatment of ALI.

We aimed to investigate whether pre-therapeutic radiomic features based on magnetic resonance imaging (MRI) can predict the clinical response to neoadjuvant chemotherapy (NACT) in patients with locally advanced cervical cancer (LACC).

A critical aspect of behavior is that mobile organisms must be able to precisely determine where and when to move. A better understanding of the mechanisms underlying precise movement timing and action planning is therefore crucial to understanding how we interact with the world around us. Recent evidence suggests that our experience of time is directly and intrinsically computed within the motor system, consistent with the theory of embodied cognition. To investigate the role of the motor system, we tested human subjects (n = 40) on a novel task combining reaching and time estimation. In this task, subjects were required to move a robotic manipulandum to one of two physical locations to categorize a concurrently timed suprasecond. Critically, subjects were divided into two groups: one in which movement during the interval was unrestricted and one in which they were restricted from moving until the stimulus interval had elapsed. Our results revealed a higher degree of precision for subjects in the free-moving group. A further experiment (n = 14) verified that these findings were not due to proximity to the target, counting strategies, bias, or movement length. A final experiment (n = 10) replicated these findings using a within-subjects design, performing a time reproduction task, in which movement during encoding of the interval led to more precise performance. Our findings suggest that time estimation may be instantiated within the motor system as an ongoing readout of timing judgment and confidence.

Receptor-transporting protein 1S (RTP1S) is an accessory protein that mediates the transport of mammalian odorant receptors (ORs) into the plasma membrane. Although most ORs fail to localize to the cell surface when expressed alone in nonolfactory cells, functional expression of ORs is achieved with the coexpression of RTP1S. However, the mechanism for RTP1S-mediated OR trafficking remains unclear. In this study, we attempted to reveal the mode of action and critical residues of RTP1S in OR trafficking. Experiments using N-terminal truncation and Ala substitution mutants of RTP1S demonstrated that four N-terminal amino acids have essential roles in OR trafficking. Additionally, using recombinant proteins and split luciferase assays in mammalian cells, we provided evidence for the dimer formation of RTP1S. Furthermore, we determined that the 2nd Cys residue is required for the efficient dimerization of RTP1S. Altogether, these findings provide insights into the mechanism for plasma membrane transport of ORs by RTP1S.

Therapeutic drug monitoring is a valuable tool supporting immunosuppressive therapy. Significant variation of immunosuppressive drug (ISD) concentrations during their use at similar doses is the basis of dose-normalization strategy. The strategy of dose-adjustment is proposed to identify variability in the rate of ISD metabolism. While the parent drug-to-metabolite ratio (metabolic ratio, MR) represents the rate of formation of individual metabolites. The present study was aimed at evaluation of associations between ISDs' metabolism rate expressed as dose-adjusted concentrations (C/D) and dose/kg-adjusted concentrations (C/D/kg) and MRs of individual metabolites of tacrolimus, cyclosporine A and MPA precursors.

The micro sequential injection analysis / lab-on-valve (µSIA-LOV) system is a miniaturized SIA system resulting from the implementation of a lab-on-valve (LOV) atop of the selection valve. It integrates the detection cell and the sample processing channels into the same device, promoting the reduction of reagent consumption and waste generation, the improvement of the versatility, and the reduction of the time of analysis. All of these characteristics are really relevant to the implementation of enzymatic reactions. Additionally, the evaluation of cholesterol in serum samples is widely relevant in clinical diagnosis, since higher values of cholesterol in human blood are actually an important risk factor for cardiovascular problems. An automatic methodology was developed based on the µSIA-LOV system in order to evaluate its advantages in the implementation of enzymatic reactions performed by cholesterol esterase, cholesterol oxidase and peroxidase. Considering these reactions, the developed methodology was also used for the evaluation of cholesterol in human serum samples, showing reliable and accurate results. The developed methodology presented detection and quantification limits of 1.36 and 4.53 mg dL-1 and a linear range up to 40 mg dL-1. This work confirmed that this µSIA-LOV system is a simple, rapid, versatile, and robust analytical tool for the automatic implementation of enzymatic reactions performed by cholesterol esterase, cholesterol oxidase, and peroxidase. It is also a useful alternative methodology for the routine determinations of cholesterol in real samples, even when compared with other automatic methodologies.

Chronic joint pain is associated to an increase in the consumption of medication and decrease in life quality in elderly people, which requires developing non-pharmacological treatments. The aim of this study was to evaluate the effectivity of a group intervention, based on animal-assisted therapy and applied to elderly people with chronic joint pain and polymedication, regarding the decrease of chronic pain, use of analgesics and improvement of life quality. A randomized controlled trial, two arms and open-label was conducted in a Primary Health Center. Twelve weekly sessions of kinesitherapy; in the EG, these exercises were performed with the additional assistance of the therapy dog. A total of 52 participants (22 Control Group (CG), 30 EG), average age 77.50 (±7.3), women 90.4%. A significant reduction on post-intervention values of pain β = -0.67(-1.27, -0.08), p = 0.03 and pain induced insomnia β = -0.53(-1.01, -0.05), p = 0.03 was found in EG for increasing baseline values. Animal-assisted therapy leads to an additional reduction in the perception of pain and pain induced insomnia in individuals with higher baseline severity. The presence of the dog improves the attachment to intervention and the satisfaction of the participants.

Titanium dioxide-carbon sphere (TiO2-CS) composites were constructed via using prefabricated carbon spheres as templates. By the removal of template from the TiO2-CS, TiO2 hollow structures (HS) were synthesized. The CS templates were prepared by the hydrothermal treatment of ordinary table sugar (sucrose). TiO2-HSs were obtained by removing CSs with calcination. Our own sensitized TiO2 was used for coating the CSs. The structure of the CSs, TiO2-CS composites, and TiO2-HSs were characterized by scanning electron microscopy (SEM), infrared spectroscopy (IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and diffuse reflectance spectroscopy (DRS). The effect of various synthesis parameters (purification method of CSs, precursor quantity, and applied furnace) on the morphology was investigated. The photocatalytic activity was investigated by phenol model pollutant degradation under visible light irradiation (λ > 400 nm). It was established that the composite samples possess lower crystallinity and photocatalytic activity compared to TiO2 hollow structures. Based on XPS measurements, the carbon content on the surface of the TiO2-HS exerts an adverse effect on the photocatalytic performance. The synthesis parameters were optimized and the TiO2-HS specimen having the best absolute and surface normalized photocatalytic efficiency was identified. The superior properties were explained in terms of its unique morphology and surface properties. The stability of this TiO2-HS was investigated via XRD and SEM measurements after three consecutive phenol degradation tests, and it was found to be highly stable as it entirely retained its crystal phase composition, morphology and photocatalytic activity.

Circulating tumor DNA (ctDNA) has emerged as a candidate biomarker for cancer screening. However, studies on the usefulness of ctDNA for postoperative recurrence monitoring are limited. The present study monitored ctDNA in postoperative blood by employing cancer-specific rearrangements. Personalized cancer-specific rearrangements in 25 gastric cancers were analyzed by whole-genome sequencing (WGS) and were employed for ctDNA monitoring with blood up to 12 months after surgery. Personalized cancer-specific rearrangements were identified in 19 samples. The median lead time, which is the median duration between a positive ctDNA detection and recurrence, was 4.05 months. The presence of postoperative ctDNA prior to clinical recurrence was significantly correlated with cancer recurrence within 12 months of surgery (P = 0.029); in contrast, no correlation was found between cancer recurrence and the presence of preoperative ctDNA, suggesting the clinical usefulness of postoperative ctDNA monitoring for cancer recurrence in gastric cancer patients. However, the clinical application of ctDNA can be limited by the presence of ctDNA non-shedders (42.1%, 8/19) and by inconsistent postoperative ctDNA positivity.

Efficient photopolymerization activated by nonharmful near-infrared (NIR) light is important for various biological applications. Here we propose a NIR light free-radical photoinitiator (PI) fabricated by incorporating oxime-ester coumarin functionality on the surface of upconversion nanoparticles (UCNPs). The coumarin groups of PI absorb the light emitted from the UCNP core, whereas the oxime ester groups undergo cleavage to form radicals. Upon irradiation at 980 nm, the mobile radicals, formed in a manner similar to that of dandelion seed release, initiate both free-radical and thiol-ene photopolymerizations. The superior efficiency of dandelion-like PIs assisted photopolymerizations can be attributed to the reduction of energy loss and increased local PI concentration due to Förster resonance energy transfer process and confinement effect, respectively. Moreover, the proposed PI system can initiate polymerization under low-power NIR laser and reduces the thermal side effects. The possibility of its potential use in deep curing applications was also demonstrated.

How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 squamous cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of which (Inflamed, Redox) comprise 87% of tumors. The Inflamed subtype is enriched with neutrophils, B-cells, and monocytes and expresses more PD-1. Redox tumours are enriched for oxidation-reduction and glutathione pathways and harbor more NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus. Proteomic subtypes are not associated with patient survival. However, B-cell-rich tertiary lymph node structures, more common in Inflamed, are associated with better survival. We identify metabolic vulnerabilities (TP63, PSAT1, and TFRC) in Redox. Our work provides a powerful resource for lung SCC biology and suggests therapeutic opportunities based on redox metabolism and immune cell infiltrates.

Iron and light are recognized as limiting factors controlling Southern Ocean phytoplankton growth. Recent field-based evidence suggests, however, that manganese availability may also play a role. Here we examine the influence of iron and manganese on protein expression and physiology in Phaeocystis antarctica, a key Antarctic primary producer. We provide taxon-specific proteomic evidence to show that in-situ Southern Ocean Phaeocystis populations regularly experience stress due to combined low manganese and iron availability. In culture, combined low iron and manganese induce large-scale changes in the Phaeocystis proteome and result in reorganization of the photosynthetic apparatus. Natural Phaeocystis populations produce protein signatures indicating late-season manganese and iron stress, consistent with concurrently observed stimulation of chlorophyll production upon additions of manganese or iron. These results implicate manganese as an important driver of Southern Ocean productivity and demonstrate the utility of peptide mass spectrometry for identifying drivers of incomplete macronutrient consumption.

In this study, we explored vagally-mediated heart rate variability (vmHRV) responses, a psychophysiological index of cognitive self-regulatory control, to map the dynamics associated with empathic responses for pain towards an out-group member. Accordingly, Caucasian participants were asked to judge the experience of African and Caucasian actors touched with either a neutral or a harmful stimulus. Results showed that (1) explicit judgment of pain intensity in African actors yielded higher rating score and (2) took longer time compared to Caucasian actors, (3) these behavioural outcomes were associated with a significant increment of RMSSD, Log-HF-HRV and HF-HRV n.u., (4) resting HF-HRV n.u. predicted the participants' lag-time to judge painful stimulations delivered to African actors. Interestingly, these dynamics were associated with a measure of implicit racial attitudes and were, in part, abolished when participants performed a concurrent task during videos presentation. Taken together our results support the idea that a cognitive effort is needed to self-regulate our implicit attitude as predicted by the 'Contrasting Forces Model'.

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

Retrieval of stored network activity pattern has been shown as a competitive transition from one attractor state to another, orchestrated by local theta oscillation. However, the fine nature of this process that is considered as substrate of memory recall is not clear. We found that hippocampal network recall is characterized by hyperactivity in the CA3 place cell population, associated with an "overexpression" of the retrieved network pattern. The overexpression was based on recruitment of cells from the same (recalled) spatial representation with low expected firing probability at the given position. We propose that increased place cell activation during state transitions might facilitate pattern completion towards the retrieved network state and stabilize its expression in the network. Furthermore, we observed frequent mixing of both activity patterns at the temporal level of a single theta cycle. On a sub-theta cycle scale, we found signs of segregation that might correspond to a gamma oscillation patterning, as well as occasional mixing at intervals of less than 5 milliseconds. Such short timescale coactivity might induce plasticity mechanisms, leading to associations across the two originally decorrelated network activity states.

Betulinic acid, a plant secondary metabolite, has gained significant attention due to its antiproliferative activity over a range of cancer cells. A promising betulinic acid analogue (2c) with better therapeutic efficacy than parent molecule to colon carcinoma cells has been reported. Despite impressive biological applications, low aqueous solubility and bioavailability create difficulties for its therapeutic applications. To overcome these lacunae and make it as a promising drug candidate we have encapsulated the lead betulinic acid derivative (2c) in a polymeric nanocarrier system (2c-NP) and evaluated its in vitro and in vivo therapeutic efficacy. Apoptosis that induces in vitro antiproliferative activity was significantly increased by 2c-NP compared to free-drug (2c), as assured by MTT assay, Annexin V positivity, JC1 analysis and cell cycle study. The therapeutic potential measured in vitro and in vivo reflects ability of 2c-NP as an effective therapeutic agent for treatment of colon carcinoma and future translation to clinical trials.

Fire blight is a devastating disease of apple and pear caused by the bacterium Erwinia amylovora. One of its main symptoms is canker formation on perennial tissues which may lead to the death of limbs and/or the entire tree. E. amylovora overwinters in cankers which play an important role in initiating fire blight epidemics. However, knowledge of pathogen biology in cankers is scarce, in part due to limitations of classical microbiology methods and the inability of most molecular techniques to distinguish live from dead cells. In this work, a viability digital PCR (v-dPCR) protocol using propidium monoazide (PMA) was developed, allowing for the first time the selective detection and absolute quantification of E. amylovora live cells in apple and pear cankers collected in two time periods. Some key factors affecting the v-dPCR performance were the maceration buffer composition, the target DNA amplicon length, the thermal cycle number and the use of sodium dodecyl sulfate or PMA enhancer for Gram-negative bacteria to improve the effect of PMA. In the future, this methodology could shed light on E. amylovora population dynamics in cankers and provide clues on the effect of management practices, host cultivar, host water/nutritional status, etc., on bacterial survival.

Radiotherapy (RT) causes morbidity and long-term side effects. A challenge in RT is to maximize cancer cells killing while minimizing damage to normal tissue. The ideal radio-protector selectively improves survival and limits damage to normal tissues while reducing survival of cancer cells. Muscle-derived dipeptide, L-carnosine (CAR) is a potent antioxidant, with radio-protective, but also anticancer properties, affecting the cell cycle of cancer cells. We tested CAR effects in lung cancer cells, differentiated and undifferentiated normal cells. We hypothesized that CAR antioxidant properties will confer protection to the two normal cell lines against RT, while preventing lung cancer cell proliferation, and that CAR may act as a radiosensitizer of lung cancer cells due to its effects on cell-cycle progression of cancer cells. Under the experimental conditions reported here, we found that CAR increased radio-sensitivity of lung (A549) cancer cells by increasing the percentage of cells in G2/M (radiosensitive) phase of cell cycle, it negatively affected their bioenergetics, therefore reduced their viability, and DNA-double strand break repair capacity. CAR had either no effect or reduced RT-induced damage in normal cells, depending on the cell type. CAR is a versatile natural occurring compound, that could improve RT-induced lung cancer cells killing, while reducing the damage to normal differentiated and undifferentiated cells.

Preaxial polydactyly (PPD) is a common congenital hand malformation classified into four subtypes (PPD I-IV). Variants in the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are linked to most PPD types. However, the genes responsible for PPD I and the underlying mechanisms are unknown.