Lung cancer is the most common cause of cancer deaths worldwide, and lung adenocarcinoma (LUAD) is the most common histological subtype. However, the prognostic and predictive outcomes differ because of the heterogeneity of programmed cell death. The purpose of this work is to investigate and develop a cuproptosis-associated lncRNA-based LUAD prediction marker. We firstly performed bioinformatic analysis of the Cuprotosis database and The Cancer Genome Atlas (TCGA) database to obtain 19 cuprotosis-related gene datasets and transcriptional data for LUAD. Univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis were utilized to construct cuproptosis-associated lncRNA modes. LUAD patients were thus classified into high-risk and low-risk categories based on prognostic risk values, with a median of It acted as a boundary. Risk models were evaluated and validated using Kaplan-Meier analysis, principal component analysis (PCA), gene set enrichment analysis (GSEA) and nomograms. Utilizing the TCGA-LUAD dataset, we identified seven predicted cuproptosis-associated lncRNAs in tumor microenvironment to create the risk model. 95.54% (214/224) of high-risk category tumor samples included cuproptosis-associated gene alterations, compared to 85.65% (203/237) of low-risk category tumor samples, with TP53 accounting for the bulk of occurrences. According to these findings, risk value was superior to other clinical variables and tumor mutation burden as a predictor of 1-, 3-, and 5-year overall survival (OS). The predictive validity of the cuproptosis-associated lncRNA-based risk model for LUAD is high, and this may have implications for how lung cancer patients are treated individually.

Polybrominated diphenyl ethers (PBDE) are a group of flame retardants used in a variety of artificial materials. Despite phasing out in most industrial countries, they persist in the environment and human tissues due to their persistence, lipophilicity, and bioaccumulation. Populational and experimental studies demonstrate male reproductive toxicity of PBDEs including increased incidence of genital malformations (hypospadias and cryptorchidism), altered weight of testes and other reproductive tissues, altered testes histology and transcriptome, decreased sperm production and sperm quality, altered epigenetic regulation of developmental genes in spermatozoa and altered secretion of reproductive hormones. A broad range of mechanistic hypotheses of PBDE reproductive toxicity has been suggested. Among these hypotheses, oxidative stress, disruption of estrogenic signaling, and mitochondria disruption are affected by PBDE concentrations much higher, than concentrations found in human tissues, making them unlikely links between exposures and adverse reproductive outcomes in the general population. Robust evidence suggests that at environmentally relevant doses, PBDEs and their metabolites may affect male reproductive health via mechanisms including AR antagonism and the disruption of a complex network of metabolic signaling.

We investigated whether a functional insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) influenced antipsychotic treatment. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed patients’ Positive and Negative Syndrome Scale (PANSS) scores, PANSS factors, and metabolic syndrome-related parameters (fasting plasma lipid and glucose levels, and body mass index). A total of 186 antipsychotic-naïve first-episode psychosis patients or nonadherent chronic psychosis individuals (99 males and 87 females) were genotyped by polymerase chain reaction analysis. The ACE-I/D polymorphism was significantly associated with changes in PANSS psychopathology only (p < 0.05). Compared to ACE-II homozygous males, ACE-DD homozygous and ACE-ID heterozygous males manifested significantly greater decreases in PANSS positive score, PANSS excitement factor, and PANSS cognitive factor. ACE-DD homozygous females manifested higher decreases in PANSS depression factor compared to ACE-II homozygous and ACE-ID heterozygous females. The polymorphism’s effect size was estimated as moderate to strong, while its contribution to the PANSS psychopathology ranged from ~5.4–8.7%, with the lowest contribution observed for PANSS positive score changes and the highest for PANSS depressive factor changes. Our results indicated that ACE-I/D polymorphism had a statistically significant but weak gender-specific impact on psychopathology data and showed no association between ACE-I/D polymorphism and metabolic syndrome-related parameters.

COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The virus infection can evolve asymptomatically or generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia in patients affected with COVID-19 according to the severity of symptoms is frequent. However, the profile of CD4+ and CD8+ T-cells regarding cytotoxicity and antiviral factor expression has not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study is to evaluate the phenotypic and functional profile of T-lymphocytes in patients with moderate and severe/critical COVID-19. During this pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe/critical cases). Albeit lymphopenia, we observed an increase in the expression of CD28, co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T-lymphocytes as well as an increase in the frequency of CD4+ T-cells, CD8+ T-cells, and NK cells that express the immunological checkpoint protein, PD-1, in patients with severe/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T-cells already at baseline level was observed, scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T-lymphocytes decreased cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed in the t-SNE technique CD4+ T-cytotoxic and CD8+ T with low granzyme production evidencing their dysfunctionality in severe/critical conditions. In addition, purified CD8+ T-lymphocytes from patients with severe COVID-19 showed an increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and curiously, reduced expression of TNF-α. The cytotoxic profile, by CD4+ T-cells, may compensate for the dysfunction/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T-cells and CD8+ T-cells in the severity of acute COVID-19 infection.

Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio-chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. Radiation is delivered concomitantly during the first 3 weeks of chemotherapy, and it is based on a 15 fractions scheme (40.5Gy/2.7Gy per fraction to whole breast and nodal levels I-IV. Chemotherapy is based on Pertuzumab-Trastuzumab-Paclitaxel followed by anthracyclines in HER2+ and CBDCA-Paclitaxel followed by anthracyclines in TN breast cancers patients. 58 patients were enrolled, 25 patients (43%) were TN and 33 patients HER2+ (57%). With a median follow-up of 24.2 months, 56 patients completed PCRT and surgery. A total of 35 patients (87.5%) achieved &gt;90% loss of invasive carcinoma cell in the surgical specimen. The 70.8% and the 53.1% of patients with TN and HER-2+ subtype respectively achieved complete pathological response (pCR). This is the first study of concurrent neoadjuvant treatment in breast cancer in which three strategies are applied simultaneously: fractionation of RT in 15 sessions, adjustment of CT to tumor phenotype and local planning by PET. The pCR rates are encouraging.

Neoadjuvant systemic therapy has now become the the standard in early breast cancer management. Chemotherapy in combination with trastuzumab +/- pertuzumab targeted therapy can improve rates of pathologic complete response (pCR) in patients with HER2-positive breast cancer. Achieving a pCR is considered a good prognostic factor, in particular in patients with more aggressive breast cancer subtypes such as TNBC or HER2 positive cancers. Furthermore, most studies demonstrate that chemotherapy in combination with trastuzumab and pertuzumab is well tolerated. The retrospective analysis presented here concentrates on neoadjuvant therapy with the TCbH-P regimen, with a particular emphasis on patients over 60 years of age. We analysed the factors affecting the achievement of pCR and presented adverse effects of the applied therapies, which opened a discussion about optimizing the therapy of older patients with HER-2 positive breast cancer.

Different types of engineered cardiac constructs are being developed nowadays by many research groups. However, the immunological properties of such artificial tissues are not yet clearly understood. Previously, we have studied microfiber scaffolds carrying iPSC-derived cardiomyocytes. In this work, we evaluated the ability of these tissue-engineered constructs to activate the expression of CD28 and CTLA-4 proteins in T-lymphocytes which are early markers of the immune response. For this purpose electrospun PLA nanofibrous scaffolds were seeded with human iPSCs-CM and cultivated for 2 weeks. After, allogeneic mononuclear cells were co-cultured during 48 hours with 3 groups of samples that were tissue-engineered constructs, pure culture of cardiomyocytes and bare scaffolds followed by analysis of CD28/CTLA-4 expression on T-lymphocytes via flow cytometry. PLA scaffolds and concanavalin A (positive control) stimulation statistically significantly increased CD28 expression on CD4+ cells (up to 61.3% and 66.3%) and on CD8+ cells (up to 17.8% and 21.7%). CD28/CTLA-4 expression didn’t increase during co-cultivation of T-lymphocytes with cardiac engineered constructs and iPSC-CM monolayers. Thus, iPSCs-CM in monolayers and on PLA nanofibrous scaffolds didn’t cause T-cell activation, which allows us to expect that such cardiac constructs are not a cause of rejection after implantation.

Airborne wind energy (AWE) systems use tethered flying devices to harvest higher-altitude winds to produce electricity. For a successful deployment of these systems, it is crucial to understand how the public perceives them. If public concerns about the technology are not taken seriously, implementation could be delayed or, in some cases, prevented, resulting in increased costs for project developers and a lower contribution of the sector to renewable energy targets. This literature review assessed the current state of knowledge on public responses to AWE. An exhaustive literature search led to the identification of 40 relevant publications that were reviewed. The literature assumed that the safety, visibility, acoustic emissions, ecological impacts, and the siting of AWE systems shape public responses to the technology. The reviewed literature views people’s responses to AWE very optimistically but lacks scientific evidence to back up its claims. It seems to overlook that the influence of AWE’s characteristics (e.g., visibility) on public responses will also depend on a range of situational and psychological factors (e.g., people’s general attitude towards AWE, the public’s trust in project developers). Therefore, empirical social scientific research is needed to increase the field’s understanding of public responses to AWE and thereby facilitate deployment.

Agaricus blazei Murrill or Himematsutake is an edible and medicinal mushroom. Agaricus blazei Murrill's fruiting body extracts have anticancer properties, although the mechanism is unknown. Basic or organic solvents, which are hazardous for human health, are generally used to prepare Agaricus blazei Murrill's extracts. Inhibition of immune checkpoint molecules and Axl receptor is an effective therapy in cancer. This study assessed whether subcritical water extracts of the Agaricus blazei Murrill's fruiting body or mycelium affect the expression of Axl and immune checkpoint molecules in lung cancer cells. We used A549 cells and mouse bone marrow-derived dendritic cells in the experiments. We prepared subcritical water extracts from the Agaricus blazei Murrill's fruiting body or mycelium. The subcritical water extracts from the Agaricus blazei Murrill's fruiting body or mycelium significantly inhibited the expression of immune checkpoint molecules and Axl compared to saline-treated cells. Also, the hot water extract, subcritical water extract, and the hot water extraction residue subcritical water extract from the Agaricus blazei Murrill's mycelium significantly enhanced the expression of maturation markers in dendritic cells. These observations suggest that the subcritical water extract from Agaricus blazei Murrill's mycelium is a promising therapeutic tool for stimulating the immune response in cancer.

We discuss two methods to detect the presence and location of a person in a small-scale room and compare the performances. The first method is Direct Intersection, which determines a coordinate point based on the intersection of spheroids defined by observed distances of high-intensity reverberations. The second method, Sonogram analysis, overlays all channel’s room impulse responses to generate an intensity map for the observed environment. We demonstrate that the former method has lower computation complexity and higher accuracy for small numbers of channels, while the latter performs more robustly.

Acrylamide (AA) present in food is considered a harmful compound for humans, but it exerts impact on microorganisms too. The aim of the study was to evaluate the impact of AA (at conc. 0-10 µg/mL) on the growth of bacteria (Leuconostoc mesenteroides, Lactobacillus acidophilus LA-5) and yeasts (Saccharomyces cerevisiae, Kluyveromyces lactis var. lactis), which naturally occur in food products. Moreover, we decided to verify whether these microorganisms could decompose acrylamide. Our results proved that AA can stimulated the growth of L. acidophilus and K. lactis. We have also reported, to the best of our knowledge for the first time, that probiotic strain of bacteria L. acidophilus LA-5 is able to degrade AA by amidase production and hence can utilize AA as a source of carbon and nitrogen if they lack in the environment. The conducted Response Surface Methodology indicated that pH as well as incubation time and temperature significantly influenced the amount of ammonia released from acrylamide by the bacteria. Concluding, our studies suggest that some strains of bacteria present in milk fermented products can exert additional beneficial impact by acrylamide degradation and preventing against its harmful impact on human body and other members of intestinal microbiota.

In the last years, more and more studies highlight the advantages of complementing traditional master classes with additional activities that improve students´ learning experience. This combination of teaching techniques is specially advised in the field of structural engineering, where intuition of the structural response it is of vital importance to understand the studied concepts. This paper deals with the introduction of a new (and more encouraging) educational tool to introduce intuitively students in the dynamic response of structures excited with an educational shaking table. Most of the educational structural health monitoring systems use sensors to determine the dynamic response of the structure. The proposed tool is based on a radically different approach, as it is based on low-cost image-recognition techniques. In fact, it only requires the use an amateur camera, a black background and a computer. In this study, the effects of both the camera location and the image quality are also evaluated. Finally, to validate the applicability of the proposed methodology, the dynamic response of small-scale buildings with different typologies is analyzed. In addition, a series of surveys were conducted in order to evaluate the activity based on student´s satisfaction and the actual acquisition and strengthening of knowledge.

The Rasch model is one of the most prominent item response models. In this article, different item parameter estimation methods for the Rasch model are compared through a simulation study. The type of ability distribution, the number of items, and sample sizes were varied. It is shown that variants of joint maximum likelihood estimation and conditional likelihood estimation are competitive to marginal maximum likelihood estimation. However, efficiency losses of limited-information estimation methods are only modest. It can be concluded that in empirical studies using the Rasch model, the impact of the choice of an estimation method with respect to item parameters is almost negligible for most estimation methods. Interestingly, this sheds a somewhat more positive light on old-fashioned joint maximum likelihood and limited information estimation methods.

The present work highlights some of the dynamic couplings observed in a series of tests performed in a wave basin with a scaled-model of a FOWT with semi-submersible substructure. The model was moored by means of a conventional chain catenary system and an actively controlled fan was used for emulating the thrust loads during the tests. A set of wave tests comprising regular and irregular waves was done for different wave angles and wind velocities. The experimental records illustrate the main coupling effects involved and how they affect the FOWT motions in waves, especially when the floater presents a non-negligible tilt angle.. In addition, an analysis of the frequency-domain dynamic model was made in order to evaluate its ability to capture these effects properly. The influence of different modes of fan response, floater trim angles (changeable with ballast compensation) and variations of the mooring stiffness with the offsets were investigated in the analysis. Results attest that significant changes in the FOWT responses may indeed arise from coupling effects, thus indicating that caution must be taken when simplifying the hydrodynamic frequency-domain models often used as a basis for the simulation of FOWTs in waves and in in optimization procedures for the design of the floater and mooring lines.

Background: This year has seen the emergence of two major crises, a significant increase in frequency and severity of hurricanes and the COVID-19 pandemic. However, little is known as to how each of these two events have impacted the other. A rapid qualitative assessment was conducted to determine the impact of the pandemic on preparedness and response to natural disasters and the impact of past experiences with natural disasters in responding to the pandemic. Methods: Semi-structured interviews were conducted with 26 representatives of 24 different community-based programs in southern Louisiana. Data were analyzed using procedures embedded in the Rapid Assessment Procedure – Informed Community Ethnography methodology, using techniques of immersion and crystallization and focused thematic analysis. Results: The pandemic has impacted the form and function of disaster preparedness, making it harder to plan for evacuations in event of a hurricane. Specific concerns included being able to see people in-person, providing food and other resources to residents who shelter in place, finding volunteers to assist in food distribution and other forms of disaster response, competing for funds to support disaster-related activities, developing new support infrastructures, and focusing on equity in disaster preparedness. However, several strengths based on disaster preparedness experience and capabilities were identified, including providing a framework for how to respond and adapt to COVID and integration of COVID response with their normal disaster preparedness activities. Conclusions: Although prior experience has enabled community-based organizations to respond to the pandemic, the pandemic is also creating new challenges to preparing for and responding to natural disasters.

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, antibiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and catecholaminergic metabolism due to its capability as a pro-oxidant and other harmful molecules, versus its involvement in oxidative stress and aberrant immune response, which it is highly dependent on NM saturation state and its extracellular release.

Mental stress represents a pivotal factor in cardiovascular diseases. The mechanism by which stress produces its deleterious effects is still under study but one of the most explored pathway is cell senescence. In this scenario, circulating microRNAs appear to be mobile regulatory elements of the telomerase activity and alternative splicing within the ”senectome” network. Anti-stress techniques seem to be able to slow-down aging process. As we have recently verified how the practice of Relaxation Response (RR), counteracting psychological stress, determines favorable changes of some inflammatory genes expression, of some neurotransmitters, hormones, cytokines and inflammatory circulating microRNAs, we aimed to verify a possible change even in serum levels of 4 senectome micro-RNAs (SE-miRNAs -20, -30, -410, -515), testing the activity of telomerase in peripheral blood mononuclear cells-PBMCs. We analyzed also alternative splicing microRNAs 134 and 183. According to our data, miRNA-20 and -30 levels and PBMCs-telomerase activity increase during the RR while -410 and -515 levels decrease. Moreover, during the RR sessions both miRNA-134 and -183 decrease. The mediators considered in this work seem to vary rapidly according to a (stress)-relaxation condition showing that psychic activity should be part of the study of aging factors.

As the novel COVID-19 disease spreads around the world, the most affected population are those who suffer from the most common chronic diseases, such as obesity, hypertension, and type 2 diabetes, which are quite associated with the so-called age-related diseases. On the other hand, since the Spanish influenza outbreak, humanity has not experienced an infectious disease that synergizes so quickly with chronic diseases, making it mortal for those individuals with comorbidities. In this context, COVID-19 is challenging for health systems all around the world due to the high prevalence of chronic diseases. Nowadays, we are facing the beginning of a new era in which health infectious and chronic diseases meet. Therefore, epidemiologic and biomedical researchers must work together to solve further contingencies, and politicians should direct science-centered decisions on public health. In the present paper, we make an urgent call to learn from the COVID-19 lessons in order to mitigate the chronic diseases prevalence and to address the influence of the infectious diseases on the aging process; since we are about to begin the Decade of Healthy Aging.

The standard of care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment in case of symptomatology onset. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive disease presentations are even more common, leading to a change of paradigm of focal treatments. In fact, acknowledgement of behaviour of disease in these setting of patients is carrying aim of radiotherapy towards modalities with radical intent. The aim of this literature review is to analyse available clinical data regarding disease behaviour, imaging, radiotherapy and chemo-radiotherapy integration outcomes for understanding bone metastasis from breast cancer and the potential impact of targeting it.

Nearly three months have passed since the emergence of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which caused the rapidly spreading Coronavirus Disease 2019 (COVID-19) pandemic. To date, there have been more than 550,000 confirmed cases and more than 25,000 deaths globally caused by COVID-19. Chinese health authorities, where the virus emerged, have taken prompt strict public health measures to control and prevent the spread of the outbreak. In the kingdom of Saudi Arabia, unprecedented precautionary strict measures were applied to slow virus entry and to mitigate the risk of the outbreak. Here, we review the experience learned during the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) epidemic in Saudi Arabia, which has been in the country since 2012, and is expected to have helped the country to be well prepared for the current COVID-19 pandemic. We also discuss the country readiness, improvement in research and development, and the unprecedented rapid precautionary measures that have been taken by the Saudi government thus far.

Defensive structure is important in transportation field for kinds of intentional or unintentional explosion. Structures subjected to unconfined and confined explosion will bear different blast loads and their dynamic responses are different. The present work focus on the dynamic response mechanism of steel plate under unconfined and confined blast loads through both numerical and experimental studies. In the experiment, Digital Image Correlation (DIC) technique was applied to record and analyze the dynamic response process of large-scale field blast test. The DIC measured curve and the numerical calculated curves agrees well in both the trends and the peak values. Then, the dynamic response mechanism of steel plate under unconfined blast (UB) load and confined blast (CB) load were compared and discussed. Results show that the dynamic response of plate can be divided into three phases under both UB and CB loads, while with different mechanism. In phase I, plastic hinge starts from the center and moves to the boundary in UB condition, while in case of CB, plastic hinge occurs close to the boundary and moves in the opposite direction. In phase II, two plastic hinge lines propagates towards each other, and a platform exists between the boundary and the central area remains undeformed in UB condition, while in CB condition, larger deformation in peripheral region rather than central area produces.

An ion exchange dialysis (IED) is used in the recovery of aluminium from residue. In this papers, the face-centered central composite design (FC-CCD) of the response surface methodology (RSM) and desirability approach is used for experimental design, modelling and process optimization of a counter flow IED system. The feed concentration, feed flowrate, sweep flowrate and sweep concentration are selected as the process variables, with the Al-transport across a Nafion 117 membrane as the target response. A total of 30 experimental runs were conducted with 6 center points. The response obtained was analysed by analysis of variance (ANOVA) and fitted to a second-order polynomial model using multiple regression analysis. The actual R2 and standard deviation of the model are 0.9548 and 0.2932 respectively. The influences of significant variables are plotted on 3D surface and contour plots. The designed variables were numerically optimized by applying the desirability function to achieve the maximum Al-transport. The optimised condition values were found to be feed concentration (1600 ppm), feed flowrate (61.76%), sweep flowrate (37.50%) and sweep concentration (0.75 N) for the 80% target response at 32hrs. Overall, the model can be used to effectively predict Al-recovery using the designed system

Background In SILIUS (NCT01214343), combination of sorafenib and hepatic arterial infusion chemotherapy did not significantly improve overall survival in patients with advanced hepatocellular carcinoma (HCC) compared with sorafenib alone. In this study, we explored the relationship between objective response by mRECIST and overall survival (OS) in the sorafenib group, in the combination group and in all patients in the SILIUS trial. Methods Association between objective response and OS in patients treated with sorafenib (n=103), combination (n=102) and all patients (n=205) were analyzed. The median OS of responders was compared with that of non-responders. Landmark analyses were performed according to objective response at several fixed time points, as sensitivity analyses, and the effect on OS was evaluated by Cox regression analysis with objective response as a time-dependent covariate, with other prognostic factors was performed. Results In the sorafenib group, OS of responders (n = 18) was significantly better than that of non-responders (n = 78) (p < 0.0001), where median OS was 27.2 (95% CI, 16.0–not reached) months for responders and 8.9 (95% CI, 6.5–12.6) months for non-responders. HRs from landmark analyses at 4, 6, and 8 months were 0.45 (p=0.0330), 0.37 (p=0.0053), and 0.36 (p=0.0083), respectively. Objective response was an independent predictor of OS based on unstratified Cox regression analyses. In the all patients and the combination group, similar results were obtained. Conclusion In the SILIUS trial, objective response was an independent prognostic factor for OS in patients with HCC.

Although transplantation procedures have been developed for patients with end-stagec hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents, such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity is commonly occurred in clinical situations, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms whereby CNIs cause neurotoxicity include: increasing the permeability or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures; mycophenolate mofetil induces depression and headache; methotrexate affects the central nervous system; mouse monoclonal immunoglobulin G2 antibody against cluster of differentiation 3 also induces headache; and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms have greatly reduced neurotoxic events. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, using drugs to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize the recent topics on the mechanisms of neurotoxicity of immunosuppressive drugs. In addition, some information about neuroprotective effects of several immunosuppressants are also discussed.

Recently, light traps using light-emitting diode (LED) lights have been applied to monitor or control insect pests. The oriental armyworm, Mythimna separata Walker, is an important insect pest that has caused damage to several cereal crops, including corn, wheat and rice. The present study aims to seek out a sensitive wavelength causing high phototactic response in M. separata. The study evaluated the phototactic responses of M. separata moths to several LED lights of different wavelengths and luminance intensities under laboratory condition. Results showed that green (520 nm) LED light resulted in significant phototactic response of M. separata moths compared to LED lights of other wavelengths. Additionally, the highest attraction rate of the moths to green LED light appeared in luminance intensity group of 200 lux compared to the other intensities groups. Experiments under optimum conditions based on the above experiments revealed that the green LED light exhibited the strongest attraction rate (64.44%) among all experimental groups. An experiment performed in a net cage also showed that green LED light resulted in the highest phototactic response of M. separata moths, 1.7 times more than a commercial black light used as control. These findings clearly demonstrate that M. separata moths have a high sensitivity to the green LED light. Therefore, a light trap equipped with green LED light could be useful for monitoring and controlling M. separata moths.

The world is progressing towards a more advanced society where end-consumers have access to local renewable-based generation and advanced forms of information and technology. Hence, it is in a current state of transition between the traditional approach to power generation and distribution, where end-consumers of electricity have typically been inactive in their involvement with energy markets and a new approach that integrates their active participation. This new approach includes the use of distributed energy resources (DER) such as renewable-based generations and demand response (DR), which are being rapidly adopted by end-consumers, where incentives are strong. This paper presents the role of DR aggregator to effectively integrate DER technologies as a new source of energy capacity, into the electricity networks using information communication technology and industry knowledge. This framework based on DR aggregators will facilitate renewable energy integration and customer engagement in electricity market efficiently. To this aim, advantages and disadvantages of DR aggregators are discussed in this paper from political, economic, social and technological (PEST) point of views. Based on this analysis, a strengths, weaknesses, opportunities, and threats (SWOT) analysis for a typical DR aggregator is presented.

The correlation and comorbidity between depression and chronic pain have been observed for a long time. Generally, it is considered that the two conditions reinforce each other, whereas the causal relationship between them is not clear. However, some evidence suggested that chronic pain may reverse the progression of depression in some cases. This article presents a selective review of clinical and pharmacological relationship between depression and pain, and their interactions at neurochemical and neurobiological levels. In addition, we open a discussion on a recent case report of repeated success of using short but continuous pain (SCP) during meditation as the only treatment for depression, compared to initial success but no remission with other conventional antidepressants on the same patient. Together this review proposes an updated model for depression and its various treatments that is based on synaptic and system homeostasis. More importantly, it suggests that SCP may benefit depression recovery through its properties that are different from either acute or chronic pain and represents a novel research area that has been largely neglected to date.

Proteases are integral enzymes of the plant immune system. Multiple aspects of defence are regulated by proteases, including the hypersensitive response, pathogen recognition, priming and peptide hormone release. These processes are regulated by unrelated proteases residing at different subcellular locations. In this review we discuss ten prominent plant proteases contributing to the plant immune system, highlighting the diversity of roles they perform in plant defence.

In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context.

In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context.

Small non-coding RNAs (sRNAs) are ubiquitously found in the three domains of life playing large-scale roles in gene regulation, transposable element silencing, and defense against foreign elements. While a substantial body of experimental work has been done to uncover function of sRNAs in Bacteria and Eukarya, the functional roles of sRNAs in Archaea are still poorly understood. Recently, high throughput studies using RNA-sequencing revealed that sRNAs are broadly expressed in the Archaea, comprising thousands of transcripts within the transcriptome during non-challenged and stressed conditions. Antisense sRNAs, which overlap a portion of a gene on the opposite strand (cis-acting), are the most abundantly expressed non-coding RNAs and they can be classified based on their binding patterns to mRNAs (3’ UTR, 5’ UTR, CDS-binding). These antisense sRNAs target many genes and pathways, suggesting extensive roles in gene regulation. Intergenic sRNAs are less abundantly expressed and their targets are difficult to find because of a lack of complete overlap between sRNAs and target mRNAs (trans-acting). While many sRNAs have been validated experimentally, a regulatory role has only been reported for very few of them. Further work is needed to elucidate sRNA-RNA binding mechanisms, the molecular determinants of sRNA-mediated regulation, whether protein components are involved, and how sRNAs integrate with complex regulatory networks.

The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults (aged 60-75 years) received a single administration of 100, 150 or 200 mg/kg body weight of tyrosine. For comparison, 17 young adults (aged 18-35 years) received a dose of 150 mg/kg body weight of tyrosine. Tyrosine plasma concentrations were determined before and 90, 120, 150, 180, 210 and 240 minutes after tyrosine intake. Working memory was assessed using the N-back task at 90 minutes after tyrosine administration. Older adults showed a dose-dependent increase in plasma tyrosine concentrations (p<.001), and the plasma response was higher than for young adults with the same dose (p<.001). Load-dependent working memory performance decreased with higher doses of tyrosine (p=.048), especially in older adults with greater dose-dependent plasma tyrosine responses (p=.035). Our results show an age-related increase in plasma tyrosine response, which was associated with a dose-dependent decline in cognitive functioning in older adults.

Soil-structure interaction (SSI) could affect the seismic response of structures. Since liquid storage tanks are vital structures and must continue their operation under severe earthquakes, their seismic behavior should be studied. Accordingly, the seismic response of liquid storage tanks founded on half space soil is scrutinized under different earthquake ground motions. To better comparison, the six considered ground motions are classified based on their pulse like characteristics, into two groups, named far and near fault ground motions. To model the liquid storage tanks, the simplified mass-spring model is used and the liquid is modeled as two lumped masses known as sloshing and impulsive, and the interaction of fluid and structure is considered using two coupled springs and dashpots. The SSI effect, also, is considered using a coupled spring and dashpot. Besides, four types of soils are used to consider wide variety of soil properties. To this end, after deriving the equations of motion, the MATLAB programming is employed to obtain the time history responses. Results show that although the SSI effect leads to decrease the impulsive displacement, overturning moment and normalized base shear, the sloshing (or convective) displacement is not affected by such effects due to its long period.

Silicone mammary implants (SMIs) frequently result in capsular fibrosis, which is marked by the overproduction of fibrous tissue surrounding the implant. This review provides a detailed examination of the molecular and immunological mechanisms driving capsular fibrosis, focusing on the role of foreign body responses (FBR) and microbial biofilm formation. We investigate how microbial adhesion to implant surfaces and biofilm development contribute to persistent inflammation and fibrotic responses. The review critically evaluates antimicrobial strategies, including preoperative antiseptic protocols and antimicrobial-impregnated materials, designed to mitigate infection and biofilm-related complications. Additionally, advancements in material science, such as surface modifications and antibiotic-impregnated meshes, are discussed for their potential to reduce capsular fibrosis and prevent contracture of the capsule. By integrating molecular insights with clinical applications, this review aims to elucidate the current understanding of SMI-related fibrotic responses and highlight knowledge gaps. The synthesis of these findings aims to guide future research directions of improved antimicrobial interventions and implant materials, ultimately advancing the management of capsular fibrosis and enhancing patient outcomes.

Herpesviruses usurp cellular stress responses to avoid immune detection while simultaneously promoting viral replication and spread. The unfolded protein response (UPR) is an evolutionarily conserved stress response that is activated when the protein load in the ER saturates its chaperone folding capacity causing an accrual of misfolded proteins. Through translational and transcriptional reprogramming, the UPR aims to restore protein homeostasis; however, if this fails the cell undergoes apoptosis. It is commonly thought that many enveloped viruses, including herpesviruses, may activate the UPR due to saturation of the ER with nascent glycoproteins and thus these viruses may have evolved mechanisms to evade the potentially negative effects of UPR signaling. Over the past fifteen years there has been considerable effort to provide evidence that different viruses may reprogram the UPR to promote viral replication. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key findings that demonstrate that the UPR is an important cellular stress response that herpesviruses have hijacked to facilitate persistent infection.

Maternal-derived immunity is a critical component for survival and success of offspring in pigs to protect from circulating pathogens like Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2). The purpose of this study was to investigate the transfer of anti-PRRSV immunity to piglets from gilts that received modified-live virus (MLV) alone (TRT 0), or in combination with one of two autogenous inactivated vaccines (AIVs, TRT 1+2). Piglets from these gilts were challenged with the autogenous PRRSV-2 strain at two weeks of age and their adaptive immune response (IR) was evaluated until 4 weeks post inoculation (wpi). The systemic humoral and cellular IR was analyzed in the pre-farrow gilts, and in piglets, pre-inoculation, and at 2- and 4-wpi. Both AIVs partially protected the piglets with reduced lung pathology and increased weight gain; TRT 1 also lowered piglet viremia best explained by the AIV-induced production of neutralizing antibodies in gilts and their transfer to the piglets. In piglets, pre-inoculation, the main systemic IFN-γ producers were CD21α+ B cells. From 0 to 4 wpi, the role of these B cells declined and CD4 T cells became the primary systemic IFN-γ producers. In lungs, CD8 T cells were the primary and CD4 T cells the secondary IFN-γ producers including a novel subset of porcine CD8α-CCR7- CD4 T cells, potentially terminally differentiated CD4 TEMRA cells. In summary, this study demonstrates that maternal AIV vaccination can improve protection of pre-weaning piglets against PRRSV-2; it shows the importance of transferring neutralizing antibodies to piglets; and it introduces two novel immune cell subsets in pigs – IFN-γ producing CD21α+ B cells and CD8α-CCR7- CD4 T cells.

This study addresses the challenge of predicting the dynamic behavior of the structures under seismic excitation. Accurate prediction of such systems' responses is critical for the design and evaluation of buildings and infrastructure. Traditional methods, including numerical models and differential equation solvers, often face significant computational burdens, especially with nonlinear hysteretic behaviors and large-scale problems. To overcome these limitations, a novel Fuzzy-based Convolutional Neural Network (FuzzyCNN) model is developed. This model integrates fuzzy logic principles with convolutional neural networks to effectively manage the uncertainties and complexities inherent in soil-structure interaction under seismic loads. The model's performance is validated through both numerical simulations and experimental data from a mid-rise concrete building subjected to seismic events. Comparative analysis with a traditional Physics-informed CNN (PhyCNN) model demonstrates the superior accuracy and robustness of the FuzzyCNN in predicting seismic responses. Key results show that the FuzzyCNN model not only enhances prediction accuracy but also handles uncertainties more effectively than the PhyCNN model. The findings suggest that the FuzzyCNN model can significantly improve the efficiency and accuracy of dynamic response predictions. This advancement offers valuable implications for engineering design, seismic risk assessment, and the development of more resilient infrastructure.

The COVID-19 pandemic has significantly impacted human health and daily life. Meteorological factors play a crucial role in virus transmission. Understanding these factors is critical for pandemic control, yet debates continue due to variations in research methods and data. This study uses a global dataset and focuses on administrative units smaller than 10,000 km². The relationship between daily COVID-19 incidence rates and meteorological factors—including temperature, relative humidity (RH), ultraviolet radiation (UVR), and diurnal temperature range (DTR)—was analyzed across 173 units in 62 countries. The results revealed significant nonlinear responses and lag effects between incidence rates and the meteorological factors. Key inflection points were observed at 0°C and 24°C for temperature, 63% for RH, 102 KJ/m² for UVR, and 15°C for DTR. Below 0°C, infection risk increased with rising temperatures; from 0°C to 24°C, risk decreased; and above 24°C, risk escalated rapidly. RH below 63% correlated inversely with infection risk, while above 63%, the correlation was positive. Infection risk decreased with UVR below 102 KJ/m² but increased beyond this threshold. These nonlinear responses are primarily driven by the differential effects of these factors on virus survival, transmission, and human immunity. Conditions around 24°C, 63% RH, 102 KJ/m² UVR, and DTR below 15°C appear optimal for human immunity, correlating with lower infection risk. High temperature and low UVR prompted immediate infection responses, while low temperatures, high UVR, and larger DTR showed delayed effects. These findings provide new, more reliable evidence for understanding the mechanisms driving COVID-19 pandemic dynamics and for preventing the future normalization of the epidemic.

Cervical cancer is 4th the most common cancer in women worldwide. Due to the prevalence of HPV in the population (80-90%), the scientists are likely to discover even more associations of this pathogen with other diseases in the future. In recent years, ISH assays that use automated signal-detecting methods in ormalin-fixed, paraffin-embedded (FFPE) cervical tissue, such as the enzyme-categorized signal-detecting system, have shown a higher sensitivity. To evaluate automatic signal detection of in situ hybridization (ISH) assay for detecting human papillomavirus (HPV) DNA, we compared the ability of an ISH probe, Inform HPV II and III (Ventana Medical Systems, Tucson, AZ), to that of PCR assays to detect HPV DNA in cervical tissue specimens with cervical intraepithelial neoplasia (CIN; CIN 1, 28 cases; CIN 2, 22 cases; and CIN 3, 20 cases) and normal cervix (2 cases). Our findings showed significant relation was confirmed between ISH III level and HPV outcome (positive/negative). Patients with positive HPV outcomes had significantly lower ISH III levels, MD = -7961.82 CI95 [-17230.00; -199.21], p = 0.005. Automatic signal detection of ISH assay is not particularly applicable to cervical tissue material. A more useful method of confirming the presence of HPV in the cervix is ​​the HPV test with genotyping, as it allows for collecting a larger amount of material from the cervical disc and canal. The interpretation of a positive or negative ISH test must be guided in the context of clinical history and morphology.

Gut dysbiosis and an inflamed bowel are growing concerns in mammals, including dogs. Probiotic supplements have been used to restore the natural microbial community and improve gastrointestinal health. Biofilm formation, antimicrobial activities, and immunological responses of probiotics are crucial to improving gut health. Thus, we tested a commercial probiotic blend (LabMAX-3), a canine kibble additive comprising Lactobacillus acidophilus, Lacticasibacillus casei, and Enterococcus faecium for their ability to inactivate common enteric pathogens; their ability to form biofilms, epithelial cell adhesion and anti-inflammatory response on Madin-Darby Canine Kidney (MDCK) cell line. Probiotic LabMAX-3 blend, or individual isolates, showed a strong inhibitory effect against Salmonella enterica, Listeria monocytogenes, enterotoxigenic Escherichia coli, and Campylobacter jejuni. LabMAX-3 formed biofilms comparable to Staphylococcus aureus. LabMAX-3 adhesion to the MDCK cell line (with or without lipopolysaccharide, LPS) pretreatment showed comparable adhesion and biofilm formation (p < 0.05) to L. casei ATCC 334 used as a control. LabMAX-3 had no cytotoxic effects on the MDCK cell line during 1 h exposure. The IL-10 and TNFα ratio of LabMAX-3, compared to the L. casei control, showed a significant increase (p < 0.05), indicating a more pronounced anti-inflammatory response. The data show that LabMAX-3, a canine kibble supplement, can improve gastrointestinal health.

The development of straddle-type monorail tour-transit systems (MTTSs) has received keen attention, raising the need for revisions on related design codes. This work presents a comprehensive assessment of the lateral stiffness limit of steel substructures in MTTSs. Firstly, a wind‒vehicle‒bridge coupling model was established, integrating multibody dynamics and finite element methods. This model was then validated against field test results, considering measured track irregularities as the excitation. Afterwards, a trend analysis and a variance-based sensitivity analysis was performed to investigate the effect of various factors on the dynamic response of MTTS. Referring to existing specifications, an evaluation index for the lateral stiffness of pier columns and track beams was proposed. Results indicate that the pier height significantly impacts the lateral displacement of the pier top, accounting for 87% of the first-order sensitivity index and 75% of the total sensitivity index. In comparison, the lateral stiffness of track beams contributes over 70% to the maximum lateral acceleration and displacement at the mid-span. Finally, the lateral limited values for the displacement at the pier top and the deflection–span ratio of the track beam were determined as 8.04 mm and L/4200, respectively. These findings can serve as valuable references for future research and designs in this field.

Drug development is a lengthy process with a high failure rate. Increasingly, machine learning is utilized to facilitate the drug development processes. These models aim to enhance our understanding of drug characteristics, including their activity in biological contexts. However, a major challenge in drug response (DR) prediction is model interpretability as it aids in the validation of findings. This is important in biomedicine, where models need to be understandable in comparison with established knowledge of drug interactions with proteins. drGAT, a graph deep learning model, leverages a heterogeneous graph composed of relationships between proteins, cell lines, and drugs. drGAT is designed with two objectives: DR prediction as a binary sensitivity prediction and elucidation of drug mechanism from attention coefficients. drGAT has demonstrated superior performance over existing models, achieving 78\% accuracy (and precision), and 76\% F1 score for 269 DNA-damaging compounds of the NCI60 drug response dataset. To assess the model's interpretability, we conducted a review of drug-gene co-occurrences in Pubmed abstracts in comparison to the top 5 genes with the highest attention coefficients for each drug. We also examined whether known relationships were retained in the model by inspecting the neighborhoods of topoisomerase-related drugs. For example, our model retained TOP1 as a highly weighted predictive feature for irinotecan and topotecan, in addition to other genes that could potentially be regulators of the drugs. Our method can be used to accurately predict sensitivity to drugs and may be useful in the identification of biomarkers relating to the treatment of cancer patients.

According to the honeycomb structure, the preliminary design of bionic wheel hub for finite element analysis, in the working condition of a wheel by the force is through the spokes pointing to the center, the working condition of two wheel by the force is through the two spokes pointing to the center, and the ordinary wheel stress and displacement value results compared, observed the maximum stress value appears in the connection between the center of the wheel and the spokes, and predict the fatigue life of the preliminary design of bionic wheel. Using finite element analysis and response surface optimization analysis method for numerical simulation, through two optimization results show that, in the use of response surface analysis model optimization, the optimized bionic wheel maximum stress is 109.34MPa, compared with the ordinary wheel maximum stress 119.77MPa, the maximum stress reduced by 8.7%. The mass of the ordinary wheel is 34.02Kg, using the response surface optimization method, the optimized wheel mass is 29.89Kg, the mass reduced by 12.13%. The optimized wheel fatigue analysis, in the stress of 109.34MPa, load loading times at least 4.217e+005, in the position at the junction with the half shaft. In line with the national standard GB/T 5334-2021[16] for commercial vehicle wheel fatigue life requirements.

Ultrasonic transducers are widely used for non-destructive testing (NDT) and evaluation in various industries. While capacitive micromachined ultrasonic transducers (CMUTs) have emerged as significant novel transducers, their application in NDT has been limited. This study designed and fabricated a novel two-element CMUT device for NDT applications. The CMUT’s structural parameters were introduced, and the device was fabricated using silicon fusion wafer-bonding technology. The transducer’s sensitivity, bandwidth, and pulse-echo response performance were tested and analyzed. Testing with aluminum blocks demonstrated that the two-element transducer can transmit and receive ultrasonic waves, with central operating frequencies of 3.35 MHz. In addition, at 3.4 MHz, the receive sensitivities of both elements were –197.434 dB and –197.413 dB, respectively, meeting the requirements for NDT systems. In pulse-echo response testing, the CMUT successfully detected signals from the aluminum block interface and located the interface’s position. This study highlights the potential of CMUTs for NDT testing and evaluation applications.

Locally advanced rectal cancer requires multimodal treatment. Radiotherapy is being explored for intensification to improve rates of pathological complete responses (ypCR-rates) that correlates with better outcomes. This study reports a comparison between standard versus escalated dose in preoperative scenario. YpCR-rates, toxicity, postoperative complications, disease-free and overall survival at 5 years have been described. From 2012 to 2019, 99 patients were analyzed retrospectively: standard arm (mean 47.5Gy) vs. dose-escalated arm (mean 54.3Gy). All patients were treated with 3DRT in 25 fractions, concomitantly capecitabine and surgery performed according to total mesorectal excision principles in both arms. YpCR was reported by “College of American Pathologist grades”; gastrointestinal (GI) and genitourinary (GU) toxicity using the “Common Terminology Criteria for Adverse Events” (CTCAE 4.0). YpCR-rates were higher in the dose-escalated group (25% vs. 10.64%; p = 0.07) with a lower rate of non-treatment response (61.36% vs. 38.64%; p = 0.11). No statistical differences between arms were found in terms of oncological outcomes, all postoperative complications (p = 0.15), second surgeries (p = 0.62), or deaths (p = 0.62). CTCAE acute-GI and GU toxicity were grade I or II in both arms. Our study shows that the dose-escalated scheme is safer and obtains higher ypCR-rates.

The surge in big data and analytics has catalysed the proliferation of cybercrime, largely driven by organisations' intensified focus on gathering and processing personal data for profit, often overlooking security considerations. Hadoop and its derivatives are prominent platforms for managing big data, however, investigating security incidents within Hadoop environments poses intricate challenges due to scale, distribution, data diversity, replication, component complexity, and dynamicity. This paper proposes a digital forensics readiness framework and an incident response script for Linux-Hadoop systems, streamlining preliminary investigations. The framework offers a novel approach to digital forensics in the domains of big data and Hadoop environments. A prototype implementing important aspects of the DFR framework was developed and evaluated through comprehensive functionality and usability testing. The results demonstrated robust performance and efficacy.

Keywords: Response surface methodology; Ultrasonication; marigold flower; polyphenols, microcapsules; antimicrobial activity.

The relationship between antitumor response and tumor marker changes was evaluated in patients with advanced hepatocellular carcinoma treated with durvalumab plus tremelimumab (Dur/Tre). Thirty-two patients were enrolled in this retrospective evaluation of treatment outcomes. According to Response Evaluation Criteria for Solid Tumors at 8 weeks, the objective response rate (OR) was 25% and the disease control rate (DC) was 56.3%. Median alpha-fetoprotein (AFP) ratio at 4 weeks was 0.310 in patients who achieved OR at 8 weeks (8W-OR group), significantly lower than the 1.105 in the non-8W-OR group (p=0.0020), but was 1.210 in patients who did not achieve DC at 8 weeks (non-8W-DC group), significantly higher than the 0.470 in the 8W-DC group (p=0.0006). Similarly, median des-γ-carboxy-prothrombin (DCP) ratio at 4 weeks was 0.125 in the 8W-OR group, significantly lower than the 1.225 in the non-8W-OR group (p=0.0001), but was 1.120 in the non-8W-DC group, significantly higher than the 0.480 in the 8W-DC group (p=0.0255). Early changes in tumor markers after Dur/Tre initiation were associated with antitumor response. In particular, changes in AFP and DCP at 4 weeks may offer useful biomarkers for early prediction of both response and progressive disease following Dur/Tre.

The combination of neural network and beamforming has been proved to be very effective in multi-channel speech separation. But its performance faces a challenge in complex environment. In this paper, an iteratively refined multi-channel speech separation method is proposed for the challenge, where the proposed is composed of initial separation and iterative separation. In initial separation, the time-frequency domain dual-path recurrent neural network neural network (TFDPRNN), minimum variance distortionless response (MVDR) beamformer and post-separation (also TFDPRNN) are cascaded for obtaining the first additional input in iterative separation. In iterative separation, the MVDR beamformer and post-separation are iteratively used, where the output of the MVDR beamformer is used as an additional input of the post-separation network and the final output comes from post-separation module. This iteration of the beamformer and post-separation is fully employed for promoting their individual optimization, which ultimately improves the overall performance of speech separation in multi-speaker scenarios. Experiments on the spatialized version of the WSJ0-2mix corpus show that our proposed method is significantly better than the current popular methods. In addition, the method also has a good effect on the dereverberation task.

We produced a recombinant eel luteinizing hormone (rec-eel LH) analog with high potency in Chinese hamster ovary DG44 (CHO DG44) cells. The eel LH mutant (LH-M), which had a linker comprising the equine chorionic gonadotropin (eCG) β-subunit carboxyl-terminal peptide (CTP) region (amino acids 115 to149), was inserted between the β-subunit and α-subunit of wild-type tethered eel LH (LH-wt). Monoclonal cells transfected with the eel LH-wt and eel LH-M plasmids were isolated from five and nine clones of CHO DG44 cells, respectively. The secreted quantities abruptly increased on day 3, with peak levels of 5,000–7,500 ng/mL on day 9. The molecular weight of eel LH-wt was 32–36 kDa while that of eel LH-M increased to approximately 38–44 kDa, indicating the detection of two bands. Treatment with peptide N-glycanase F decreased the molecular weight by approximately 8 kDa. The oligosaccharides at the eCG β-subunit O-linked glycosylation sites were appropriately modified post-translation. The EC50 value and maximal responsiveness of eel LH-M increased by approximately 2.90- and 1.29-fold, respectively, indicating that the mutant exhibited more potent biological activity than eel LH-wt. Phosphorylated extracellular regulated kinase (pERK1/2) activation resulted in a sharp peak 5 min after agonist treatment, with a rapid decrease thereafter. These results indicate that the new rec-eel LH analog which contains the eCG β-subunit CTP linker comprising O-linked glycosylation sites, had more potent activity than the wild-type in vitro. Taken together, this new eel LH analog can be produced in large quantities using a stable CHO DG44 cell system.

CO2 geological sequestration in coal seams can achieve the dual objectives of CO2 emission reduction and enhanced coalbed methane production, making it a highly promising carbon capture and storage technology. However, the injection of CO2 into coal reservoirs in the form of supercritical fluid (ScCO2) leads to complex physicochemical reactions with the coal seam, altering the properties of the coal reservoir and impacting the effectiveness of CO2 sequestration and methane production enhancement.In this paper, theoretical calculations based on ReaxFF-MD were conducted to study the interaction mechanism between ScCO2 and the macromolecular structure of both low-rank and high-rank coal, to address the limitations of experimental methods. The reaction of ScCO2 with low-rank coal and high-rank coal exhibits significant differences. At swelling stage, the low-rank coal experiences a decrease in aromatic structure and aliphatic structure, high-rank coal shows an increase in aromatic structure and a decrease in aliphatic structure, while swelling phenomenon is more pronounced in high-rank coal. At dissolution stage, low-rank coal is initially decomposed into two secondary molecular fragments, and then recombine to form new molecular structure, the aromatic structure increased and the aliphatic structure decreased. In contrast, high-rank coal occurs stretches-breakage-movement-reconnection, a reduction in aromatic structure and an increase in aliphatic structure.The primary reasons for these variations lie in distinct molecular structure compositions and the properties of ScCO2, leading to different reaction pathways of functional group and aromatic structure. The reaction pathways of functional groups and aromatic structures in coal can be summarized as follows: the breakage of the O-H bond in hydroxyl groups, the breakage of the C-OH bond in carboxyl groups, transformation of aliphatic structures into smaller hydrocarbon compounds or formation of long-chain alkenes, and various pathways involving broken, rearrangement, recombination of aromatic structures. In low-rank coal, there is a higher abundance of oxygen-containing functional groups and aliphatic structures. The breakage of O-H and C-OH chemical bonds results in the formation of free radical ions, while some aliphatic structures detach to produce hydrocarbons. Additionally, some of these aliphatic structures combine with carbonyl groups and free radical ions to generate new aromatic structures. Conversely, in high-rank coal, the lower content of oxygen-containing functional groups and aliphatic structures, along with stronger intramolecular forces, results in fewer chemical bond breakages and makes it less conducive to the formation of new aromatic structures.These results elucidate the specific deformations of different chemical groups, offering a molecular-level understanding of the interaction between CO2 and coal.

This study aimed to produce single-chain recombinant eel follicle-stimulating hormone (rec-eel FSH) analogs with high activity in Chinese hamster ovary DG44 (CHO DG44) cells. We recently reported that an O-linked glycosylated carboxyl-terminal peptide (CTP) of the equine chorionic gonadotropin (eCG) β-subunit plays contributes on high activity and time-dependent secretion in mammalian cells. We constructed a mutant (FSH-M) in which a linker including the eCG β-subunit CTP region (amino acids 115 to149) was inserted between the β-subunit and α-subunit of wild-type single chain eel FSH (FSH-wt). Plasmids containing eel FSH-wt and eel FSH-M were transfected into CHO DG44 cells. Single cells expressing each protein were isolated from 10 and 7 clones, respectively. Secretion increased gradually during the cultivation period and peaked at 4,000–5,000 ng/mL on day 9. The molecular weight of eel FSH-wt was 34–40 kDa, while that of eel FSH-M increased substantially, with two bands at 39–46 kDa. Treatment with PNGase F to remove the N glycosylation sites decreased the molecular weight remarkably to approximately 8 kDa. The EC50 value and maximal responsiveness of eel FSH-M were approximately 1.23- and 1.06-fold higher than those of eel FSH-wt, indicating that the mutant showed slightly higher biological activity. Phosphorylated extracellular regulated kinase (pERK1/2) activation exhibited a sharp peak at 5 min, followed by a rapid decline. These findings indicate that the new rec-eel FSH molecule with the eCG β-subunit CTP linker showed potent activity and could be produced in massive quantities using the stable CHO DG44 cell system.

Reservoir routing has been a routine procedure in hydrology, hydraulics and water management. It is typically based on the mass balance (continuity equation) and a conceptual equation relating storage and outflow. If the latter is linear, then there exists an analytical solution of the resulting differential equation, which can directly be utilized to find the outflow from known inflow, and to obtain macroscopic characteristics of the process, such as response and residence times, and their distribution functions. Here we streamline the reservoir routing framework and extend it to find approximate solutions for nonlinear cases. The proposed framework can also be useful for climatic tasks, such as describing the mass balance of atmospheric carbon dioxide and determining characteristic residence times, which have been an issue of controversy. Application of the theoretical framework results in excellent agreement with real world data. In this manner, we easily quantify the atmospheric carbon exchanges, and obtain reliable and intuitive results, without the need to resort to complex climate models. The mean residence time of atmospheric carbon dioxide turns out to be no more than four years and the response time is smaller than that, thus opposing the much longer mainstream estimates.

Buckypaper (BP), a flexible and porous material, exhibits photovoltaic properties when exposed to light. In this study, we have employed Radio Frequency (RF) Sputtering of Zinc Oxide (ZnO) followed by rapid thermal annealing to enhance the photovoltaic response of BP. We investigated the impact of various sputtering parameters, such as the gas flow ratio of argon to oxygen and deposition time, on the morphology, composition, resistivity, and photovoltaic characteristics of ZnO-modified BP. Additionally, the photovoltaic performance of the samples under different illumination modes and wavelengths was compared. It was found that optimal sputtering conditions—argon to oxygen flow ratio of 1:2, deposition time of 20 minutes, and power of 100 watts—resulted in a ZnO film thickness of approximately 45 nanometers. After annealing at 400°C for 10 minutes, the ZnO-modified BP demonstrated a significant increase in photocurrent and photovoltage, along with a reduction in resistivity, compared to unmodified BP. Moreover, under gradient illumination, the ZnO-modified BP exhibited a photovoltage enhancement of 14.70 times and a photocurrent increase of 13.86 times, compared to uniform illumination. Under blue light, it showed a higher photovoltaic response than under other colors. The enhancement in photovoltaic response is attributed to the formation of a Schottky junction between ZnO and BP, an increased carrier concentration gradient, and an expanded light absorption spectrum. Our results validate that ZnO sputtering followed by annealing is an effective method for modifying BP for photovoltaic applications such as solar cells and photodetectors.

With the rapid development of tumor immunotherapy, nanoparticle vaccines have attracted much attention as a potential therapeutic strategy. The potential role of the mannose-modified lipid calcium phosphate nanoparticle vaccine in enhancing the anti-tumor immune response was investigated. The aim of this study was to investigate the effect of mannose modification on the immune response of nanoparticles in regulating the tumor microenvironment through systematic review and analysis and to explore its potential clinical application in tumor therapy. Currently, despite the potential advantages of nanoparticle vaccines in immunotherapy, achieving an effective immune response in the tumor microenvironment remains a challenge. Tumor immune escape and overexpression of immunosuppressive factors limit its clinical application. Therefore, this study will explore how to intervene in the immunosuppressive mechanism in the tumor microenvironment through mannose-modified lipid calcium phosphate nanoparticle vaccines so as to improve the immunotherapy effect of tumor patients and provide new ideas and strategies for the field of tumor therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Despite new methods of diagnostics and treatment as well as extensive biological and immunosuppressive treatment, the etiology of RA is not fully understood. Moreover, the problem of diagnosis and treatment of RA patients is still current and affects a large group of patients. It is suggested that these ER-related features may impair adaptation to chronic stress, inferring the risk of rheumatoid arthritis. The main goal in this study was evaluation of changes in mRNA translation to determine chronic ER stress conditions in rheumatoid arthritis patients. The study group consist of 86 individuals including total 56 rheumatoid arthritis patients and 30 healthy controls. The expression level of mRNA form blood samples of RA patients as well as controls of the PERK-UPR associated genes: p-eIF2, BCL-2, PERK, ATF4, BAX were investigated by Real-Time qPCR. GAPDH expression was used as a standard control. Considering the median, the expression of PERK, BCL-2, p-eIF2, ATF4, BAX was found to be significantly increased in the blood of RA patients compared with the control group. The p-value for the PERK gene was 0.0000000036, the p-value for the BCL-2 gene was 0.000000014, the p-value for the p-eIF2 gene was 0.006948, the p-value for the ATF4 gene was 0.0000056 and the p-value for the BAX gene was 0.00019, respectively. Thus, it can be concluded that targeting of the components of the PERK-dependent UPR signaling pathway via small-molecule PERK inhibitors, may contribute to the development of novel, innovative treatment strategies against rheumatoid arthritis.

To facilitate the computation of the uniaxial compressive strength value of the cemented paste backfill under the condition of high sand-cement ratio, and to analyze the size effect of the cemented paste backfill with high sand-cement ratio under varied aspect ratios, the cemented paste backfill specimens with sand-cement ratios of 8:1-24:1 and aspect ratios of 0.5, 1, and 2 were prepared. Through response surface experiments and finite element analysis, the influence of three aspect ratios on the cemented paste backfill strength was explored, and the failure characteristics and size effect mechanisms of cemented paste backfill with various aspect ratios were analyzed. The model of strength conversion between cemented paste backfill with different aspect ratios was established. The results show that the compressive strength of the cemented paste backfill decreases with the increase of the aspect ratio under the same mass concentration and sand-cement ratio. When the aspect ratio is 0.5 and 1, the splitting failure is the main factor; when the aspect ratio is 2, the shearing failure is the main factor. The three-dimensional stress caused by the end effect of the cemented paste backfill is the main reason for the high strength when the aspect ratio is 0.5. Due to the one-dimensional stress zone generated in the middle of the cemented paste backfill with an aspect ratio of 2 in the laboratory, its strength value is closer to the actual uniaxial compressive strength value of the cemented paste backfill. The strength values of the cemented paste backfill with aspect ratios of 0.5 and 1 were higher than the actual uniaxial compressive strength values in the laboratory. The rationality of the theoretical analysis was verified by the ABAQUS analysis results. According to the experimental results, a strength conversion model between different aspect ratios is established, which can provide a reference for the design of the uniaxial compressive strength of the cemented paste backfill.

The wave energy converter (WEC) technology constantly develops new designs and models. To encourage its development within the energy sector, research is required to improve current designs and create durable and effective devices. However, it is also crucial to investigate the suitability of a WEC to a site-specific sea condition as this can impact its optimal power absorption and constructability. This study evaluates and compares the efficiency of a heaving buoy with varied geometries in one of the most energetic places along the Mexican coast. A statistical analysis of the wave climate on the coast of Ensenada during the last 42 years is performed to define the conditions to which the device is subjected. The location of the WEC in shallow waters is chosen using a computational model which solves the modified mild slope equation in its elliptic shape. The heaving buoy floater is studied using three distinct geometries: a semi-sphere, a cylinder, and a proposed rounded semi-rectangle. The hydrodynamic response of the three geometries is then analysed in the frequency and time domain using ANSYS AQWA. The hydrodynamic study involves the assessment of the floating body dynamics, exerted forces, the power absorbed as well as the suitability of the proposed power take-off (PTO) system. Findings reveal that the proposed geometry absorbs the most energy, with an annual power of 135.11 MW, and that the transmission PTO design is appropriate for this type of technology.

Ralstonia solanacearum is the pathogen responsible for Ralstonia solanacearum, which is soil-borne, infests plant conduits to cause disease.They are not easy to control and are harmful.Therefore the development of a controlled-release agent responsive to the pathogen's soil temperature and moisture conditions could aid in its control. Corn kernel powder is used as a carrier for Tetramycin biopesticide, with various compounds tested for bonding.They were then made by extrusion moulding.Temperature and wetness responsive components, including Pentaerythritol Tetrastearate, Pentaerythritol Tetraoleate, Polyethylene Glycol Stearate, and Polyethylene Glycol Monooleate,are compounded and coated onto Tetramycin cores to form an intermediate shell layer. Finally, Ethyl cellulose(EC)and Hydroxypropyl methyl cellulose(HPMC) are dissolved and sprayed onto the outermost layer to complete the pellet's shell layer.After the evaluation of texture performance test,DSC analysis,TG test,temperature and humidity response performance test, as well as pellet cross-section SEM observation, field effectiveness test, etc., the preferred formulations were screened.The results showed that the preferred Core formulation:Corn kernel powder:Tetramycin aqueous:Xanthan gum mass ratio=13.5:23:2; Intermediate Shell layer:PETS: PETO: PEG400MO mass ratio=10:30:10; and Outer Shell layer: Ethyl cellulose (EC):Hydroxypropyl methyl cellulose (HPMC) mass ratio=5:1.Under soil conditions of high incidence of Ralstonia solanacearum, i.e., sustained warmth (30-35℃) and high humidity (30% moisture content), the formulated pills showed a release rate of 95.18% to 96.24% over a period of 35 days. Moreover, they showed a stepwise cyclic release process under alternating warm and humid-dry and cold conditions.In field tests on tobacco, a relative preventive efficacy of 54.74% was achieved 106 days post-transplanting. Soil bacterial community structure analysis revealed a significant decrease (2.28-2.84 times) in the abundance of Solanaceae Raelia under Tetramycin pellet treatment compared to the control. Additionally, fungal community structure showed highter consistency initially across various soil depths, with diversity differences between soil layers reestablished later (106 days), while the predominant categories of bacteria and fungi remained unchanged.In this study, we successfully developed a nucleoshell-type slow-controlled release pill embedded with Tetramycin. This pill effectively responded to temperature and humidity changes, resulting in high efficacy in disease prevention.This development holds significant promise for effectively improving drug utilization and easing application challenges, offering broad prospects for Ralstonia solanacearum prevention and control in agriculture.

Keywords: early childhood; education; quality; measurement; monitoring; majority world; Item Response Theory; psychometrics

Provenance trials provide a valuable opportunity to evaluate the impact of extreme events on growth and wood properties. In this study, we have evaluated 81 Norway spruce provenances, tested in three provenance trials established in the Romanian Carpathians in 1972. The response to drought of the Norway spruce provenances – resistance, recovery, resilience, and relative resilience, has been examined, as well as the relationship between climate and growth, and the correlations between wood traits, the coordinates of origin and drought resilience indices. In each provenance trial, there were significant differences between provenances and years regarding wood widths and latewood percentage (LWP). Regarding the drought extreme events, the years when it occurred in all three provenance trials were 2000 and 2003. Significant differences between provenances for at least one drought resilience index have been found in all provenance trials, for the year 2000. By using subperiods of 25 years, changes in the relationship between climate and growth have been observed. Several provenances with high radial growth and good resistance and/or recovery have been identified. Provenances that performed better in common garden experiments could be used in assisted migration even beyond the current natural range.

Chert rock is a by-product of sand quarrying (about 40% in the geological section). All attempts to use ordinary technologies for aggregate production from chert have been economically unsuccessful, resulting in significant chert "waste" accumulation covering vast quarry areas. This paper presents the study results of the effect of microwave irradiation on the mechanical properties of chert gravel, which is mineralogically relatively homogenous and consists of fine quartz grains. The results show that an increase in irradiation time decreases the strength of chert gravel (by a factor of 4-6 for the 2.5 min of irradiation), while the quenching changes the fractional content of the samples after the crushing test, decreasing the Gravel-to-Sand ratio.

This review compiles research findings pertaining to Nuclear Distribution C (NudC) genes and their involvement in various cellular processes, including nuclear migration, intracellular transport, nuclear positioning and cell cycle progression. Structural and functional similarities of NudC pro-teins across diverse organisms highlight their evolutionary conserved nature and pivotal roles in upholding cellular functions. Special attention is given to the growing importance of NudC family members in plants, elucidating their contributions to plant growth, development and responses to environmental challenges. Within this framework, we spotlight two Arabidopsis NudC genes, BOB1 and NMig1, for their indispensable roles in embryo and postembryonic development, and involvement in stress responses and tolerance mechanisms. Furthermore, we accentuate the chaperone activity of plant NudC family members, a crucial function in mitigating the adverse effects of stress and bolstering plant resilience in the face of environmental challenges. These insights underscore the promising potential of NudC members as valuable targets for enhancing crop performance, particularly when directed towards optimizing plant morphology and fortifying en-vironmental resistance to enhance overall crop productivity.

Cut chrysanthemum, renowned as a highly favored floral choice globally, experiences a significant decline in production due to the practice of continuous cropping. The adverse physiological effects on cut chrysanthemums have been observed as a result of the degradation of soil physical and chemical properties, coupled with the proliferation of pathogens. It is noteworthy that the 'Guangyu' cultivar in Xinxiang, Henan province, China, has been specifically impacted by these effects. This study effectively identified and validated the precise pathogen accountable for wilt disease initially. Subsequently, an analysis was conducted to examine the invasion pattern of the pathogen and the physiological response of the chrysanthemum. Finally, PacBio platform was employed to investigate the dynamic alterations in the microbial community within the soil rhizosphere, comparing the effects of seven years of monocropping with the first year. The findings indicated that Fusarium solani was the primary causative agent responsible for wilt disease, as it possessed the ability to invade and establish colonies in plant roots, leading to alterations in various physiological parameters of the plants. Furthermore, the practice of continuous cropping had been observed to significantly disturb the microbial community composition, potentially acting as an additional influential factor in the advancement of wilt.

The initiation of micro-cracks in concrete is primarily due to its brittleness, which causes severe impacts on the overall behavior of the concrete. However, incorporating fibers in concrete could significantly improve its mechanical properties. The current study demonstrates the influence of two types of fibers on the mechanical properties of concrete. Nylon Fiber Threads (NFT) and Nylon Fiber Strands (NFS) at a fiber content of 2.5 kg/m³ were incorporated in the concrete mix. Concrete with a compressive strength of 30 MPa and a water-cement ratio of 0.4 was produced to investigate the fresh and mechanical properties of conventional and nylon-fiber reinforced concrete (NFRC). The concrete prims and cylinders were tested for compressive, splitting, and flexural strength using ASTM standards (ASTM C-39, C-496, and D-790, respectively). It was found that NFT-reinforced samples achieved higher mechanical properties of concrete (13.05%) compared to NFS-reinforced samples. Test results showed that incorporation of nylon fibers (NF) in concrete decreased the compressive strength of cylindrical and cubical specimens by 0–10% and 5–15%, respectively. However, it increased the splitting tensile and flexural strengths by 0-15%, and 5-15% respectively. Furthermore, the incorporation of NF in concrete significantly improved the ductility and delayed the crack initiation in concrete.

Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection by HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms have generated the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFN-, then IFN-α plus ribavirin (IFN-RBV); then, pegylated-IFN--RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing the patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced SVR (&gt; 90%); the compounds were able to inhibit HCV replication without significant side effects, even in pediatric populations. The management of coinfected patients HBV-HCV and HCV-HIV has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research focuses on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection to different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.

During meat processing, lactic acid bacteria (LAB) have to competitively adapt to the hostile en-vironment produced by curing additives (CA). The objective of this study was to investigate the ability of Latilactobacillus curvatus CRL 705, a bioprotective strain of meat origin, to adapt to CA. A physiological and proteomic approach was performed. CRL 705 was grown in a chemically de-fined medium (CDM) containing specific concentrations of CA (NaCl, nitrite, sucrose and ascor-bic acid). The results showed minor differences in growth kinetics in the presence of CA. Glucose consumption, present in CDM, and production of lactic acid and bacteriocins were not signifi-cantly affected. Proteomic analyses indicated that most of the identified proteins (36 out of 39) mainly related to carbohydrate metabolism (18%), posttranslational modifications (15.6%), energy production and conversion (11.1%), translation (11.1%) and nucleotide metabolism (8.9%), were under expressed. In response to the studied CA, CRL 705 slowed down its general metabolism, achieving slight changes in physiological and proteomic parameters. The observed performance is another characteristic that extends the well-known competitive profile of CRL 705 as a meat starter- and -bioprotective culture. This is the first report dealing with the impact of CA on LAB proteomics.

Citrus peels are considered as a rich source of valuable biomolecules like pectin as polymer of polysaccharide acid. In this study, response surface methodology was used to optimize pectin extraction from Citrus clementina peels using citric acid as extraction solvent. The effect of parameters conditioning the extraction process and pectin yield (pH, temperature, extraction time, solid/liquid ratio, and raw material particle size) was investigated using a Box-Behnken design. The quality of the extracted pectin was assessed both chemically (moisture, ash, protein, and sugar content) and functionally (gelling power and emulsifying activity). According to the screening experiment, the factors pH, temperature, and particle size were the main factors influencing the pectin yield. The adjusted mathematical model enabled us to plot response surfaces in order to determine optimal extraction conditions. The highest production yield of pectin (26.6%) was obtained at the optimal conditions of: pH = 1.5; temperature 100 °C and particle size = 0.1 mm for an extraction time of 30min. Compared to the predicted value of 26.6%, the experimental extraction yield was about 21.4% of pectin. Concerning the functional properties, the extracted pectin has a high gelling power of 164°SAG and an emulsifying activity of 38.5%.

Ship pilots and maritime safety administration have an urgent need for more accurate and earlier warnings on strong wind gusts. This study firstly investigates the “Oriental Star” cruise ship cap-sizing event in 2015, one of the deadliest shipwreck events in recent years, and explores all related hydro-meteorological components in a global mesoscale model. It is found that, rather than the missing signal in raw surface wind prediction, the cumulus precipitation variable (CP) increases dramatically during the accident occurrence, which significantly corresponds to the sub-grid strong wind gust. The effective lead-time can be extended from 24hr (deterministic model) to 48hr (en-semble model). This finding is then verified in another two recent deadly cruise boat accidents. The introduction of the new variable is bearing the hope of improvement to the current maritime safeguard system, on predicting sub-grid strong wind gusts for small-size cruise boats in offshore and inland rivers. Finally, an automatic-response system is developed to provide economical con-vection prediction via Inmarsat email communication, aiming to explore operational severe con-vective gust early-warning and appropriate numerical mesoscale model application.

In this study, we meticulously compared the practical performance of four bootstrap methods for assessing the significance of causal analysis in time series data, recognizing that their evaluation has not been sufficiently conducted in the field. The methods investigated were uncorrelated Phase Randomization Bootstrap (uPRB), which generates surrogate data with no cross-correlation between variables by randomizing the phase in the frequency domain; Time Shift Bootstrap (TSB), which generates surrogate data by randomizing the phase in the time domain; Stationary Bootstrap (SB), which calculates standard errors and constructs confidence regions for weakly dependent stationary observations; and AR-sieve bootstrap (ARSB), a resampling method based on autoregressive (AR) models that approximates the underlying data-generating process. Our study found that the AR-sieve bootstrap (ARSB) method outperformed the others in detecting both self-excitation and causality among variables. In contrast, the uncorrelated phase-randomized bootstrap (uPRB) and Stationary Bootstrap (SB) methods demonstrated limitations in specific scenarios. This detailed comparison highlights the need for selecting suitable bootstrap methods to ensure accurate results, ultimately guiding researchers in their choice of method for real data analysis.

The dynamic response of a Bell-and-Bloom magnetometer to a parallel (to the bias field) time-dependent field is modelled beyond the commonly assumed quasi-static regime. The results unveil features that are related to the parametric nature of the considered system. It is shown that a for low-amplitude time-dependent field different operating conditions are possible and that, beside the commonly reported low-pass-filter behaviour, a band-pass response emerges. Moreover, we numerically show that for larger field amplitude the system, due to its parametric nature, has a kind of ``non-linear'' response.

Transdermal drug delivery (TDD) is one of the key approaches for treating diseases, avoiding first-pass effects, reducing systemic adverse drug reactions and improving patient compliance. Microneedling, iontophoresis, electroporation, laser ablation and ultrasound facilitation are often used to improve the efficiency of TDD. Among them, microneedling is a relatively simple and efficient means of drug delivery. Microneedles usually consist of micron-sized needles (50-900 μm in length) in arrays that can successfully penetrate the stratum corneum and deliver drugs in a minimally invasive manner below the stratum corneum without touching the blood vessels and nerves in the dermis, improving patient compliance. Hydrogel-forming microneedles (HFMNs) are safe, non-toxic, no residual matrix material, high drug loading capacity, controlled drug release and are suitable for long-term, multiple drug delivery. This work reviewed the characteristics of skin structure and transdermal drug delivery; introduced TDD strategies based on hydrogel microneedles; summarised the characteristics of HFMNs TDD systems and the evaluation methods of HFMNs; and the application of HFMNs drug delivery systems in disease treatment. The HFMNs drug delivery system has a wide scope for development, but the translation to clinical application still has more challenges.

The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN- pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN- receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. CXCL-9,-10,-11/CXCR3 axis, dependent on IFN- signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN- pathway in the formation of brain metastasis of ER- breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.

The mRNA vaccines for SARS-CoV-2 have demonstrated efficacy and immunogenicity in the re-al-world setting. However, most of the research on vaccine immunogenicity has been centered on characterizing the antibody response, with limited exploration into the persistence of spike-specific memory B cell response. Here we monitored the durability of the memory B cell response and characterize the trajectory of spike-specific B cell phenotypes in healthy individuals who have received two doses of the BNT162b2 vaccine up to 9 months post-vaccination. To profile the spike-specific B cell response we applied the tSNE and Cytotree automated approaches. Our data showed the induction of spike-specific IgA+ and IgG+ plasmablasts and IgA+ activated cells 7 days after the second dose which disappeared 3 months later, while subsets of spike-specific IgG+ resting memory B cells became predominant 9 months after vaccination, and they were capable to differentiate into spike-specific IgG secreting cells when in vitro restimulated. Other subsets of spike-specific B cells, such as IgM+ or unswitched IgM+IgD+ or IgG+ double negative/atypical cells, were also elicited by the BNT162b2 vaccine and persisted up to month 9. The analysis of circulating spike-specific IgG, IgA and IgM was in line with the plasmablasts observed. The longitudinal analysis of the antigen-specific B cell response elicited by mRNA-based vaccines provides valuable insights into our understanding of the immunogenicity of this novel vaccine platform destined to a future widespread use, and it is crucial in guiding future decisions and vaccination schedules.

The aim of this study was to evaluate the intensity of the annual sexual behavior (SB) of Boer bucks under tropical conditions in southern Mexico. For one year, 16 extensively grazing males were evaluated for SB individually with estrogenized goats. From the beginning of the experiment and every 30 days, body weight (BW), body condition (BC), testicular circumference (TC), odor intensity (OI) and SB (nudging, ano-genital sniffing, flehmen, mounting attempts, mounts with intromission, and self-urination) were recorded. The bucks showed a more intense SB during the months of November to May than during the months of June to October (p < 0.05). Greater frequency was found for nudging, ano-genital sniffing, mounting attempts, and self-urination in the months of November to May (p < 0.001). BW was lower during the months of January to August than in the months of September to December (p < 0.05). On the other hand, TC increased from October to December (p < 0.05). Similarly, the OI in males varied over time (time effect; p < 0.001). In fact, an increased odor was found from October to December. The conclusions were that breed male goats from the tropics of Guerrero have a more intense SB during the months of November to May, which corresponds to the time of the year when forage availability is the greatest.

The heat release response of the flame to acoustic excitation is a critical factor for understanding combustion instability. In the present work, the nonlinear heat release response of a methane-air non-premixed flame to the low frequency acoustic excitations is experimentally investigated. The flame describing function (FDF) was measured based on the overall CH* chemiluminescence intensity and the velocity fluctuations obtained by two-microphone method. The CH* chemiluminescence images and the schlieren images were analyzed to reveal the mechanism of nonlinear response. The excitation frequency ranges from 10Hz to 120Hz. The forced relative velocity fluctuation amplitude ranges from 0.10 to 0.50. The corresponding flame Strouhal number (Stf) ranges from 0.43 to 4.67. The study has shown that the flame length responds more sensitively to changes in excitation amplitude when subjected to relatively high frequency excitations. The normalized flame length (Lf/D) decreases from 3.79 to 2.37 with the increase of excitation amplitude at excitation frequency of 100Hz. The number of oscillation zones along the flame increases with increasing excitation frequency, which is consistent with the increase of the Stf. The low-pass filtering characteristic of FDF is caused by the dispersion of multiple oscillation zones, as well as the cancellation effect of the adjacent oscillation zones under relatively high frequency excitation. The cancellation effect of the positive and negative oscillation zones with various Stf is main mechanism for the local gain peak and valley. When two adjacent oscillation regions have approximate amplitudes, the overall phase-lag becomes more sensitive to changes in excitation frequency and amplitude. This sensitivity leads to nonlinear anomalous changes in the phase-lag near the frequency corresponding to the gain valley. The calculated disturbance convection time is consistent with the measured time delay in the short flame scenario. Future research is necessary to establish whether the observed agreement occurs due to the oscillation zone consistently occurring proximate to the flame's center of mass, coupled with a precise determination of the average convective velocity.

Background: Pathologic complete response (pCR) of breast cancer after neoadjuvant chemotherapy (NAC) is highly related to molecular subtypes. Patients who achieved tumor pCR after NAC have a better prognosis. However, despite of better prognosis, pCR patients have a potential for recurrence. There is little evidence of risk factors of recurrence in patients with pCR. We aim to analyze factors associated with tumor recurrence in patients who achieved pCR. Methods: This study retrospectively reviewed the data of patients diagnosed with breast cancer who achieved pCR after receiving NAC between January 2009 and December 2018 in Samsung Medical Center. pCR was defined as no residual invasive cancer in the breast and axillary nodes even if there is residual ductal carcinoma in situ (ypT0 or ypTis with ypN0). Breast cancers are classified into 4 subtypes based on hormone receptors (HR) and human epithelial growth factor receptor 2 (HER2) status. Patients who had bilateral breast cancer, inflammatory breast cancer, distant metastasis, unknown subtype, and histologically unique case were excluded from the study. Results: In total 483 patients were included in this study except for patients who corresponded to the exclusion criteria. The median follow-up duration was 59.0 months (range, 0.5-153.3 months). Breast cancer recurred in 4.1% of patients (20 of 483). There was a significant difference in clinical T (p = .004) and clinical N (p = .034) stage in the Kaplan-Meier curve for disease-free survival. Molecular subtypes (p = .573), Ki67 (p = 1.000), and breast surgery type (p = .574) were not associated with tumor recurrence in patients who achieved pCR after NAC. In the clinical T stage and clinical N stage, there was a significant difference between recurrence and no-recurrence groups (clinical T stage; p = .045, clinical N stage; p = .002). Univariable Cox regression revealed statistical significance in the clinical T stage (p = .049) and clinical N stage (p = .010), while multivariable Cox regression demonstrated non-significance in the clinical T stage (p = .320) and clinical N stage (p = .073). Conclusion: Results in this study showed that clinical T, clinical N stage, and molecular subtypes were not statistically significant predictors of recurrence in patients who achieved pCR after NAC. It is hypothesized that a multicenter-based study would lead to the identification of factors as predictors of recurrence after achieving pCR.

Respiratory tract epithelium infection plays a primary role in Nipah virus (NiV) pathogenesis and transmission. Knowledge about infection dynamics and host responses to NiV infection in respir-atory tract epithelia is scarce. Studies in non-differentiated primary respiratory tract cells or cell lines indicate insufficient interferon (IFN) responses. However, studies are lacking to determin-ing complex host response patterns in differentiated respiratory tract epithelia to understand NiV replication and spread in swine. Here we characterized infection and spread of NiV in differenti-ated primary porcine bronchial epithelial cells (PBEC) cultivated at the air-liquid-interface (ALI). After the initial infection of only a few apical cells, lateral spread for 12 days with epithelium disruption was observed without releasing substantial amounts of infectious virus from the api-cal or basal sides. Deep time course proteomics revealed pronounced upregulation of genes re-lated to type I/II- IFN, immunoproteasomal subunits, TAP-mediated peptide transport and MHC I antigen presentation. Spliceosomal factors were downregulated. We propose a model in which NiV replication in PBEC is slowed by a potent and broad type I/II-IFN host response with con-version from 26S proteasomes to immunoproteasomal antigen processing and improved MHC I presentation for adaptive immunity priming. NiV induced cytopathic effects could reflect the focal release of cell-associated NiV, which may contribute to efficient airborne viral spread between pigs.

This study investigated whether export performance is correlated with innovation. We explicitly considered five types of innovation: a) process innovation; b) product innovation; c) process and product innovation; d) product innovation new to the firm; and e) product innovation new to the market. We en-larged the findings of R&D-export and R&D-investment relations using a vast sample of cross-European firms. We considered innovation as endogenous and determined by R&D through a process characterized by the role of the regional technological environment. Our analysis enabled us to propose an integrated model incorporating R&D, innovation and export, in a framework of simultaneous equations which consider their mutual correlations. To the best of our knowledge, this work is the first in recent years to empirically compute the relation between R&D and tangible investment at the micro level. Econometric results showed that product and process innovation are positively linked to the export intensity of European manufacturing firms. The results also showed complementarity effects between the two kinds of innovation. The av-erage effect on export intensity from carrying out process innovation is larger than that found for product innovation, except in cases where the product is new to the market. When both types of innovation have been carried out, a larger effect results than that found for product or process innovation alone. Furthermore, the average marginal effect on export intensity from innovations of any kind among those studied here is highly positive and significant.

Neural networks require a large quantity of training spectra and detector responses in order to learn to solve the inverse problem of neutron spectrum unfolding. In addition, due to the under-determined nature of unfolding, non-physical spectra which would not be encountered in usage should not be included in the training set. While physically realistic training spectra are commonly determined experimentally or generated through Monte Carlo simulation, this can become prohibitively expensive when considering the quantity of spectra needed to effectively train an unfolding network. In this paper, we present three algorithms for the generation of large quantities of realistic and physically motivated neutron energy spectra. Using an IAEA compendium of 251 spectra, we compare the unfolding performance of neural networks trained on spectra from these algorithms, when unfolding real-world spectra, to two baselines. We also investigate general methods for evaluating the performance of and optimizing feature engineering algorithms.

The molecular mechanisms underlying heat stress tolerance in animals to high temperatures remain unclear. This experiment was performed with Sprague-Dawley rats housed at 22 ℃ (control group; CT), and 42 ℃ for 30 min (H30), 60 min (H60), and 120 min (H120). Transcriptomic analysis using RNA-Sequencing (RNA-Seq) from blood (CT and H120), liver (CT, H30, H60, and H120), and adrenal glands (CT, H30, H60, and H120) was performed. The differentially expressed mRNA isoforms (DEIs) were identified and annotated by the CLC Genomics Workbench. Biological process and metabolic pathway analyses were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A total of 225, 5,764, and 4,988 DEIs in the blood, liver, and adrenal glands were observed. Furthermore, the number of novel differentially expressed transcript lengths with annotated genes and the novel differentially expressed transcript with non-annotated genes were 136 and 8 in blood, 3,549 and 120 in the liver, as well as 3,078 and 220 in adrenal glands, respectively. A total of 35 genes were involved in the heat stress response, out of which Dnaja1, LOC680121, Chordc1, AABR07011951.1, Hsp90aa1, Hspa1b, Cdkn1a, Hmox1, Bag3 and Dnaja4 were commonly identified in the liver and adrenal glands, suggesting that these genes may regulate heat stress response through interactions between liver and adrenal glands. The results suggest that the identified mRNA isoforms could be considered as potential candidates for selecting mammals to improve thermotolerance.

Guessing effects frequently occur in testing data in educational or psychological applications. Different item response models have been proposed to handle guessing effects in dichotomous test items. However, it has been pointed out in the literature that the oftenemployed three-parameter logistic model poses implausible assumptions regarding the guessing process. The four-parameter guessing model has been proposed as an alternative to circumvent these conceptual issues. In this article, the four-parameter guessing model is compared with alternative item response models for handling guessing effects through a simulation study and an empirical example. It turned out that model selection for item response models should be rather based on the AIC than the BIC. However, the RMSD item fit statistic used with typical cutoff values was found to be ineffective in detecting misspecified item response models. Furthermore, sufficiently large sample sizes are required for sufficiently precise item parameter estimation. Moreover, it is argued that the criterion of statistical model fit should not be the sole criterion of model choice. The item response model used in operational practice should be valid with respect to the meaning of the ability variable and the underlying model assumptions. In this sense, the four-parameter guessing model could be the model of choice in educational large-scale assessment studies.

Flaviviruses replicate in membrane factories associated with the endoplasmic reticulum (ER). Significant levels of flavivirus viral protein accumulation contribute to ER stress. As a consequence, the host cell exhibits an Unfolded Protein Response (UPR), subsequently stimulating appropriate cellular responses such as adaptation, autophagy or apoptosis. The correct redox conditions of this compartment are essential to form native disulfide bonds in proteins. ZIKA virus (ZIKV) has ability to induce persistent ER stress leading to activation of UPR pathways. In this study, we wondered whether ZIKV affects the redox balance and consequently the oxidative protein folding in the ER. We found that ZIKV replication influences redox state leading to aggregation of viral envelope protein as amyloid-like structures in the infected cells.

A major challenge in the clinical management of patients with mesial temporal lobe epilepsy (MTLE) is identifying those who do not respond to antiseizure medication (ASM), allowing for the timely pursuit of alternative treatments, such as epilepsy surgery. Here, we investigated changes in plasma metabolites as biomarkers of pharmacoresistance in patients with MTLE. Furthermore, we used the metabolomics data to gain insights into the mechanisms underlying MTLE and response to ASM. We performed an untargeted metabolomic method using magnetic resonance spectroscopy and multi- and univariate statistical analyses to compare data obtained from plasma samples of 28 patients with MTLE compared to 28 controls. The patients were further divided according to response to ASM: 20 patients were refractory to treatment, and eight were responsive to ASM. We only included patients using carbamazepine in combination with clobazam. We compared the group of patients with controls and found that the profiles of glucose (p = 0.01), saturated lipids (p = 0.0002), isoleucine (p = 0.0001), β-hydroxybutyrate (p = 0.0003), and proline (p = 0.02) were different in patients compared to controls (p &lt; 0.05). In addition, lipoproteins (p = 0.05), lactate (p = 0.05), glucose (p = 0.05), unsaturated lipids (p = 0.05), isoleucine (p = 0.05), and proline (p = 0.05), could discriminate between the two groups of patients classified according to response to ASM. The identified metabolites were linked to different biological pathways related to cell energy metabolism, and pathways linked to inflammatory processes and the modulation of neurotransmitter release and activity in MTLE. In contrast, we found that pyruvate metabolism may be linked to resistance to ASM. In conclusion, in addition to insights into the mechanisms underlying MTLE and the response to treatment with ASM, our results suggest that plasma metabolites may be used as biomarkers of disease and response to ASM in patients with MTLE. These findings warrant further studies exploring the clinical use of metabolites to assist in decision-making when treating patients with MTLE.

Anticipating future successional forest trends in the face of ongoing global change is an essential conservation target. Mountain forests are especially sensitive to environmental shifts, and their past responses to climatic and anthropogenic (external) drivers may provide a basis for improving predictions of future developments. This paper uses independent high-resolution palynological and paleoclimatic reconstructions to statistically analyze the long-term effects of external drivers on regional forest succession in the central Iberian Pyrenees during the last 500 years. The dominant taxa of these forests (Quercus, Betula, Pinus) showed significant relationships with summer temperature, summer drought and autumn precipitation. Immediate and delayed (by two or more decades) responses of these trees to climatic drivers were identified. Regional succession showed a closed path, starting at the end points around the attraction domain of pine-dominated forests. This trajectory was determined by a trend toward anthropogenic forest clearing (16th to 18th centuries) and a reverse trend of natural forest recovery (18th to 20th centuries). Forest clearing was due to burning, facilitated by drought, and was followed by the expansion of cropping and grazing lands. Forest recovery was fostered by reduced human pressure and rising temperatures. The statistical approach used in this work has unraveled ecological relationships that remained unnoticed in previous works and would be important for predicting future successional trends under changing climates. The reported response lags of individual taxa to climatic drivers may complicate the establishment of reliable ecological relationships and should be addressed in future studies.

Brucellosis infection induces fever, chills, sweats, headache, myalgia, arthralgia, anorexia, fa-tigue, and mood disorders. In mice, it causes a rise in IL-6, TNF-, and IFN-; and reduces sero-tonin and dopamine levels in hippocampus. There is loss in muscle strength and equilibrium and increased anxiety and hopelessness. Imipramine (ImiP) is a tricyclic antidepressant that increases the capacity of macrophages to destroy intracellular microorganisms in vivo. The effect of ImiP was evaluated in Balb/c mice infected with Brucella abortus 2308. Serum levels were determined in IFN-, IL-6, TNF-, IL-12, MCP-1, and IL-10 by FACS; the bacterial count in the spleen, by CFU; the serotonin concentration in the hippocampus, by HPLC; and strength, equilibrium, and mood by behavioral tests. Our results showed that infected vs. control mice had a significant rise in lev-els of IFN-, IL-6, TNF-, and IL-12 with a low IFN-/IL-6 ratio, elevated bacterial-counts, alter-ations in serotonin concentration at hippocampus, and decreased muscular strength, equilibrium, and mood. Infected mice treated with ImiP vs. infected mice showed: 1) improved mood; 2) in-creased hippocampal serotonin availability, splenic dendritic cells, and macrophage phagocytic activity; and 3) upturn inflammation and reduced CFU ability. Our results support that ImiP fa-vors positive outcomes in subjects handling Brucella infections likely by improving psychoim-mune resilience.

Huntington’s disease (HD) is a late-onset; progressive, dominantly inherited neurological disorder marked by an abnormal expansion of polyglutamine (poly Q) repeats in Huntingtin (HTT) protein. The pathological effects of mutant Huntingtin (mHTT) are not restricted to the nervous system but systemic abnormalities including immune dysregulation have been evidenced in clinical and experimental settings of HD. Indeed, mutant huntingtin (mHTT) is ubiquitously expressed and could induce cellular toxicity by directly acting on immune cells. However, it is still unclear if selective expression ofmHTT exon1 in neurons could induce immune responses and hemocyte function. In the present study, we intended to monitor perturbations in the hemocytes population and their physiological functions in Drosophila, caused by pan-neuronal expression of mHTT protein. We found that pan-neuronal expression of mHtt significantly alters crystal cells and plasmatocyte count in larvae and adults with disease progression. Interestingly, plasmatocytes isolated from diseased conditions exhibit a gradual decline in phagocytic activity ex vivo at progressive stages of the disease as compared to age-matched control groups. We also observed an increased production of reactive oxygen species (ROS) in plasmatocytes at advanced stages of the disease. In addition, diseased flies displayed elevated reactive oxygen species (ROS) in circulating plasmatocytes at the larval stage and in sessile plasmatocytes of hematopoietic pockets at of disease. All the parameters were monitored progressively, targeting the circulation at larvae stage and hematopoietic pockets in adults at different disease stages, and many alterations were documented in the early stage itself. These findings strongly implicate that neuronal expression of mHtt alone is sufficient to induce non-cell-autonomous immune dysregulation in vivo. Based on these findings, we propose that further insight into the mechanisms through which neuronal expression of mHtt might be inflicting the innate immune responses would facilitate therapeutic inventions aimed at amelioration of HD pathology and improving the quality of life of the patients.

Complete pathologic response (pCR) predicts the long-term outcome of neoadjuvant treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers able to guide adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether shifts in the serum concentration of thymidine kinase 1 (sTK1) during NAC could be utilized as a biomarker. In the PROMIX trial, women with localized HER2- BC received neoadjuvant epirubicin/docetaxel in six cycles. sTK1 was measured with an ELISA in 54 patients at cycles 1-4 and in a total of 131 patients before and 48h after cycle 1. The prognostic significance of the results was evaluated by log-rank tests of Kaplan–Meier estimates. Treatment resulted in a 2-fold increase of sTK1 before and 3-fold increase 48h after the cycles, except for the first cycle, where half of patients reacted with a decrease (post/pre sTK1- ratio <1.12) and the other half reacted with an increase (ratio >1.12). OS rates in ER+ patients with ratios of >1.12 and <1.12 were 97.7% and 78% (p=0.005), respectively, and DFS rates were 90.7% and 68% (p=0.006), respectively. Thus, response of sTK1 at the first cycle of chemotherapy could be used both as an early biomarker for guidance of chemotherapy and for the study of inherent tumor chemo-sensitivity, which could predict long-term outcome prior to therapy.

A large number of smart devices (things) are being deployed with the swift development of Inter- net of Things (IOT). These devices, owned by different organizations, have a wide variety of services to offer over the web. During a natural disaster or emergency (i.e., a situation), for example, relevant IOT services can be found and put to use. However, appropriate service matching methods are required to find the relevant services. Organizations that manage situation responses and organizations that provide IOT services are likely to be independent of each other, and therefore it is difficult for them to adopt a common ontological model to facilitate the service matching. Moreover, there exists a large conceptual gap between the domain of discourse for situations and the domain of discourse for services, which cannot be adequately bridged by existing techniques. In this paper, we address these issues and propose a new method, WikiServe, to identify IOT services that are functionally relevant to a given situation. Using concepts (terms) from situation and service descriptions, WikiServe employs Wikipedia as a knowledge source to bridge the conceptual gap between situation and service descriptions and match functionally relevant IOT services for a situation. It uses situation terms to retrieve situation related articles from Wikipedia. Then it creates a ranked list of services for the situation using the weighted occurrences of service terms in weighted situation articles. WikiServe performs better than a commonly used baseline method in terms of Precision, Recall and F measure for service matching.

In this work, we investigate by ab initio calculations and optical experiments the sensitiv- ity of graphene quantum dots in their use as devices to measure the presence, and concentration, of heavy metals in water. We demonstrate that the quenching or enhancement in the optical response (absorption, emission) depends on the metallic ion considered. In particular, two test cases of opposite behaviour are considered: Cd 2+ , where we observe an increase in the optical response for increasing concentration, and Pb 2 whose emission spectra are quenched along the concentration rise. We envisage that quantum dots of graphene may be routinely used as cheap detectors to measure the degree of poisoning ions in water

The New World (NW) mammarenavirus group includes several zoonotic highly pathogenic viruses, such as Junin (JUNV) or Machupo (MACV). Contrary to Old World mammarenavirus, these viruses are not able to completely suppress the innate immune response, and trigger a robust interferon (IFN)-I response via retinoic acid-inducible gene I (RIG-I). Nevertheless, pathogenic NW mammarenaviruses trigger a weaker IFN response than their non-pathogenic relatives do. RIG-I activation leads to upregulation of a plethora of IFN-stimulated genes (ISGs), which exert a characteristic antiviral effect either as lone effectors, or resulting from the combination with other ISGs or cellular factors. The dsRNA sensor-protein kinase receptor (PKR) is an ISG that plays a pivotal role in the control of the mammarenavirus infection. In addition to its well-known protein synthesis inhibition, PKR further modulates the overall IFN-I response against different viruses, including mammarenaviruses. For this study, we employed Tacaribe virus (TCRV), the closest relative of the human pathogenic JUNV. Our findings indicate that PKR does not only increase IFN-I expression against TCRV infection, but also affects the kinetic expression and the extent of induction of Mx1 and ISG15 at both levels, mRNA and protein expression. Moreover, TCRV fails to prevent the effect of PKR on viral protein translation and its viral titer is inhibited when PKR is pre-stimulated via IFN-I. Here, we provide first evidence of the specific immunomodulatory role of PKR over selected ISGs, altering the dynamic of the innate immune response course against TCRV. IMPORTANCE: The mechanisms for innate immune evasion are key for emergence and adaptation of human pathogenic arenaviruses, and highly pathogenic mammarenaviruses such as JUNV or MACV trigger a weaker IFN response than non-pathogenic mammarenaviruses. Within the innate immune response context, PKR plays an important role in sensing and restricting the infection of TCRV virus. Although the mechanism of PKR for protein synthesis inhibition is well described, its immunomodulatory role is less understood. In this study, we found that TCRV protein expression and viral propagation are inhibited from early times after infection, and when externally activated, PKR inhibits TCRV viral progeny production. Our present findings further characterize the innate immune response in absence of PKR, unveiling the role of PKR in defining the ISG profile after viral infection.

Nowadays, the human population is facing the third and may be the worst pandemic caused by human coronaviruses (CoVs). The virus was first reported in Wuhan, China on 31 December 2019 and spread within short time to almost all countries of the world. Genome analysis of the early virus isolates has revealed high similarity with SARS-CoV and hence the new virus was officially named SARS-CoV-2. Since CoVs have the largest genome among all RNA viruses, they can adapt many point mutation and recombination events; particularly in spike gene, that enable these viruses to rapidly change and evolve in nature. CoVs are known to cross the species boundaries by using different cellular receptors. SARS-CoV-2 is believed to originate in bats and transmitted to human being through an ill-defined intermediate host. In the current review, different aspects of SARS-CoV-2 biology and pathogenicity are discussed including virus genetics and evolution, spike protein and its role in evolution and adaptation to novel hosts, and virus transmission and persistence in nature. In addition, the immune response developed during SARS-CoV-2 infection is demonstrated with special reference to the interplay between immune cells and their role in disease progression. We believe that SARS-CoV-2 outbreak will not be the last and spillover of CoVs from bats will continue. Therefore, establishing intervention approaches to reduce the likelihood of future CoVs spillover from the natural reservoirs is a priority.

Previous studies investigated the effects of seed rates and seed recycling practices on the yield and yield related variables. However, higher yield does not always guarantee cost-efficiency. This study aimed at investigating the yield effects of plot-level seed rate along with the cost-benefit analysis of seed recycling practices. This study has introduced the dose-response model to the existing analytical methods used in analyzing the effect of different agrochemicals on crop yield. A multi-stage stratified sampling technique was used to select a total of 450 sample respondents. Data was gathered using a mix of data collection tools. Descriptive statistics along with the dose-response model have been applied for data analysis. Farmers of the study were found to be dissimilar in terms of their seed rate application. The dose-response analysis indicated that the highest average wheat yield has been associated with a seed rate of 50 kg ha-1 above what is recommended. The yield effect of seed recycling has also been assessed and a one-time seed recycling has caused a yield decline of 665 kg ha-1 as compared to the non-recycled seeds. The cost reduced by using recycled seed is by far lower than the economic gains associated with using unrecycled and fresh seeds. The cost-benefit analysis made clear that farmers can reduce their seed costs through seed recycling but their yields and net income can be best improved by using unrecycled CBWS. Thus, farmers must be encouraged to make use of unrecycled seed by establishing agricultural credit schemes geared towards seed procurement and seed price subsidy as key strategies to reduce economically wasteful seed recycling practices.

Neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyloidal lateral sclerosis (ALS), and Huntington disease (HD) are the most concerned disorders due to the lack of effective therapeutics and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, yet they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and ER-stress, which combats with stress conditions, but the overwhelming cellular stress response induces cell damage. Small molecules such as flavonoids could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the mechanistic ways of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

Creative thinking is increasingly recognised as an essential ability that should be part of school curricula. Given the move towards online learning and assessment, we investigate whether mathematical creativity can be assessed at-scale in the Numbers game, an arithmetic game in Math Garden, a popular online math practice platform. In the Numbers game, a generalisation of the 24 Game, children are asked to figure out how to compute a target number using basic arithmetic operations and a given set of numbers. We argue that creative thinking is required when the search space is complex, and propose that the base-pattern, i.e., the sequence of the operations needed to solve a Numbers game item, indicates search space complexity. We then demonstrate that items with disordered base-patterns are more likely to require mathematical creativity to figure out. Specifically, our analysis shows that for items with only one solution sequence, those with disordered base-patterns are more difficult and take longer to solve compared to items with ordered base-patterns. For items where multiple solution sequences are possible, nine times out of ten children choose ordered over disordered base-patterns. We conclude that the Numbers game has potential for assessing mathematical creativity at-scale.

This paper proposes the use of non-uniform extended surfaces installed externally to the tubes of the radiation section of fired heaters, in order to obtain a better heat flux distribution to the coils. To this end, the heat transfer mechanisms present in such equipment were studied through computational fluid dynamics (CFD), using simplified geometries that represent typical sizes of fired heaters. Also, a simplified model for the combustion was considered. Although this model oversimplifies the physics of the problem, it was able to give satisfactory results for the parameters being optimized, considering the main objective of this paper, that is to minimize the non-uniformity of heat flux in the tubes of the radiant section of fired heaters. It was possible to obtain optimized geometric parameters for different types of extended surfaces evaluated, coupling the results of these models with the Particle Swarm optimization method through the use of a response surface technique,. The results indicate a significant improvement in the uniformity of the heat flux distribution to the tubes through the use of the proposed extended surfaces. Thus, this solution reveals to be an interesting alternative to reduce the risks of fluid degradation and coking formation. Future studies must investigate the non-uniformity of the heat flux due to the presence of the flame and consider the interaction between the reactive flow and the participating medium. Nevertheless, this paper presents some results that justify the optimization of such extended surfaces taking into consideration thermal radiation.

Objectives: COVID-19, a respiratory disease caused by SARS-COV2 and transmitted from person-to-person through viral droplets remains a global pandemic. There is a need to understand the transmission modes, populations at risk, and how to mitigate the spread and case fatality in the United States (US) and globally. The current study aimed to assess the global COVID-19 transmission and case fatality, examine similar parameters by countries and determine evidence-based practice in extreme epidemiology response in epidemic curve flattening and case fatality reduction. Methods: A cross-sectional ecologic design was used to assess the preexisting data on confirmed COVID-19 cases and mortality in March 2020 from the CDC, WHO, Worldodomter, and STATISTA. A rapid assessment between March 23^rd and 31^st, 2020, was utilized for the extreme epidemiology response. The case fatality, termed fatality proportion, was examined using mortality in relation to confirmed cases involving the world, United States of America (USA), United Kingdom (UK), Italy, France, Spain, China, Germany, India and South Korea. Results: The COVID-19 is a global pandemic, with the US as the epicenter for transmission, representing 20.9% of all confirmed cases worldwide, while Italy is the epicenter for case fatality, 30.6% of mortality as at 03/31/ 2020. The fatality proportion (FP) in Italy was 11.4%, Spain (8.8%), France (6.8%) and UK (6.4%). Despite the increased number of confirmed cases, the lowest FP was observed in Germany (0.96%) and South Korea (1.66%). There is increasing linear tends in transmission in the US, R²=0.97 as well as positive daily percentage change, ranging from 1.27% to 20.5%. Conclusions: The USA remains the epicenter for COVID-19 transmission, while Italy is the epicenter for case fatality. The observed relatively low case fatality in Germany and South Korea is due to an “extreme epidemiology” response through the application of Wuhan, China’s early data on COVID-19 transmission control measures and optimized patient care. These data are suggestive of relaxing the clinical guidelines in the United States in COVID-19 testing, application of contact tracing and testing, case isolation and most importantly enhancing resources for case management and social and physical distancing globally, hence epidemic curve flattening and case fatality reduction.

There is a large body of research on determining the impact of field variability of soil on crop yields. In contrast, site-specific information about crop responses to agronomic treatments is less frequent. On-Farm Precision Experimentation (OFPE) brings important information to understand the spatial variation of crop response to agronomic practices and thus to improve agronomic decisions. The objective of this work was to investigate the spatial variability of corn yield responses to nitrogen and seed rates using OFPE in four fields in the US Midwest. Geographically weighted regression was applied to generate local regression coefficients, which were used to delineate response zones in each field. The results showed the existence of great potential to adjust the rates of these inputs according to the response of each zone identified by the proposed method. The results of this study can be applied to reevaluate expectations on variable rate prescriptions guided largely by soil and variability.

In this study, a preload monitoring method using impedance signatures obtained from a piezoelectric-based smart interface is presented for bolted girder connections. Firstly, the background theory of the piezoelectric-based smart interface and its implementation into health monitoring of bolted connections are outlined. A simplified electro-mechanical (EM) impedance model of a smart interface-embedded bolted connection system is formulated to interpret mechanistic understanding of EM impedance signatures under the effect of bolt preload. Secondly, finite element modeling of a bolted connection is carried out to show the numerical feasibility of the presented method and to predetermine the sensitive frequency band of impedance signatures. Finally, impedance measurements are conducted on a lab-scaled bolted girder connection to verify the predetermined sensitive frequency range and to assess the bolt preload changes in the test structure.

Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these maladies has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic derangements stemmed from over nutrition frequently aggravated by modern sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults [1]. In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.