Search

Background: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Ginsenoside may be an ideal agent for UC treatment. However, its efficacy and safety are unknown. We aim to conduct a systematic evaluation to assess the effects and potential mechanisms of ginsenosides in animal models of UC. Methods: Six electronic databases will be searched (PubMed, Embase, Web of Science, China Knowledge Network (CNKI), China Science and Technology Journal Database (CQVIP), and Wanfang Data Knowledge). SYRCLE list will be used to assess the quality of literature, and STATA 15.1 for data analysis. Time-dose effects analysis will be used to reveal the time-dosage response relations between ginsenosides and UC. Results: Ultimately, fifteen studies involving 300 animals were included. Preliminary evidence was shown that ginsenosides could reduce Disease Activity Index (DAI) scores, weight loss, histological colitis score (HCS), spleen weight, Malondialdehyde (MDA), Myeloperoxidase (MPO) activity, interleukin-1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and increase colon length (CL), myeloperoxidase (GSH), interleukin 4 (IL-4), interleukin 10 (IL-10), Zonula Occludens-1 (ZO-1) and occludin. Results of time-dose interval analysis indicated that ginsenosides at a dosage of 5–200 mg/kg with an intervention time of 7–28 days were relatively effective. Conclusions: Preclinical evidence suggests that ginsenoside is a novel treatment for UC. And the mechanisms of ginsenosides in treating UC may involve anti-inflammatory, antioxidant, barrier protection, intestinal flora regulation, and immune regulation. Although, due to the high heterogeneity, further large-scale and high-quality preclinical studies are needed to examine the protection of ginsenosides against UC. [ABSTRACT FROM AUTHOR]

14 It is conceivable that there are non-ideal agents the desires of which cannot possibly change, in some sense of possibility, but it is possible for ideal agents to change their desires in any relevant sense of possibility, whatever it might be, as that is necessary for idealization to work. Therefore, secure environments do not "uniquely facilitate" the knowledge Fichte thinks agents need. Alternatively, one may treat the ideal agent as an I advisor i , where the idea is that I A i 's reasons to depend on what I A+ i would advise I A i , I qua i actual agent, to do. According to desire-based versions of reasons internalism, roughly yet famously, an agent I A i has a reason to just in case she or her idealized counterpart desires to .[1] Unless further assumptions are made, it therefore seems like the reasons an agent has vary with their desires. However, like ordinary agents, ideal agents are able to gain or lose their knowledge, so knowledge should be treated like other kinds of necessary conditions for acting on possibly varying desires. [Extracted from the article]

Boron neutron capture therapy (BNCT) is a high-LET particle radiotherapy clinically tested for treating malignant gliomas. Boronophenylalanine (BPA), a boron-containing phenylalanine derivative, is selectively transported into tumor cells by amino acid transporters, making it an ideal agent for BNCT. In this study, we investigated whether the amino acid 5-aminolevulinic acid (ALA) could sensitize glioma stem cells (GSCs) to BNCT by enhancing the uptake of BPA. Using human and mouse GSC lines, pre-incubation with ALA increased the intracellular accumulation of BPA dose-dependent. We also conducted in vivo experiments by intracerebrally implanting HGG13 cells in mice and administering ALA orally 24 h before BPA administration (ALA + BPA-BNCT). The ALA preloading group increased the tumor boron concentration and improved the tumor/blood boron concentration ratio, resulting in improved survival compared to the BPA-BNCT group. Furthermore, we found that the expression of amino acid transporters was upregulated following ALA treatment both in vitro and in vivo, particularly for ATB0,+. This suggests that ALA may sensitize GSCs to BNCT by upregulating the expression of amino acid transporters, thereby enhancing the uptake of BPA and improving the effectiveness of BNCT. These findings have important implications for strategies to improve the sensitivity of malignant gliomas to BPA-BNCT. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) is a chronic, potentially cancerous disease with limited treatment options. Quercetin may be a novel treatment for IBD. However, its efficacy and safety are unknown. Our goal was to conduct a systematic evaluation to summarize the preclinical effects of quercetin, which may help guide future studies. Methods: The literature was drawn from three English databases (PubMed, Embase, and Web of Science), and the quality of the included literature was assessed using the SYRCLE list (10 items). The meta-analysis was performed using STATA 15.1 software. Results: A total of 11 animal studies with 199 animals were involved. The current meta-analysis showed that quercetin could reduce histological score (HS), Disease Activity Index (DAI), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nitric oxide(NO), malondialdehyde (MDA), myeloperoxidase (MPO) activity and increase colon length (CL), weight change degree (WCD), interleukin-10 (IL-10), glutathione (GSH), superoxide dismutase (SOD) activity and catalase (CAT) activity, which may involve anti-inflammatory, anti-oxidative stress, cytoprotective, barrier protection, flora regulation. Conclusions: In conclusion, preclinical evidence suggests that quercetin is an ideal agent for IBD treatment. However, the validity of the findings may be compromised by the low methodological quality and the small number of studies included. There may be some discrepancies between the results of the current analysis and the real situation. More rigorous experimental designs and more comprehensive studies are needed to test the protection of quercetin against IBD. [ABSTRACT FROM AUTHOR]

In his penetrating book on the criminal culpability of children, Gideon Yaffe advances a novel theory of desert. According to the theory, the punishment you deserve for committing a given crime is the punishment the prospect of which would have led you to deliberate correctly about how to act, had that punishment been presented to you beforehand as an inevitable consequence of your committing the crime. Although fascinating and ambitious, Yaffe's theory of desert struggles as an account of who deserves what, and it falls short of explaining why and how desert is normatively significant—why and how desert matters. [ABSTRACT FROM AUTHOR]

Molecular imaging using positron emission tomography (PET) provides sensitive detection and mapping of molecular targets. While cancer-associated fibroblasts and integrins have been proposed as targets for imaging of pancreatic ductal adenocarcinoma (PDAC), herein, spatial transcriptomics and proteomics of human surgical samples are applied to select PDAC targets. We find that selected cancer cell surface markers are spatially correlated and provide specific cancer localization, whereas the spatial correlation between cancer markers and immune-related or fibroblast markers is low. Claudin-4 expression increases ~16 fold in cancer as compared with normal pancreas, and tight junction localization confers low background for imaging in normal tissue. We develop a peptide-based molecular imaging agent targeted to claudin-4 with accumulation to ~25% injected activity per cubic centimeter (IA/cc) in metastases and ~18% IA/cc in tumors. Our work motivates a data-driven approach to selection of molecular targets. Improved imaging methods are crucial to map pancreatic ductal adenocarcinoma (PDAC). Here, the authors analyse PDAC samples using spatial transcriptomics and proteomics, identify claudin-4 as a potential theranostic target, and develop an imaging agent to track claudin-4 in primary and metastatic PDAC tumours. [ABSTRACT FROM AUTHOR]

Aims and Objectives: Dexmedetomidine is a relatively new, potent, and highly selective α2-adrenergic receptor agonist used for perioperative sympatholytic, analgesia, and sedation. We conducted this study to evaluate the effects of dexmedetomidine as an adjunct to local anaesthesia for maxillofacial soft tissue injuries as day care in the emergency department on patient hemodynamics and analgesic efficacy. Materials and Methods: Eighty patients gave informed consent to participate in the study. They were divided into Groups P and D, each of which consisted of 40 participants. Patients received saline injections in Group P, and Group D received dexmedetomidine (DEX) with local anaesthesia infiltration to both groups. Hemodynamic parameters, duration of surgery, pain of first rescue analgesia, Pain score, patient satisfaction, and surgeons satisfaction were recorded and quantified using unpaired t tests or Mann–Whitney and ANOVA tests. Data and qualitative data parameters were compared using Chi-square test. A P value < 0.05 was considered significant. Results: Our study showed statistically significant reduced heart rate, systolic, and diastolic blood pressures in DEX compared to the placebo group where none had hypotension or bradycardia in clinical settings. The dexmedetomidine group had shorter operative time and decreased need for analgesia due to lower VAS scores. Patient and surgeon satisfaction were superior in the DEX group compared to the other groups. Conclusion: Dexmedetomidine effectively suppresses the hemodynamic stress response during minor surgical procedures. We conclude that dexmedetomidine is an effective medication to be used in the emergency room for day-care procedures, as a potent analgesic, anxiolytic providing hemodynamically stable patients, with minimal side effects. We summarise that considering the above properties of dexmedetomidine can be incorporated into ERAS (early return after surgery) protocol, making it an optimal drug of choice as an alternative to moderate sedative drugs, in managing soft tissue injuries of maxillofacial region. [ABSTRACT FROM AUTHOR]

Sensors, controllers, and actuators in a networked control system collaborate to execute a distributed closed-loop feedback control system. Currently, NCS includes network components that remain unidentified, such as heightened latency and packet loss, which may be persistent or fluctuate over time. The current predicament stems from the increased complexity of inspection and control systems, which is attributed to the vast expansion of communication networks. Implementing proactive strategies to mitigate the effects of communication network disruptions on control systems is crucial. A comprehensive study has identified various techniques for controller development. Initiatives are underway to mitigate the impact of network-wide random delays and improve the efficiency of the NCS system. To reach this goal, this study uses a meta-heuristic optimization method called the Whale Optimization Algorithm (WOA) along with a fuzzy-PID controller for a Networked Control System (NCS) plant. The proposed work will be evaluated under two operational scenarios of the NCS plant: one incorporating a random delay condition and the other excluding it. The effectiveness of the proposed method is evaluated by measuring and comparing its closed-loop performance to a traditional PID controller. The outcomes for both NCS plant scenarios illustrate the efficacy of the proposed initiative regarding closed-loop performance.Article highlights: The major highlights of this work are as follows: To simulate two operational scenarios for the NCS plant, one with and one without a random delay condition, and implement fuzzy PID control for the NCS plant in the aforementioned instances. Utilizing the Whale Optimization Algorithm (WOA) to address the unknown network delays for both models while simultaneously optimizing the fuzzy parameters. Incorporating the controller’s output into the fitness function to avoid excessive deviation and evaluating the performance of the closed-loop system for both scenarios through result comparison. [ABSTRACT FROM AUTHOR]

As nanomedicine-based clinical strategies have continued to develop, the possibility of combining chemotherapy and singlet oxygen-dependent photodynamic therapy (PDT) to treat pancreatic cancer (PaC) has emerged as a viable therapeutic modality. The efficacy of such an approach, however, is likely to be constrained by the mechanisms of drug release and tumor oxygen levels. In the present study, we developed an Fe(III)-complexed porous coordination network (PCN) which we then used to encapsulate PTX (PCN-Fe(III)-PTX) nanoparticles (NPs) in order to treat PaC via a combination of chemotherapy and PDT. The resultant NPs were able to release drug in response to both laser irradiation and pH changes to promote drug accumulation within tumors. Furthermore, through a Fe(III)-based Fenton-like reaction these NPs were able to convert H2O2 in the tumor site to O2, thereby regulating local hypoxic conditions and enhancing the efficacy of PDT approaches. Also these NPs were suitable for use as a T1-MRI weighted contrast agent, making them viable for monitoring therapeutic efficacy upon treatment. Our results in both cell line and animal models of PaC suggest that these NPs represent an ideal agent for mediating effective MRI-guided chemotherapy-PDT, giving them great promise for the clinical treatment of PaC. [ABSTRACT FROM AUTHOR]

Modern production systems are increasingly using artificial agents (e.g., robots) of different kinds. Ideally, these agents should be able to recognize the state of the world, to act optimizing their work toward the achievement of a set of goals, to change the plan of action when problems arise, and to collaborate with other artificial and human agents. The development of such an ideal agent presents several challenges. We concentrate on two of them: the construction of a single and coherent knowledge base which includes different types of knowledge with which to understand and reason on the state of the world in a human-like way; and the isolation of types of contexts that the agent can exploit to make sense of the actual situation from a perspective and to interact accordingly with humans. We show how to build such a knowledge base (KB) and how it can be updated as time passes. The KB we propose is based on a foundational ontology, is cognitively inspired, and includes a notion of context to discriminate information. The KB has been partially implemented to test the use and suitability of the knowledge representation for the agent's control model via a temporal planning and execution system. Some experimental results showing the feasibility of our approach are reported. [ABSTRACT FROM AUTHOR]

Addressing drug-induced liver injury is crucial in drug development, often causing Phase III trial failures and market withdrawals. Traditional animal models fail to predict human liver toxicity accurately. Virtual twins of human organs present a promising solution. We introduce the Virtual Hepatic Lobule, a foundational element of the Living Liver, a multi-scale liver virtual twin. This model integrates blood flow dynamics and an acetaminophen-induced injury model to predict hepatocyte injury patterns specific to patients. By incorporating metabolic zonation, our predictions align with clinical zonal hepatotoxicity observations. This methodology advances the development of a human liver virtual twin, aiding in the prediction and validation of drug-induced liver injuries. [ABSTRACT FROM AUTHOR]

This paper discusses a scenario borrowed from Williamson (2000) and repurposes it to argue for the possibility of conflict between two prima facie categorical norms of epistemic rationality: the norm to respect one's evidence and the norm to be coherent. It is argued, pace Williamson, that in the conflict defining the scenario, the evidence norm overrides the coherence norm; that a rational agent with our evidence would lack evidence about some of their own credences; and that for agents whose evidence is limited in this way, incoherence fails to entail irrationality. The above possibility claim has also been defended by Worsnip (2018), albeit on a quite different premise set and in conjunction with a coherence-centered account of epistemic rationality that issues predictions incompatible with those licensed by the evidence-centered account recommended here, as illustrated towards the end of the paper. [ABSTRACT FROM AUTHOR]

Mandarin Chinese is typologically unusual among the world's languages in having flexible word order despite a near absence of inflectional morphology. These features of Mandarin challenge conventional linguistic notions such as subject and object and the divide between syntax and semantics. In the present study, we tested monolingual processing of argument structure in Mandarin verb-final sentences, where word order alone is not a reliable cue. We collected participants' responses to a forced agent-assignment task while measuring their electroencephalography data to capture real-time processing throughout each sentence. We found that sentence interpretation was not informed by word order in the absence of other cues, and while the coverbs BA and BEI were strong signals for agent selection, comprehension was a result of multiple cues. These results challenge previous reports of a linear ranking of cue strength. Event-related potentials showed that BA and BEI impacted participants' processing even before the verb was read and that role reversal anomalies elicited an N400 effect without a subsequent semantic P600. This study demonstrates that Mandarin sentence comprehension requires online interaction among cues in a language-specific manner, consistent with models that predict crosslinguistic differences in core sentence processing mechanisms. [ABSTRACT FROM AUTHOR]

Freshwater mussels preserve valuable information about hydrology, climate, and population dynamics, but developing seasonal chronologies can be problematic. Using clumped isotope thermometry, we produced high-resolution reconstructions of modern and historic (~ 1900) temperatures and δ18Owater from mussel shells collected from an impounded river, the Brazos in Texas, before and after damming. We also performed high-resolution growth band analyses to investigate relationships between mussel growth rate, rainfall, and seasonal temperature. Reconstructed δ18Owater and temperature vary little between the modern (3R5) and historic shell (H3R). However, a positive relationship between reconstructed δ18Owater and growth rate in H3R indicates that aside from diminished growth in winter, precipitation and flow rate are the strongest controls on mussel growth in both modern and pre-dam times. Overall, our results demonstrate (1) the impact, both positive and negative, of environmental factors such as flow alteration and temperature on mussel growth and (2) the potential for clumped isotopes in freshwater mussels as a paleohydrology and paleoclimate proxies in terrestrial environments. [ABSTRACT FROM AUTHOR]

We typically see child soldiers as not morally responsible because of their age and/or because they are victims of adult exploitation. Work on child soldiers and their moral responsibility is relatively sparse within just war thinking and political philosophy (Thomason in Ethical Theory Moral Pract, 19:115–127, 2016a; Thomason in Seeing child soldiers as morally compromised warriors [Online]. The Critique. Available: http://www.thecritique.com/articles/seeing-child-soldiers-as-morally-compromised-warriors/ [Accessed 2 April 2020], 2016b), and instead focuses mostly on whether child soldiers are liable to attack (McMahan, in Gates, Reich (eds) Child soldiers in the age of fractured states, University of Pittsburgh Press, Pittsburgh, PA, 2010; Vaha in J Military Ethics, 10:36–51, 2011). This paper brings these two areas together. Many of us have the intuition that combatants should exercise at least some constraint when fighting against child soldiers. I will argue that, contra McMahan (2010), exercising restraint in this way is a requirement of justice. I will argue that agents can be more or less liable to attack (liability to attack is on a spectrum) in defensive killing cases depending on how morally responsible they are for the threat they cause. I will outline how, whilst child soldiers are not wholly responsible for the threat they cause to combatants, their responsibility is also not completely diminished. I will argue that child soldiers are therefore liable to attack, but to a lesser extent than fully responsible agents. I will show that combatants fighting against child soldiers are therefore required, as a matter of justice, to use the most proportionate method of attack which may not always be to kill the child soldier. I will conclude that combatants are therefore required, as a matter of justice, to exercise a degree of restraint when fighting against child soldiers. [ABSTRACT FROM AUTHOR]

Pessimists about moral deference argue that there is something special about moral beliefs which make it impermissible for agents to defer on moral matters. In this paper, I argue that, even if pessimists are right that there is something special about moral beliefs, that is not enough to render moral deference impermissible. A stronger requirement—the rationality requirement—makes deferring to experts not only permissible but also rationally required. When one does not defer to one's perceived moral expert, one either violates Belief Consistency or violates Belief Closure. The moral considerations, such as moral understanding or virtue, for not deferring to experts either fail to show that not deferring is a better option than deferring or fail to show that those moral considerations outweigh rationality requirements. [ABSTRACT FROM AUTHOR]

This study develops a view of Hume's is/ought distinction as an extension of Scottish jurisprudence that, in turn, was influenced by Pufendorf's discussion of entia moralia. Further, it investigates the unique role that Hume's sentimentalism played in the production of elements in the context of liberalism under the rule of law, independently of previous philosophical traditions. First, we observe that Hume's is/ought distinction corresponds to a distinction between uncivilized and civilized entities, rather than between amoral rationality and moral passions. Next, analyzing Hume's argument for "moral evidence," we find that such evidence is necessary for various activities, such as consent or trading, in the field of moral entities as civil societies. Finally, a study of Hume's stance with respect to civil and common laws shows that his moral sentimentalism, which includes the is/ought distinction and moral evidence, suggests a new possibility for social development that is distinct from previous rational forms of jurisprudence. From this discussion, a unique sprout of modern liberalism can be seen in Hume's theory of justice. [ABSTRACT FROM AUTHOR]

To enhance the plausibility of naturalistic moral realism, David Copp develops an argument from epistemic defeaters aiming to show that strongly a priori synthetic moral truths do not exist. In making a case for the non-naturalistic position, I locate Copp's account within the wider literature on peer disagreement; I identify key points of divergence between Copp's doctrine and conciliatorist doctrines; I introduce the notion of 'minimal moral competence'; I contend that some plausible benchmarks for minimal moral competence are grounded in substantive moral considerations; and I discuss two forms of spinelessness that Copp's moral naturalism could result in. [ABSTRACT FROM AUTHOR]

Purpose of Review: Although urethral bulking therapy has been available for more than 50 years, the ideal agent is still lacking and its result is considered inferior to surgery. In this review, we summarize the latest advances and evidences in the field of urethral bulking agents for treatment of stress urinary incontinence (SUI). Recent Findings: The use of ultrasound evaluation post-urethral bulking provides insights for the optimal position and configuration of the bulking agent. Novel agents are available and show promising results in pre-clinical and clinical studies. More clinical data is available for currently available agent, e.g., Bulkamid. The field of cell-based urethral injection and regenerative medicine provides exciting future in treatment of SUI. Summary: Urethral bulking therapy remains important in the treatment of SUI especially in high medical risk group or patients with recurrent SUI post-surgery. Further researches in novel bulking agents and regenerative medicine may further enhance its role and eliminate its current limitations. [ABSTRACT FROM AUTHOR]

The paper reexamines an agent-based model of opinion formation under bounded confidence with heterogeneous agents. The paper is novel in that it extends the standard model of opinion dynamics with the assumption that interacting agents share the desire to exchange opinion. In particular, the interaction between agents in the paper is modeled via a dynamic preferential-matching process wherein agents reveal their preferences to meet according to three features: coherence, opinion difference, and agents' positive sentiments towards others. Only preferred matches meet and exchange opinion. Through an extensive series of simulation treatments, it follows that the presence of sentiments, on one hand, hardens the matching process between agents, which leads to less communication. But, on the other hand, it increases the diversity in preferred matches between agents and thereby leads to a better-integrated social network structure, which reflects in a reduction of the opinion variance between agents. Moreover, at combinations of (a) high tolerance, (b) low sensitivity of agents to opinion volatility, and (c) low levels of confidence, agents are occasionally drawn away from the consensus, forming small groups that hold extreme opinions. [ABSTRACT FROM AUTHOR]

Background: Modern-day obstetrics recommend induction of labor by medical or mechanical methods where continuation of pregnancy causes detrimental effect to the health of mother or fetus. One of the prerequisites for successful vaginal delivery includes a favorable or ripe cervix. We undertook the present study to find out the safety and efficacy of mifepristone for pre-induction cervical ripening and its effect on Bishop's score in term pregnancy. Methods: A total of 100 patients with term pregnancy were enrolled for this study. 200 mg of mifepristone was administered orally, and efficacy of mifepristone was assessed based on improvement in modified Bishop's score at 48 h. If there was inadequate improvement in Bishop's score after 48 h, additional intracervical cerviprime was administered for induction. Results: Out of 100 patients, 50 women delivered vaginally after administration of mifepristone. Twenty-four patients delivered vaginally within 48 h of administration of mifepristone. We observed the Bishop's score of 6 or more at 48 h in 69% participants. Fifty patients required additional intracervical cerviprime. Thirty participants underwent cesarean section. Mean Modified Bishop's score at 0 h was 1.87 and improved to 6.92 after 48 h after mifepristone. A statistically significant difference was found with mean Bishop's score with p value < 0.005. Conclusion: In our study, we found that mifepristone is a safe and effective cervical ripening agent in term pregnancy with unfavorable cervix. It is well tolerated and leads to significant cervical ripening with improvement in Bishop's score favoring vaginal delivery. [ABSTRACT FROM AUTHOR]

Biocontrol agents must be released into low densities of insect pests. However, the movement patterns of biocontrol agents rapidly switch from intensive search of prey within patches to extensive search between patches when densities of prey/hosts are very low. This switching can result in the extinction of these agents on the crop, due to either dispersal from crop fields or starvation. We predicted that the foraging behavior of remaining longer per patch (i.e., giving-up time) would be effective in preventing or delaying the emigration of released agents from crop fields, thus improving the efficacy of pest control. We verified this hypothesis using Orius strigicollis, which often establishes poorly after release during periods of low prey density. Selected lines of O. strigicollis with low walking activity were established by artificial selection. Their giving-up time was extended compared with wild-type lines. After feeding on thrips, the selected lines showed search behavior that involved slower travel, more turns, and more time spent immobile compared with the wild-type lines. This behavior was very similar to that observed for intensive search behavior. In greenhouse trials, the selected lines remained on eggplants longer than the wild-type lines and exhibited remarkable pest control efficacy. These results indicate that extension of patch residence time by selective breeding contributes to the early establishment of O. strigicollis and the suppression of thrips. [ABSTRACT FROM AUTHOR]

Purpose: Direct oral anticoagulants (DOACs) have been approved, for over a decade, by both European and American medicine agencies, for treatment and prevention of several cardiovascular conditions. Since then, an increasing amount of data has been added to the medical literature day by day, resulting in a dichotomy in selection of the appropriate agent, dosage, and duration of treatment for special populations with multiple comorbidities. Considering these issues, we have prepared a comprehensive review for the clinical practitioner, to optimize the DOAC utilization in clinical practice. Methods: A thorough literature search and review was conducted, concerning mainly the last decade. Our review focused on the current guidelines and the most recently published studies in PubMed, Science Direct Scopus, and Google Scholar to date. Conclusion: The purpose of this study is to provide guidance for healthcare professionals for making proper decisions when confronted with clinical challenges. Nevertheless, further research is required to establish DOAC superiority in complicated cases, where there is clinical uncertainty. [ABSTRACT FROM AUTHOR]

The use of molecular techniques in biological studies has rapidly grown and the tools have become more powerful, widely available, as well as cheaper and easier to implement. For classical biological control of weeds, molecular population genetics can uncover information about invasions that was recently unknowable but can be critical to improving control success, including clarifying taxonomy, hybridization and cryptic species, host plant evolutionary relationships with other plant species, and population structure and origin of invasions. This review provides recent examples of uses of molecular population genetics and phylogenetics that have improved our knowledge of target species, hoping to inspire and guide researchers as they begin planning a classical biological control of weeds program. [ABSTRACT FROM AUTHOR]

Much government and personal conduct is premised on the idea that a person made thereby to suffer deserves that suffering thanks to prior wrongdoing by him. Further, it often appears that one kind of suffering is more deserved than another and, in light of that, conduct inflicting the first is superior, or closer to being justified than conduct inflicting the second. Yet desert is mysterious. It is far from obvious what, exactly, it is. This paper offers and argues for a theory of comparative desert. It offers an account of the conditions under which one harm is more deserved for past wrongdoing than another. The theory offered here can be stated, roughly, like so: One harm is more deserved for a wrongful act than another if, in light of it more than the other, the act is supported by reasons for the agent in a way similar to the way it ought to have been supported by reasons for him. The central task of the paper is to explain, elaborate and offer an argument for this theory. The paper also shows that, under the theory, differences in culpability-as between, for instance, intentionally rather than knowingly bringing about a harm-make a difference to desert. And the paper shows that under the proposed theory it is easier for the state to justify inflicting a punishment that is more deserved than it is to justify inflicting a punishment that is less deserved. [ABSTRACT FROM AUTHOR]

According to textbooks, no physical observable can be discerned allowing to distinguish a liquid from a gas beyond the critical point. Yet, several proposals have been put forward challenging this view and various transition boundaries between a gas-like and a liquid-like behaviour, including the so-called Widom and Frenkel lines, and percolation line, have been suggested to delineate the supercritical state space. Here we report observation of a crossover from gas-like (Gaussian) to liquid-like (Lorentzian) self-dynamic structure factor by incoherent quasi-elastic neutron scattering measurements on supercritical fluid methane as a function of pressure, along the 200 K isotherm. The molecular self-diffusion coefficient was derived from the best Gaussian (at low pressures) or Lorentzian (at high pressures) fits to the neutron spectra. The Gaussian-to-Lorentzian crossover is progressive and takes place at about the Widom line intercept (59 bar). At considerably higher pressures, a liquid-like jump diffusion mechanism properly describes the supercritical fluid on both sides of the Frenkel line. The present observation of a gas-like to liquid-like crossover in the self dynamics of a simple supercritical fluid confirms emerging views on the unexpectedly complex physics of the supercritical state, and could have planet-wide implications and possible industrial applications in green chemistry. Within the phase diagram of pure substances, the supercritical state is not fully understood. Here the authors experimentally observe a gas-like to liquid-like crossover in the self-dynamics of supercritical fluid methane upon pressure increase. [ABSTRACT FROM AUTHOR]

Is logic normative for belief? A standard approach to answering this question has been to investigate bridge principles relating claims of logical consequence to norms for belief. Although the question is naturally an epistemic one, bridge principles have typically been investigated in isolation from epistemic debates over the correct norms for belief. In this paper we tackle the question of whether logic is normative for belief by proposing a Kripkean model theory accounting for the interaction between logical, doxastic, epistemic and deontic notions and using this model theory to show which bridge principles are implied by epistemic norms that we have independent reason to accept, for example, the knowledge norm and the truth norm. We propose a preliminary theory of the interaction between logical, doxastic, epistemic and deontic notions that has among its commitments bridge principles expressing how logic is normative for belief. We also show how our framework suggests that logic is exceptionally normative. [ABSTRACT FROM AUTHOR]

The thesis that agents should calibrate their beliefs in the face of higher-order evidence—i.e., should adjust their first-order beliefs in response to evidence suggesting that the reasoning underlying those beliefs is faulty—is sometimes thought to be in tension with Bayesian approaches to belief update: in order to obey Bayesian norms, it's claimed, agents must remain steadfast in the face of higher-order evidence. But I argue that this claim is incorrect. In particular, I motivate a minimal constraint on a reasonable treatment of the evolution of self-locating beliefs over time and show that calibrationism is compatible with any generalized Bayesian approach that respects this constraint. I then use this result to argue that remaining steadfast isn't the response to higher-order evidence that maximizes expected accuracy. [ABSTRACT FROM AUTHOR]

Background: The urgent demand for innovative theranostic strategies to combat bacterial resistance to antibiotics is evident, with substantial implications for global health. Rapid diagnosis of life-threatening infections can expedite treatment, improving patient outcomes. Leveraging diagnostic modalities i.e., positron emission tomography (PET) and single photon emission computed tomography (SPECT) for detecting focal infections has yielded promising results. Augmenting the sensitivity of current PET and SPECT tracers could enable effective imaging of pathogenic bacteria, including drug-resistant strains.UBI (29–41), an antimicrobial peptide (AMP) fragment recognizes the S. aureus membrane through electrostatic binding. Radiolabeled UBI (29–41) is a promising SPECT and PET-based tracer for detecting focal infections. 2-APBA (2-acetyl-phenyl-boronic acid), a non-natural amino acid, specifically targets lysyl-phosphatidyl-glycerol (lysyl-PG) on the S. aureus membranes, particularly in AMP-resistant strains. We propose that combining UBI with 2-APBA could enhance the diagnostic potential of radiolabeled UBI. Results: Present work aimed to compare the diagnostic potential of two radiolabeled peptides, namely UBI (29–41) and 2-APBA modified UBI (29–41), referred to as UBI and UBI-APBA. APBA modification imparted antibacterial activity to the initially non-bactericidal UBI against S. aureus by inducing a loss of membrane potential. The antibacterial activity demonstrated by UBI-APBA can be ascribed to the synergistic interaction of both UBI and UBI-APBA on the bacterial membrane. To enable PET imaging, we attached the chelator 1,4,7-triazacyclononane 1-glutaric acid 4,7-acetic acid (NODAGA) to the peptides for complexation with the positron emitter Gallium-68 (68Ga). Both NODAGA conjugates were radiolabeled with 68Ga with high radiochemical purity. The resultant 68Ga complexes were stable in phosphate-buffered saline and human serum. Uptake of these complexes was observed in S. aureus but not in mice splenocytes, indicating the selective nature of their interaction. Additionally, the APBA conjugate exhibited superior uptake in S. aureus while preserving the selectivity of the parent peptide. Furthermore, [68Ga]Ga-UBI-APBA demonstrated accumulation at the site of infection in rats, with an improved target-to-non-target ratio, as evidenced by ex-vivo biodistribution and PET imaging. Conclusions: Our findings suggest that linking UBI, as well as AMPs in general, with APBA shows promise as a strategy to augment the theranostic potential of these molecules. [ABSTRACT FROM AUTHOR]

This article provides a comprehensive analysis of Motivation Reason Internalism and its limitations. It explores different versions of internalism and argues that they are either unnecessary or insufficient. The author introduces the idea of a third cause for motivation that is neither cognitive nor affective. The article also examines the relationship between normative reasons and different types of actions. It concludes that contextual motivation internalism, which considers an agent's contextual rationality and sensitivity to accessible information, is the most plausible explanation. The text addresses objections to this perspective and discusses the limitations of desire and motivation in relation to reason. [Extracted from the article]

The General Medical Council (GMC) instructs doctors to act 'reasonably' in obtaining consent from patients. However, the GMC does not explain what it means to be reasonable: it is left to doctors to figure out the substance of this instruction. The GMC relies on the Supreme Court's judgment in Montgomery v Lanarkshire Health Board; and it can be assumed that the judges' idea of reasonability is adopted. The aim of this paper is to flesh out this idea of reasonability. This idea is commonly personified as the audience that has to be satisfied by the doctor's justification for offering, or withholding, certain treatments and related information. In case law, this audience shifted from a reasonable doctor to a 'reasonable person in the patient's position'; and Montgomery expands the audience to include 'particular' patients, too. Senior judges have clarified that the reasonable person is a normative ideal, and not a sociological construct; but they do not set out the characteristics of this ideal. John Rawls has conceived the reasonable person-ideal as one that pursues fair terms of co-operation with other members of society. An alternative ideal can be inferred from the feminist ethic of care. However, the reasonable patient from Montgomery does not align with either theoretical ideal; but, instead, is an entirely rational being. Such a conception conflicts with both real-life constraints on rationality and the doctor's duty to care for the patient, and it challenges the practice of medicine. [ABSTRACT FROM AUTHOR]

Purpose of Review: Despite effective available treatments, gout management is often unsuccessful in getting patients to target serum urate goal and in managing flares in the setting of comorbidities. Studies addressing future treatment options for short- and long-term management are reviewed. Recent Findings: URAT-1 blocking agents have been helpful but have had limitations related to effects on renal function, lack of efficacy with renal impairment, and potential to increase renal stones. Dotinurad may function in the setting of decreased renal function. Arhalofenate has anti-URAT-1 activity and may also blunt gout flares. A new xanthine oxidase inhibitor (XOI), tigulixostat, is under study. New uricase treatments manufactured in combination with agents that can reduce immunogenicity may make uricase treatment simpler. A unique strategy of inhibiting gut uricase may offer the benefits of avoiding systemic absorption. For gout flares, IL-1β inhibitor studies in progress include different dosing schedules. Dapansutrile, an oral agent under investigation, inhibits activation of the NLRP3 inflammasome and may be an effective anti-inflammatory. Summary: New treatments for gout that are under study may work in the setting of comorbidities, simplify management, utilize new mechanisms, or have reduced side effects. [ABSTRACT FROM AUTHOR]

In this paper I argue that luck and fortune are distinct concepts that apply to different sets of events. I do so by suggesting that lucky events are best understood as significant events that are either modally fragile or improbable (depending on whether you accept a modal account or a probability account of luck), whereas fortunate events are best understood as significant events that are outside of our control. I call this the Pure Control Account of Fortune. I show that this account of fortune forces control theorists about luck to be fortune reductionists but allows those who endorse a modal or probability account of luck to be fortune realists. Additionally, I argue that this account of fortune helps us overcome prominent counterexamples and challenges found in the luck literature. [ABSTRACT FROM AUTHOR]

The susceptibility of LIBs to fire and explosion under extreme conditions has become a significant challenge for large-scale application of lithium-ion batteries (LIBs). However, the suppression effect of fire-extinguishing agent on LIBs fire is still far from being satisfactory attributed to special combustion characteristics of LIBs fire. This manuscript provides a comprehensive review on the origin and behavior of LIBs fire, and the selection of the typical fire-extinguishing agents for LIBs. Novel fire suppression strategies are also discussed. Several agents such as liquid nitrogen, dodecafluoro-2-methylpentan-3-one (C6F12O) and water-based fire-extinguishing agents possess better fire-extinguishing and cooling capabilities. Unfortunately, there are some shortcomings that restrict their application. The ideal fire-extinguishing agents for LIBs should be both highly thermally conductive, highly electrically insulating, highly efficient in extinguishing LIBs fire, cheap, non-toxic, residue-free and toxic gases-absorbing. Some perspectives and outlooks are given that the combination of ideal fire-extinguishing agent and novel fire-extinguishing strategy can insure a high level of safety for present and future LIB-based technologies. [ABSTRACT FROM AUTHOR]

A number of pharmacological options for the treatment of obesity are available, but their efficacy is limited to losses of 5–10% of patient weight and their use should be secondary to lifestyle changes. The safety and efficacy of anti-obesity drugs, as well as the characteristics and co-morbidities of the patient, should be taken into consideration when treating obesity, as not all treatments are appropriate for all patients. A variety of new anti-obesity drugs are currently undergoing clinical investigation, but none appears to be the ideal agent to treat obesity. [ABSTRACT FROM AUTHOR]

With the beginning of the Human Genome Project, an emerging field of science was brought to the forefront of the pharmaceutical community. Pharmacogenetics facilitates optimization of the current patient-centered care model and pharmacotherapy as a whole. Utilizing these ever-expanding branches of science to nonsteroidal anti-inflammatory drugs (NSAIDs) can provide novel opportunities to affect patient care. With a wide range of NSAID choices available as treatment options for relieving pain and/or reducing inflammation or fever, a more systematic way of selecting the ideal agent for the patients based upon their genetic information could spare them from a potentially permanent health-care condition. Furthermore, if a patient possesses or lacks certain alleles, serious adverse events can be anticipated and avoided. The tailoring of drug therapy can be achieved using the published data and cutting-edge genetic testing to attain a higher standard of care for patients. [ABSTRACT FROM AUTHOR]

Background: None of the current pleurodesing agents fulfil all the criteria for best pleural sclerosant. Therefore, the search for the ideal agent for chemical pleurodesis still continues. The aim of the present study was to compare the effectiveness of erythromycin, tetracycline, AerosilTM200 (hydrophilic fumed amorphous silica), and erythromycin plus AerosilTM 200 in producing pleurodesis in rats. In the present study, talc was not used as a pleurodesing agent due to an unavailability of its sterile and pure form in Iran. Methods: Overall, 75 adult male Spraque-Dawley rats were randomized to 5 treatment groups. Each group received an intrapleural injection via 5 Fr Silastic tubes of one of the following sterile agents: 35mg/kg erythromycin in 2 ml of saline, 35mg/kg tetracycline in 2 ml of saline, 35mg/kg AerosilTM 200 in 2ml of saline, erythromycin (35mg/kg in 2 ml of saline) plus AerosilTM 200 (35mg/kg in 2 ml of saline), or 2 ml of saline as a control. The animals were euthanized and necropsied 30 days after injection. The pleurae were assessed for macroscopic and microscopic evidence of surrounding inflammation and fibrosis. Results: The median macroscopic score in the AerosilTM 200 group was significantly higher than that in the erythromycin group (P < 0.005). The median microscopic score in the erythromycin group was significantly lower than that in the AerosilTM 200 and erythromycin plus AerosilTM 200 groups (P < 0.005). Furthermore, maximum and minimum pleural fibrosis was observed in the erythromycin plus AerosilTM 200 and erythromycin groups, respectively (P < 0.05). Conclusion: This study suggests that AerosilTM 200 with or without erythromycin may be more potent pleurodesis agent than erythromycin and tetracycline. [ABSTRACT FROM AUTHOR]

While the addition of an anthropomorphic interface agent to a learning system generally has little direct impact on learning, it potentially has a huge impact on learner motivation. As such agents become increasingly ubiquitous on the Internet, in virtual worlds, and as interfaces for learning and gaming systems, it is important to design them to optimally impact motivation. The focus of this paper is on the design of agents and avatars (one's self-representation as a visual agent) for enhancing motivational and affective outcomes, such as improving self-efficacy, engagement and satisfaction, moderating frustration, and/or improving stereotypes. Together with motivational messages and dialogue (which are not discussed here), the agent's appearance is the most important design feature as it dictates the learner's perception of the agent as a virtual social model, in the Bandurian sense. The message delivery, through a human-like voice with appropriate and relevant emotional expressions, is also a key motivational design feature. More research is needed to determine the specifics with respect to the ideal agent voice and the role of other nonverbal communication (e.g., deictic gestures) that may contribute to the agent's role as an embodied motivator, particularly in the long-term. [ABSTRACT FROM AUTHOR]

Standard principles of rational decision assume that an option’s utility is both comprehensive and accessible. These features constrain interpretations of an option’s utility. This essay presents a way of understanding utility and laws of utility. It explains the relation between an option’s utility and its outcome’s utility and argues that an option’s utility is relative to a specification of the option. Utility’s relativity explains how a decision problem’s framing affects an option’s utility and its rationality even for an agent who is cognitively perfect and lacks only empirical information. The essay rewrites standard laws of utility to accommodate relativization to propositions’ specifications. The new laws are generalizations of the standard laws and yield them as special cases. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a major cause of cancer-related mortality. Most colorectal cancers arise in precursor lesions over a number of years. The carcinogenetic pathway is modulated by a wide array of genetic and epigenetic factors. Two major approaches to halting carcinogenesis are chemoprevention and early detection. Chemoprevention is an attractive emerging option—advances in understanding the carcinogenetic pathways and progress in evaluating various putative agents are promising. However, several issues regarding efficacy, safety, and acceptability require answers before an ideal agent can come into widespread use. Early detection and removal of precursor lesions show promise in reducing disease burden. Although the concept has been around and has been widely advocated for several years, participation in screening remains low. The ideal test in terms of practicality, accuracy, and safety is still debated. This article reviews the recent literature related to screening and chemoprevention of colorectal cancer. [ABSTRACT FROM AUTHOR]

We analysed the in vitro effects of a new hydroxamate derivative, ITF2357, on AML cells. ITF2357 potently induced histone acetylation. ITF2357 0.1 μM blocked proliferation and induced apoptosis in AML1/ETO-positive Kasumi-1 cells, while AML1/ETO-negative HL60, THP1 and NB4 cell lines were sensitive only to 1 μM ITF2357. Apoptosis was induced by 0.1 μM ITF2357 in AML1/ETO-positive primary blasts and U937-A/E cells induced to express AML1/ETO, but not in U937-A/E cells non-expressing AML1/ETO. In Kasumi-1 cells 0.1 μM ITF2357 induced AML1/ETO degradation through a caspase-dependent mechanism. ITF2357 0.1 μM also determined DNMT1 efflux from, and p300 influx to, the nucleus. Moreover, 0.1 μM ITF2357 determined local H4 acetylation and release of DNMT1, HDAC1 and AML1/ETO, paralleled by recruitment of p300 to the IL-3 gene promoter. ITF2357 treatment, however, did not induce re-expression of IL-3 gene. Accordingly, the methylation level of IL-3 promoter, as well as of several other genes, was unmodified. In conclusion, ITF2357 emerged as an anti-leukaemic agent very potent on AML cells, and on AML1/ETO-positive cells in particular. More relevantly, clearly emerged from our results that ITF2357 could be an ideal agent to treat AML subtypes presenting AML1/ETO fusion protein which determine HDAC involvement in leukaemogenesis.Oncogene (2008) 27, 1767–1778; doi:10.1038/sj.onc.1210820; published online 24 September 2007 [ABSTRACT FROM AUTHOR]

Hypertension affects 65 million people in the US, and is a major cause of morbidity and mortality, but less than one-third of patients with hypertension are treated to goal blood pressure. Multiple factors have been cited, and include suboptimal adherence to treatment and lifestyle modifications, limited access to healthcare services, and the failure of health professionals to treat hypertension aggressively. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a goal blood pressure of <140/90mm Hg for most patients and <130/80mm Hg for those with diabetes mellitus or chronic kidney disease. The ‘ideal’ antihypertensive agent would have a number of characteristics: (i) effective in lowering blood pressure to recommended goals; (ii) high efficacy as monotherapy; (iii) rapid onset of effect; (iv) convenient once-daily dose administration to maximise compliance; (v) sustained efficacy over 24 hours; (vi) response increases with higher doses (clear dose-response effect); and (vii) optimum tolerability profile. Although the ideal agent does not yet exist and will vary from patient to patient, drug development and new formulations have provided more options for clinicians and patients and certain drug classes appear to show promise because they possess many beneficial characteristics. Hypertension treatment needs to be tailored to individual patients’ age, race, socioeconomic situation, concomitant conditions and family history. Physicians and other clinical providers have an important role to play in hypertension management, particularly by combining culturally sensitive patient care with aggressive treatment. Regular follow-up that is directed at achieving goal blood pressure, while monitoring the patient for possible drug-related adverse effects, will help ensure and support adherence to treatment regimens. By supporting the integration of lifestyle changes into this plan, the clinician can further influence and have a positive impact on a patient’s overall cardiovascular profile. [ABSTRACT FROM AUTHOR]

The treatment of coronary artery disease has reached many milestones – from balloon angioplasty to drug-eluting stents. The last decade witnessed the revolution of bare metal stents with new designs, alloys and strut thicknesses. Yet restenosis, the aphorismic ‘Achilles heel’, remains to be conquered. The restenosis rates with balloon angioplasty alone are 30–40% and are reduced to 20–30% with stents. Although intravascular brachytherapy proved to be a durable and safely used technique to treat in-stent restenosis, clinical event rates were not reduced to single digits. Drug-eluting stents are showing positive results in this direction, but it is too early to predict their efficacy in various subsets of lesions. With the increased usage of these stents, there are reports of problems such as late stent malapposition, subacute and late thromboses, and aneurysm formations due to the vessel toxicity associated with this method of treatment. Furthermore, when multivessel stenting is considered, the cost of drug-eluting stents is a significant problem given the fact that these are no longer ‘zero restenosis’ devices. There is a definite need for a simple, safe and durable solution to restenosis. Oral agents are an alternative delivery strategy that can target multiple coronary lesions, which are targets for catheter-based revascularisation with any approved metal stent and with potentially lower cost. Although oral agents have been an interesting option to treat restenosis and several agents have been tested in trials since the 1980s, the results were disappointing. The development of devices such as intravascular ultrasound has led to a greater understanding of restenosis mechanisms, and the focus on pathophysiological mechanisms, which centred mainly on platelets, growth factors and lipids, has changed to inflammation, endothelium and smooth muscle cell proliferation. Accordingly, the targets of pharmaceutical agents have shifted from platelets to cell cycle inhibition, smooth muscle cell proliferation and migration, synthesis of extra cellular matrix, and inflammatory mediators. Initial encouraging results with oral drugs such as cilostazol, sirolimus (rapamycin) and thiazolidinediones indicate a definite place for this strategy to reduce restenosis. A desirable oral agent would be anti-inflammatory, inhibit smooth muscle cell migration and proliferation, promote endothelial growth, and be well tolerated and free from significant adverse effects. It may be useful to start with a high loading dose before stent implantation and then follow with a short-term lower maintenance dose. Future trials should be aimed at finding an ideal agent, effective loading dose, maintenance dose and optimum duration of therapy. [ABSTRACT FROM AUTHOR]

Oral capecitabine is a highly active, well-tolerated and convenient treatment for breast and colorectal cancer. This trial assessed the efficacy and safety of single-agent capecitabine in patients with previously treated ovarian cancer. A total of 29 patients with platinum-pretreated relapsed ovarian cancer were enrolled in this prospective, open-label, single-centre, phase II study. Patients received oral capecitabine 1250 mg m(-2) twice daily on days 1-14 of a 21-day cycle. Tumour response was evaluated using serum CA125. Out of 29 enrolled patients, 28 were evaluable, and a response was observed in eight patients (29%, 95% confidence interval (CI), 13-49%). Median progression-free and overall survivals were 3.7 (95% CI, 2.8-4.6) and 8.0 (95% CI, 4.1-11.8) months, respectively. After 6 months of treatment, 28% (95% CI, 13-48%) of patients remained progression-free and 62% (95% CI, 42-79%) were still alive. The most common clinical adverse events were hand-foot syndrome (HFS), nausea and diarrhoea. Grade 3 HFS occurred in 14% of patients, grade 3 vomiting in 10%. Efficacy and safety of capecitabine compare favourably with other monotherapies in platinum-refractory epithelial ovarian cancer. The convenience and improved safety profile of capecitabine compared with intravenous. regimens make it an ideal agent for administration in the outpatient setting. [ABSTRACT FROM AUTHOR]