On June 18, 2023, the U.S. Supreme Court in the matter of Amgen, Inc. et al. v. Sanofi, et al.1 unanimously upheld the 2021 decision of the U.S. Court of Appeals for the Federal Circuit,2 striking down as overbroad Amgen’s patent claim to an entire functional genus of monoclonal antibodies. Amgen’s patent claims were not limited to antibody structure or antibody amino acid sequences. This is significant because Amgen’s patent claims did have amino acid sequences, but they were directed to (...) the epitope. (shrink)

Recent evidence indicates that the presence of serine proteinase inhibitors in plant leaves can reduce predation by insects. Plants can now be transformed with proteinase inhibitor genes with strong promoters to express the inhibitor proteins in relatively high levels at specific times. Inhibitors having variable specificities against digestive proteinases of insects and pathogens can now be assessed for their possible role(s) in natural plant defense and for their potential usefulness in protecting crop plants against herbivores.

Soluble components of Notch signalling can be applied to manipulate a central pathway essential for the development of metazoans and often deregulated in illnesses such as stroke, cancer or cardiovascular diseases. Commonly, the Notch cascade is inhibited by small compound inhibitors, which either block the proteolysis of Notch receptors by γ‐secretases or interfere with the transcriptional activity of the Notch intracellular domain. Specific antibodies can also be used to inhibit ligand‐induced activation of Notch receptors. Alternatively, naturally occurring endogenous (...) class='Hi'>inhibitors of Notch signalling might offer a specific way to block receptor activation. Examples are the soluble variants of the canonical Notch ligand Jagged1 and the non‐canonical Notch ligand Dlk1, both deprived of their transmembrane regions upon ectodomain shedding, or the bona fide secreted molecule EGFL7. We present frequently used methods to decrease Notch signalling, and we discuss how soluble Notch inhibitors may be used to treat diseases. (shrink)

This paper investigates the drivers and inhibitors of Internet privacy concern. Applying the Multidimensional Development Theory to the online environment, we identify the important factors under four dimensions—i.e., environmental, individual, information management, and interaction management. We tested our model using data from an online survey of 2417 individuals in Hong Kong. The results show that the factors under all four dimensions are significant in the formation of Internet privacy concern. Specifically, familiarity with government legislation, Internet knowledge, benefit of information (...) disclosure, privacy protection, and social presence reduce Internet privacy concern, while individuals’ previous privacy invasion experience, risk avoidance personality, and sensitivity of information requested by websites increase Internet privacy concern. We conducted an analysis of unobserved heterogeneity to confirm the significance of these factors. A follow-up moderation analysis shows that the individual factors moderate the effects of the information management factor and the interaction management factors. The findings provide an integrated understanding of the formation of Internet privacy concern. (shrink)

Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi‐induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system (...) that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers. (shrink)

The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA‐approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non‐specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. Bach1 (...) is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, we discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy. (shrink)

Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was (...) suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I . In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (shrink)

Little has been published about the drivers, factors and challenges involved in the business practice of creating corporate sustainability performance within a company. This working paper describes research that employed an in-depth, grounded-theory case study approach to explore the issue within two EU-based utility companies. From the analysis of interviews, project meeting observations and a survey with in-house delivery experts, a key preliminary output of this research has been the creation of a Force-Factor Corporate Sustainability Performance Framework that categorises the (...) main driver and inhibitor elements a dynamic, explanatory model. This can serve as a useful platform for further academic and practitioner-based research, as well as describing key levers and obstacles to establishing a progressive performance in corporate sustainability. (shrink)

Since their derivation, human embryonic stem (hES) cells have been used for a variety of applications including developmental biology, pathology, chemical biology, genomics, and proteomics. However, their most important potential application is the generation of cells and tissues, which can be used for cell‐based therapies. One of the main drawbacks of hES cell culture is that they are particularly sensitive to dissociation, which is required for passaging, expansion, cryopreservation, and other applications. Recently, it has been discovered that an inhibitor of (...) Rho kinase (ROCKi; Y‐27632) increases the survival rate of dissociated, single hES cells. This breakthrough has allowed new methods in hES cell culture to be developed, with the promise of increasing hES cell numbers into the realm of clinical relevance. In our studies demonstrating that ROCKi dramatically increases hES cell cryopreservation efficiency, we have observed that ROCKi treatment does not decrease hES cell's susceptibility to apoptosis. Rather, we hypothesize that ROCKi treatment desensitizes single hES cells to their environment reducing the odds that individual cells will undergo anoikis. (shrink)

In eukaryotes, double‐stranded RNAs (dsRNAs) or short, interfering dsRNAs (siRNAs) can reduce the accumulation of a sequence‐related mRNA, often resulting in a loss‐of‐function phenotype—a process termed RNA interference (RNAi). Unfortunately, some mRNAs are resistant to the effects of dsRNA. Experiments designed to unravel RNAi mechanisms in Caenorhabditis elegans have led to the identification of two worm proteins, RRF‐31,2 and, now, ERI‐1,3 that can inhibit RNAi responses. Animals defective in either protein can display enhanced RNAi phenotypes for mRNAs that were previously (...) resistant to dsRNA. Since ERI‐1 is a conserved protein, development of procedures to enhance RNAi effectiveness in other systems may be possible. BioEssays 26:715–718, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

This study determined the effects of techno-stressors on employees' well-being. It also determined the moderating role of technostress inhibitors in techno-stressors and employees' well-being. We employed a time-lagged design and self-administered survey method to collect data from banking employees. We retrieved 355 usable responses. The results showed that techno-stressors significantly and negatively affected employees' well-being. Technostress inhibitors significantly and positively affected the employee's well-being. The moderating effects of techno-stressors and technostress inhibitors showed that six of nine moderating (...) effects were significant and positive. The results implied that technostress inhibitors help to improve employees' well-being. In the end, we present some implications for theory and practice. (shrink)

A correction to this paper has been published: https://doi.org/10.1007/s10551-021-04854-9.

We present a method to determine the reaction type and kinetic constants for enzyme inhibitors that decreases the number of experimental assays by at least a factor of five. It is based on a new theoretical formalism in terms of concentrations that dismisses the requirement of estimating initial velocities. Expressions for the time evolution of the concentrations of all the reactants are also given.

Discrimination can closely follow disclosure of neurodivergence in the workplace. This traditional review of the literature therefore aims to critically explore factors that facilitate and inhibit mental discrimination in workplace environments, and produce an evidence-based, anti-discrimination guide supporting neurodivergent employees. Applying content analysis to 64 scholarly articles retrieved from Scopus, ProQuest Central and PsycINFO databases, this traditional review offers three main messages which should be of value to HR policymakers and practitioners. First, the spirit of diversity and inclusion needs to (...) be practically applied in recruitment processes so that neurodivergent applicants are not exposed to discrimination. Second, employees or prospective employees should not feel that they will be punished for disclosing their neurodivergence. Finally, sanist workplaces that refuse to be inclusive and accommodating of neurodivergent persons might experience lost productivity as a result. (shrink)

Protein synthesis inhibitors prolong the half‐lives of most mRNAs at least fourfold in the somatic cells of higher eukaryotes and in yeast cells. Some mRNAs are stabilized because the inhibitors affect mRNA‐specific regulatory factors; however, hundreds or thousands of other mRNAs are probably stabilized by a common mechanism. We propose that mRNA stabilization in cells treated with a translation inhibitor reflects a physiological process that occurs during each mitosis and is important for cell survival. Transcription and translation rates (...) decline drastically during a 1–2 hour interval of mitosis. We hypothesize that translational repression during this interval somehow inactivates a critical component of the mRNA degradation machinery. As a result, mRNA half‐lives are prolonged during the interval when transcription is repressed. If labile mRNAs were not stabilized during mitosis they, and perhaps also the labile proteins they encode, would be depleted as the cell entered G1 phase, with deleterious consequences. Stabilization during mitosis, or in response to translation inhibitors, thus preserves the capacity of the cell to synthesize essential proteins as it enters G1 or recovers from inhibitor treatment. mRNA stabilization might serve a similar purpose during starvation or any stress negatively affecting translation. (shrink)

Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high-confidence prenylation predictions by PrePS with a cut-off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 and few other proteins encoded by Herpesviridae, Nef, E1A, NS5A, PB2, HN, L83L, (...) MC155R, other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1-based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections. Many human viruses, including HCV, HIV1, ASFV, and a number of Adeno-, Pox-, and herpesviruses, including CMV, encode the substrates for mammalian prenylation enzymes. Prenylation is advantageous for viral infection; its suppression by FT/GGT and FPPS inhibitors has antiviral effects. In bacteriophages, prenylation may aid in moderation of microbial infections. (shrink)

Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high-confidence prenylation predictions by PrePS with a cut-off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 and few other proteins encoded by Herpesviridae, Nef, E1A, NS5A, PB2, HN, L83L, (...) MC155R, other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1-based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections. Many human viruses, including HCV, HIV1, ASFV, and a number of Adeno-, Pox-, and herpesviruses, including CMV, encode the substrates for mammalian prenylation enzymes. Prenylation is advantageous for viral infection; its suppression by FT/GGT and FPPS inhibitors has antiviral effects. In bacteriophages, prenylation may aid in moderation of microbial infections. (shrink)

Plasminogen activator inhibitor‐1 (PAI‐1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI‐1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI‐1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the “PAI‐1 paradox”. Many factors are responsible for the upregulation of PAI‐1 in the tumor microenvironment. We hypothesize that there is a breast cancer (...) predisposition to a more aggressive stage when PAI‐1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyperinsulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the “PAI‐1 cycle”. Sustained by MetS, adipocytokines alter PAI‐1 expression to promote angiogenesis, tumor‐cell migration and procoagulant microparticle formation from endothelial cells, which generates thrombin and further propagates PAI‐1 synthesis. All of these factors culminate in a chemotherapy‐resistant breast tumor microenvironment. The PAI‐1 cycle may partly explain the PAI‐1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI‐1 and how an increased level of PAI‐1 can be linked to a poor prognosis. BioEssays 29:1029–1038, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

This article analyses the biochemical object of tnf inhibitors from the perspective of living with an autoimmune disease. The author tries to tease out how the concept of immune inhibition is used in tandem with the biochemical object of tnf inhibitors to dominate in defining and narrating what health and disease, normal and pathological, cure and healing can mean in the context of autoimmune bodies. Specifically, and within the ‘pathological’ framework of autoimmune diseases, the pharmacological treatment of tnf (...) inhibition is designed to suppress the ‘overly’ active immune system, thus acting as a negative or suppressing biochemical agent aimed at putting the ‘malfunctioning’ immune system back in balance. As can be seen in the current conjuncture, tnf inhibitors officially —and governmentally— place those taking them in a risk group, as they 'lower' their overall bodily immunity and make them more vulnerable to infectious diseases, while stabilizing their patho-logical, ‘over’-immune uninhibited condition. Part personal narrative of being diagnosed with an autoimmune condition, part speculative autoimmune theory inspired by such a diagnosis, the article ultimately calls for a different form of embodiment that is neither negative nor affirmative, and yet is resistant even to itself. (shrink)

Serine proteinase cleavage of proteins is essential to a wide variety of biological processes and is primarily regulated by protein inhibitors. Many inhibitors are conformationally rigid simulations of optimal serine proteinase substrates, which makes them highly efficient competitive inhibitors of target proteinases. In contrast, members of the serpin family of serine proteinase inhibitors display extensive flexibility and polymorphism, particularly in their reactive site segments and in β‐sheet secondary structure, which can take up and expel strands. Reactive (...) site and β‐sheet polymorphism appear to be coupled in the serpins and may account for the extreme stability of serpinproteinase complexes through the insertion of the reactive site strand into a β‐sheet. These unusual properties may have opened an adaptive pathway of proteinase regulation that was unavailable to the conformationally rigid proteinase inhibitors. (shrink)

The goal of the paper is to offer a model of self-awareness that fits the testimony of both good and bad responders to selective serotonin reuptake inhibitors (SSRIs), of which fluoxetine (Prozac; Lilly, Indianapolis, IN) is probably the most well known. After a review of troubling current uncertainties concerning how and for whom SSRIs are therapeutic, it is argued that SSRIs, as a rule, lessen the emotionality of SSRI subjects in favor of an increased cognitive and volitional orientation. Traditional (...) empiricist and rationalist accounts self-awareness fail to provide models that adequately explain how such a shift from an active emotional response to an increased cognitive/volitional orientation is possible. Instead, notions of self-awareness, as understood by founding phenomenologist, Edmund Husserl, fit the testimony of SSRI subjects. (shrink)

BET proteins such as Brd3 and Brd4 are chromatin‐associated factors, which control gene expression programs that promote inflammation and cancer. The Nrf2 transcription factor is a master regulator of genes that protect the organism against xenobiotic attack and oxidative stress. Nrf2 has demonstrated anti‐inflammatory activity and can support cancer cell malignancy. This review describes the discovery, mechanism and biomedical implications of the regulatory interplay between Nrf2 and BET proteins. Both Nrf2 and BET proteins are established drug targets. Small molecules that (...) either activate or suppress these proteins are currently tested in clinical trials. The crosstalk between Nrf2 and BET proteins may have important, and until now overlooked, implications for the therapeutic effects of these drugs. Based on the information covered in this review, it should be possible to design combinatorial treatment strategies for cancer and inflammatory diseases, which may improve the efficacy of targeting a Nrf2 or BET proteins individually. (shrink)

The new class of anti-inflammatory drugs, the COX-2 inhibitors, have been commercially successful to the point of market dominance within a short time of their launch. They attract a price premium on the basis that they are associated with fewer adverse gastric events than traditional anti-inflammatory drugs. This marketing continues even though a pivotal safety study with one of the COX-2 inhibitors, rofecoxib, showed a significant increase in myocardial infarction with rofecoxib use compared with a traditional anti-inflammatory drug. (...) This finding has led to a series of publications containing pooled analyses of existing data that both support and refute the possibility of increased cardiovascular risk with COX-2 inhibitors.These medical journal publications have served to obfuscate rather than provide guidance for medical practitioners. Consideration of a research ethics committee approach to this issue suggests that it would deal with the controversy in a straightforward manner—namely, it would simply inform research participants of the trial results with rofecoxib. The certainty of this research ethics committee approach raises the issue of whether it should be applied in normal medical practice outside of the research environment. A consideration of the legal tests for disclosure of information suggests that therapeutic medical practice should mirror that within the research environment, in this case. (shrink)

Parkinsonism (PD) is a neurodegenerative disorder of the brain resulting in dopamine deficiency caused by the progressive death of dopaminergic neurons. PD is characterized by a combination of rigidity, poverty of movement, tremor and postural instability. Selegiline is a selective and irreversible propargylamine type B monoamine oxidase (MAO‐B) inhibitor. This drug, which inhibits dopamine metabolism, has been effectively used in the treatment of PD. However, its therapeutic effects are compromised by its many neurotoxic metabolites. To circumvent this obstacle, a novel (...) MAO‐B inhibitor, rasagiline, was developed. Paradoxically, the neuroprotective mechanism of propargylamines in different neuronal models appears to be independent of MAO‐B inhibition. Recent investigations into the neuroprotective mechanism of propargylamines indicate that glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), MAO‐B and/or other unknown proteins may represent pivotal proteins in the survival of the injured neurons. Delineation of the mechanism(s) involved in the neuroprotective effects exerted by MAO‐B inhibitors may provide the key to preventive novel therapeutic modalities. BioEssays 26:80–90, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

Rationale In Belgium, several policies regulating reimbursement of acid suppressant drugs and evidence-based recommendations for clinical practice were issued in a short period of time, creating a unique opportunity to observe their effect on prescribing. Aims and objectives To describe the evolution of prescriptions for acid suppressants and explore the interaction of policies and practice recommendations with prescribing patterns. Method Monthly claims-based data for proton pump inhibitors (PPIs) and H-2-antihistamines by general practitioners, internists and "astroenterologists were obtained from the (...) Belgian national health insurance database (1997-2005). The evolution of reimbursed defined daily doses and expenses after introduction of reimbursement regulations and dissemination of practice recommendations was explored. Results Recommendations had no impact on prescribing. All changes can be related to concomitant policies. Lifting reimbursement restrictions for cheaper products did not control growth or save costs in the Iona term. Only restricting reimbursement of all PPIs managed to curb the growth. We observed an unintended increase of non-omeprazole PPIs by gastroenterologists. Conclusions Reimbursement policies influence prescribing, but their effect can be unintended. A dialogue between policymakers and guideline developers, and evidence-based policies that are linked to clinical guidelines, could be an effective way to pursue both cost-containment and quality of care. (shrink)

It is widely accepted that ethical leadership is beneficial for the organization, the leader, and followers. Yet, little has been said about potential limitations of ethical leadership, particularly boundary conditions involving the same person perceived to display ethical leadership. Drawing on conservation of resources theory, we argue that supervisor-induced hindrance stress and job hindrance stress are factors linked to the supervisor and work environment that may limit the positive impact of ethical leadership on employee deviance and turnover intentions. Specifically, we (...) expect that high levels of hindrance stress drain resources, specifically perceptions of social support, by inhibiting the completion of work, particularly in combination with the high expectations of ethical leaders. We test our model across two time-lagged field studies. Our results demonstrate that supervisor-induced hindrance stress mitigates some of the beneficial impact of ethical leadership and that job hindrance stress further strains these relationships. Overall, our results suggest that both forms of hindrance stress jointly impact the effectiveness of ethical leadership on important outcomes, and do so partly because of their influence on perceived social support. We discuss theoretical contributions to the ethical leadership and stress bodies of literature, as well as practical implications for managers and organizations wishing to develop ethical leaders. (shrink)

© Copyright 2015, Mary Ann Liebert, Inc..Signal transducer and activator of transcription factor 3 is hyperactivated in head and neck squamous cell carcinomas. Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network was screened for the ability to inhibit interleukin-6 -induced pSTAT3 activation. For contractual reasons, the primary high-content screening campaign was (...) conducted over several months in 3 distinct phases; 1,068 primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton. (shrink)

Beckwith‐Wiedemann syndrome is a human congenital disorder characterized by a wide variety of growth abnormalities, including developmental defects and predisposition to certain tumors. Genetic evidence has suggested a role for p57KIP2, a member of a family of cell cycle inhibitory genes, in Beckwith‐Wiedemann syndrome. Two independent groups(1,2) have reported the generation and characterization of mice lacking functional p57KIP2, These mice demonstrate a number of abnormal phenotypes which overlap with, although do not completely recapitulate, Beckwith‐Wiedemann syndrome. These findings advance the molecular (...) characterization of a human disorder, and provide insight into the interplay between regulation of cell division and development. (shrink)

Three‐dimensional (3D) structures have been used to explore the evolution of proteins for decades, yet they have rarely been utilized to study the molecular evolution of peptides. Here, we highlight areas in which 3D structures can be particularly useful for studying the molecular evolution of peptide toxins. Although we focus our discussion on animal toxins, including one of the most widespread disulfide‐rich peptide folds known, the inhibitor cystine knot, our conclusions should be widely applicable to studies of the evolution of (...) disulfide‐constrained peptides. We show that conserved 3D folds can be used to identify evolutionary links and test hypotheses regarding the evolutionary origin of peptides with extremely low sequence identity; construct accurate multiple sequence alignments; and better understand the evolutionary forces that drive the molecular evolution of peptides.Also watch the video abstract. (shrink)

Bromodomain‐containing 4 (BRD4), a member of Bromo and Extra‐Terminal (BET) family, recognizes acetylated histones and is of importance in transcription, replication, and DNA repair. It also binds non‐histone proteins, DNA and RNA, contributing to development, tissue growth, and various physiological processes. Additionally, BRD4 has been implicated in driving diverse diseases, ranging from cancer, viral infection, inflammation to neurological disorders. Inhibiting its functions with BET inhibitors (BETis) suppresses the progression of several types of cancer, creating an impetus for translating these (...) chemicals to the clinic. The diverse roles of BRD4 are largely dependent on its interaction partners in different contexts. In this review we discuss the molecular mechanisms of BRD4 with its interacting partners in physiology and pathology. Current development of BETis is also summarized. Further understanding the functions of BRD4 and its partners will facilitate resolving the liabilities of present BETis and accelerate their clinical translation. (shrink)

Spirituality is as an individual, dynamic, and a complex concept. Meleis's theory includes spirituality in many aspects, and looking at this dimension within this specific theory may help in understanding spirituality as a critical dimension in transitions, as processes, but also as a dimension of self–transition as individual development and growing. Therefore, spirituality is an inherent and integral element of the several foundations of this theory, especially in nursing therapeutics, patterns of responses and transition conditions (facilitators and inhibitors).

Since the introduction of Prozac (fluoxetine), a number of so‐called selective serotonin reuptake inhibitors (SSRIs) have been developed and introduced. These mood enhancers are being presently prescribed for people whose problems are not recognized mental illnesses. It is probable that in the near future the combination of data from advanced biochips and brain imaging will accelerate the development of neurotechnology. So‐called neuroceuticals, used for therapy and enhancement, and to improve different aspects of mental health, will be efficient neuromodulators. The (...) scientific, ethical, and social issues raised by mood enhancement and alteration of personal resilience require further exploration. The chapter talks about the notion of personal autonomy, cosmetic psychopharmacology, power for autonomous, and moral accountability in this context. It suggests that empirical research should also cover psychological and sociological research into perceptions and experiences of individuals who have used these drugs. (shrink)

Wansing’s extended intuitionistic linear logic with strong negation, called WILL, is regarded as a resource-conscious refinment of Nelson’s constructive logics with strong negation. In this paper, (1) the completeness theorem with respect to phase semantics is proved for WILL using a method that simultaneously derives the cut-elimination theorem, (2) a simple correspondence between the class of Petri nets with inhibitor arcs and a fragment of WILL is obtained using a Kripke semantics, (3) a cut-free sequent calculus for WILL, called twist (...) calculus, is presented, (4) a strongly normalizable typed λ-calculus is obtained for a fragment of WILL, and (5) new applications of WILL in medical diagnosis and electric circuit theory are proposed. Strong negation in WILL is found to be expressible as a resource-conscious refutability, and is shown to correspond to inhibitor arcs in Petri net theory. (shrink)

This chapter discusses three different ways of talking about mood enhancement. First, if we do want to enhance, what is good enhancement? Second, if one wants to enhance, what is the usefulness of enhancement? Third, if we want to enhance, what might be the beneficial (or harmful) effects? To illustrate the conceptual analysis in this chapter, two classes of drugs to enhance mood are used. First is the class of selective serotonin reuptake inhibitors (SSRIs) and the other class is (...) of beta blocking agents, which are claimed to be good as “memory‐smoothing” drugs. Three different ways of using the terms “good” or “bad” are shown to be in play in mood enhancement: instrumental goodness and badness, utalitarian goodness and badness, and benefactorial goodness and badness. Mood‐improving and memory‐smoothing drugs may serve different purposes, which are linked to the general purpose of improving the mood or smoothing memories. (shrink)

Alzheimer's disease remains the most common form of dementia. Dementia symptoms vary depending on individual personality, life experience, and social and cultural influences. As dementia progresses, involvement of multi-disciplinary health care professionals is needed to manage the disease. Alzheimer research is progressing rapidly. While 5% of all Alzheimer's disease may be genetically determined, the majority is not. Susceptibility genes can reveal the risk of contracting Alzheimer's disease. Early life risk factors such as education, nutrition, and vascular disease may increase the (...) likelihood of dementia in later life. In the United States, two acetylcholinesterase inhibitors have been approved as cognitive enhancers. Possible prevention and symptomatic treatment interventions have focused on estrogen replacement therapy, antioxidants, and anti-inflammatory medications. Research advances have improved the clinical management of dementia. Ethical implications to the patient, family, and society are multiple and remain challenging. (shrink)

The documented efficacy and long-term benefit of antidepressants in patients with recurrent forms of severe anxiety or depressive disorders support their use in those individuals with these disorders, who experience suicidal thoughts or behavior. In general, it is assumed that antidepressants are beneficial for all symptoms of depression, including suicidality. However, some evidence suggests that Selective Serotonin Reuptake Inhibitors [SSRIs] may cause worsening of suicidal ideas in vulnerable patients. Systematic reviews and pooled analysis of experimental, observational, and epidemiological studies (...) have investigated the use of SSRIs and their association with suicidality. Taking account of the methodological limitations of these studies, the current evidence fails to provide a clear relationship between their use and risk of suicidality in adults. However, in children and adolescents, there appears to be a bit of increased risk of suicidal ideations and attempts, but not of completed suicides. This risk can be anticipated and managed clinically. Clinicians are, therefore, advised to maintain a close follow-up during the initial treatment periods and remain vigilant of this risk. This advisory, however, should not deter clinicians from the use of effective dosages of antidepressants for a sufficient period of time, in every age group of patients, when clinically needed, and if found suitable otherwise. (shrink)

Mutations in the methyl‐CpG‐binding protein 2 (MeCP2) cause Rett syndrome, a severe neurodevelopmental disease associated with ataxia and other post‐natal symptoms similar to autism. Much research interest has focussed on the implications of MeCP2 in disease and neuron physiology. However, little or no attention has been paid to how MeCP2 turnover is regulated. The post‐translational control of MeCP2 is of critical importance, especially as subtle increases or decreases in MeCP2 amounts can affect neuron morphology and function. The latter point is (...) of particular importance for gene therapeutic approaches in which exogenous wild‐type MeCP2 is being introduced into diseased neurons. Further to this, we propose two hypotheses. The first hypothesis discusses the poly‐ubiquitin‐mediated post‐translational regulation of MeCP2 through its two PEST domains. The second hypothesis explores the use of histone deacetylase inhibitors to modulate the amounts of MeCP2 expressed in conjunction with the aforementioned therapeutic approaches. (shrink)

Selective serotonin reuptake inhibitors (SSRIs) have gained a degree of prominence across recent moral enhancement literature as a possible intervention for dealing with antisocial and aggressive impulses. This is due to serotonin's purported capacity to modulate persons’ averseness to harm. The aim of this article is to argue that the use of SSRIs is not something worth getting particularly excited about as a practicable intervention for moral enhancement purposes, and that the generally uncritical enthusiasm over serotonin's potential as a (...) moral enhancer is a consequence of the paucity of viable options for envisaging practicable moral enhancement interventions. While there are many conceptual issues raised by the idea of moral enhancement generally, and by the idea of serotonin as a morally affective agent, the aim here is to look at practical concerns. It is argued that SSRIs do not, nor cannot in the reasonably foreseeable future, be made to work as a reliably safe or reliably effective means for moral enhancement, even within the very limited remit of treating “reactive” aggression. SSRIs might be effective as a limited and partial mental health intervention (even this is questionable), but not as a generally effective moral enhancement technology. (shrink)

A number of concerns have been raised about the possible future use of pharmaceuticals designed to enhance cognitive, affective, and motivational processes, particularly where the aim is to produce morally better decisions or behavior. In this article, we draw attention to what is arguably a more worrying possibility: that pharmaceuticals currently in widespread therapeutic use are already having unintended effects on these processes, and thus on moral decision making and morally significant behavior. We review current evidence on the moral effects (...) of three widely used drugs or drug types: propranolol, selective serotonin reuptake inhibitors, and drugs that effect oxytocin physiology. This evidence suggests that the alterations to moral decision making and behavior caused by these agents may have important and difficult-to-evaluate consequences, at least at the population level. We argue that the moral effects of these and other widely used pharmaceuticals warrant further empirical research and ethical analysis. (shrink)

Donepezil, an acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease, has been widely cited in media and bioethics literature on cognitive enhancement (CE) as having the potential to improve the cognitive ability of healthy individuals. In both literatures, this claim has been repeatedly supported by the results of a small study published by Yesavage et al. in 2002 on non-demented pilots (30-70 years old). The factors contributing to this specific interpretation of this study's results are unclear.