The modern biopharmaceutical industry traces its roots to the dawn of the twentieth century, coincident with marketing of aspirin-a signature event in the history of modern drug development. Although ...the archetypal discovery process did not change markedly in the first seven decades of the industry, the past fifty years have seen two successive waves of transformative innovation in the development of drug molecules: the rise of 'rational drug discovery' methodology in the 1970s, followed by the invention of recombinant protein-based therapeutic agents in the 1980s. An incipient fourth wave is the advent of multispecific drugs. The successful development of prospectively designed multispecific drugs has the potential to reconfigure our ideas of how target-based therapeutic molecules can work, and what it is possible to achieve with them. Here I review the two major classes of multispecific drugs: those that enrich a therapeutic agent at a particular site of action and those that link a therapeutic target to a biological effector. The latter class-being freed from the constraint of having to directly modulate the target upon binding-may enable access to components of the proteome that currently cannot be targeted by drugs.
La musique vainc le diable, comme doit avoir dit Pythagore. Cette étude aborde le problème, pour la troisième fois déjà et à nouveau sur les traces de Stephen Jaeger, qui a défendu à ce propos aussi ...la thèse que bon nombre de ces principes spéculatifs tombaient dans la littérature vernaculaire. On suggère que l'harmonie cosmique est réunie à la Cour médiévale, telle que la Table Ronde d'Arthur, et que l'équilibre sous-entendu dans le concept de l'harmonie du monde se reflète. volens nolens, à la cour des rois médiévaux, princes et évèques (Jaeger, Origins of Courtliness). Une seconde analogie soutient que le concept d'harmonie cosmique correspond à la sphère sociale et humaine; comme le préconise Boethius, les humains peuvent aiguiser leur caractère en répondant convenablement à l'harmonie cosmique, conduisant ainsi à une connaissance personnelle plus profonde. Trois thèmes sont discutés: a) les buts de l'échelle de valeur de la littérature médiévale raffinée; b) l'arrière plan de la notion d'harmonie cosmique -que l'on retrouve dans la description de la Perfection, ou Homme Nouveau, une «union mystérieuse»- et qui est décrite dans deụx traités importants du douzième siècle, la Cosmographia de Bernardus Silvestris et l'Anticlaudianus de Alan of Lille. La dernière préoccupation est le but de l'harmonie du monde étant donné qu'elle suggère une fusion raffinée du divin et de l'humain, du cosmic et du social, du terrestre et du céleste, du macrocosme et du microcosme.
Genomic alterations may make cancer cells more dependent than normal cells on mechanisms of proteostasis, including protein folding and degradation. This proposition is the basis for the clinical use ...of proteasome inhibitors to treat multiple myeloma and mantle cell lymphoma. However, proteasome inhibitors have not proved effective in treating other cancers, and this has called into question the general applicability of this approach. Here, I consider possible explanations for this apparently limited applicability, and discuss whether inhibiting other broadly acting components of the ubiquitin-proteasome system - including ubiquitin-activating enzyme and the AAA-ATPase p97/VCP - might be more generally effective in cancer therapy.
Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer’s disease (FAD). ...How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1−/− mice. Neither mutation altered Psen1 mRNA expression, but both abolished γ-secretase activity. Heterozygosity for the KI mutation decreased production of Aβ40 and Aβ42, increased the Aβ42/Aβ40 ratio, and exacerbated Aβ deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism.
•FAD-linked Presenilin-1 mutations cause complete loss of PS1 function in vivo•FAD-linked Presenilin-1 mutations abolish γ-secretase activity•FAD-linked Presenilin-1 mutations impair hippocampal memory and synaptic function•FAD-linked Presenilin-1 mutations cause age-dependent neurodegeneration
How Presenilin mutations cause Alzheimer’s disease is a key unresolved problem. Xia et al. show, unexpectedly, that such mutations cause AD-like symptoms in mice through a loss-of-function mechanism, suggesting that restoring Presenilin function may be a promising therapeutic strategy.
Decision making is often considered to arise out of contributions from a model-free habitual system and a model-based goal-directed system. Here, we investigated the effect of a dopamine manipulation ...on the degree to which either system contributes to instrumental behavior in a two-stage Markov decision task, which has been shown to discriminate model-free from model-based control. We found increased dopamine levels promote model-based over model-free choice.
► Dopamine increases relative degree of model-based to model-free behavior
Decision making arises out of contributions from model-free habitual and model-based goal-directed systems. Wunderlich et al. investigate how dopamine affects each system to contribute to instrumental behavior, finding that increased dopamine levels preferentially promote model-based goal-directed choice.
Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD ...pathogenesis posits that accumulation of β-amyloid (Aβ) peptides, particularly Aβ42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of Aβ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance Aβ42 production, they typically reduce Aβ40 generation and impair other PS-dependent activities. Third, γ-secretase inhibitors can enhance the production of Aβ42 while blocking other γ-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that Aβ42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of γ-secretase.
Summary
Metal based‐antimicrobials have potential for profiling sustainability solutions to infection care and health; with biotechnological applications providing novel compounds. Yet they must be ...used wisely for sustainable use in human and agricultural health with thoughts towards bioremediation for recovery should be considered.
The mesostriatal dopamine system is prominently implicated in model-free reinforcement learning, with fMRI BOLD signals in ventral striatum notably covarying with model-free prediction errors. ...However, latent learning and devaluation studies show that behavior also shows hallmarks of model-based planning, and the interaction between model-based and model-free values, prediction errors, and preferences is underexplored. We designed a multistep decision task in which model-based and model-free influences on human choice behavior could be distinguished. By showing that choices reflected both influences we could then test the purity of the ventral striatal BOLD signal as a model-free report. Contrary to expectations, the signal reflected both model-free and model-based predictions in proportions matching those that best explained choice behavior. These results challenge the notion of a separate model-free learner and suggest a more integrated computational architecture for high-level human decision-making.
► Humans learn both a world model and reinforcement-driven choice preferences ► BOLD responses in striatum and prefrontal cortex reflect both sorts of learning ► Across subjects, striatal BOLD tracks individual differences in model use ► Unexpectedly, ventral striatum shows combined model-based/free influences
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