Mechanistic Paradigm Research Articles

Comparative Study of Paradigm on Science: Holistic View by Frithjof Capra and Knowledge Formulation by Yuval Noah Harari

An paradigm of science, since the beginning of the formation of scientific formulation, it has always undergone a change, as well as Thomas Kuhn's scientific revolution theory. The paradigm is always tested with new theories until finally the obsolete paradigm is no longer used or is still partially used. At first the mechanistic paradigm introduced by Isaac Newton has long been a basic reference. But then, this paradigm is tested by the many problems of science, especially physics that no longer cannot be solved with this paradigm. The paradigm problem is a long search process because the paradigm not only regulates the workings of science in the laboratory, but also determines the results that have a significant impact on humans. The process of finding new paradigm is being pursued by two figures to be discussed, Fritjhof Capra and Yuval Noah Harari. Both give more attention to the paradigm of modern science that is unable to answer new challenges. Capra provides a new paradigm solution which he calls a holistic paradigm that seeks to see reality as an integration with a series of inseparable life networks. Whereas Harari, through his two best-selling books, Homo Sapiens and Homo Deus, revealed the latest theories and discoveries in the fields of physics, chemistry, biology to art, from his description he produced a synthesis of paradigm changes in reformulating knowledge which has positive implications for human survival. The method that will be used is the comparative method, thus the thinking of both of them will be abstracted in their similarities and differences of thought. The purpose of this research is to explore the latest science paradigm process proposed by the two figures, Capra and Harari.

La gestione del bosco come sistema biologico complesso: una questione di teoria e di metodo

For a long time, forest practice has been characterized by a linear paradigm: forest cultivation and management have been centred on the volume/regeneration relationship, considered respectively source of income and basis for sustained production. According to this paradigm, forest management has worked out a series of forest regulation methods with the aim of obtaining the “fully regulated forest”. These methods are firmly anchored to the mechanistic view of nature. Considering the forest as a complex adaptive system means overcoming the reductionist and mechanist paradigm and entails a shift towards a systemic approach in silviculture and forest management. The objectives and theoretical assumptions of classical forest regulation methods are discussed according to the new systemic paradigm. Managing forests as complex adaptive systems and sustaining their ability to adapt to future changes is possible only if there is also a change in forest management methods so that they are consistent with the new theoretical approach.

Solar Energy Harvesting with Carbon Nitrides and N‐Heterocyclic Frameworks: Do We Understand the Mechanism?

AbstractThe photocatalytic splitting of water into molecular hydrogen and molecular oxygen with sunlight is the dream reaction for solar energy conversion. For decades, transition metal oxide semiconductors and supramolecular organometallic structures have been extensively explored as photocatalysts for solar water splitting. More recently, polymeric materials consisting of triazine or heptazine building blocks have attracted considerable attention as hydrogen‐evolution photocatalysts. The mechanism of hydrogen evolution with these materials is discussed throughout the current literature in terms of the familiar concepts developed for photoelectrochemical water splitting with semiconductors since the 1970s. We discuss in this Minireview an alternative mechanistic paradigm for photoinduced water splitting with carbon nitrides, which focusses on the specific features of the photochemistry of aromatic N‐heterocycles in aqueous environments. Using ab initio electronic‐structure calculations, it is shown that a water molecule which is hydrogen‐bonded to an N‐heterocycle can be decomposed into hydrogen and hydroxyl radicals by two simple sequential photochemical reactions. This concept is illustrated by the discussion of excited‐state reaction paths and their energy profiles for hydrogen‐bonded complexes of pyridine, triazine and heptazine with a water molecule. It is shown that the excited‐state hydrogen‐transfer and hydrogen‐detachment reactions are essentially barrierless, in sharp contrast to water oxidation in the electronic ground state, where high barriers prevail. We also discuss in some detail the products of possible reactions of the highly reactive photogenerated hydroxyl radicals with the chromophores. We hypothesize that the challenge of efficient solar hydrogen generation with carbon nitride materials is less the decomposition of water as such, but rather the controlled recombination of the photogenerated radicals to the closed‐shell products H2 and H2O2.

A dynamic N6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors

N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates drug resistance remains unknown. Here we show that developing resistant phenotypes during tyrosine kinase inhibitor (TKI) therapy depends on m6A reduction resulting from FTO overexpression in leukemia cells. This deregulated FTO-m6A axis pre-exists in naïve cell populations that are genetically homogeneous and is inducible/reversible in response to TKI treatment. Cells with mRNA m6A hypomethylation and FTO upregulation demonstrate more TKI tolerance and higher growth rates in mice. Either genetic or pharmacological restoration of m6A methylation through FTO deactivation renders resistant cells sensitive to TKIs. Mechanistically, the FTO-dependent m6A demethylation enhances mRNA stability of proliferation/survival transcripts bearing m6A and subsequently leads to increased protein synthesis. Our findings identify a novel function for the m6A methylation in regulating cell fate decision and demonstrate that dynamic m6A methylome is an additional epigenetic driver of reversible TKI-tolerance state, providing a mechanistic paradigm for drug resistance in cancer.

Stereoselective oxidative glycosylation of anomeric nucleophiles with alcohols and carboxylic acids

Oligosaccharides, one of the most abundant biopolymers, are involved in numerous biological processes. Although many efforts have been put in preparative carbohydrate chemistry, achieving optimal anomeric and regioselectivities remains challenging. Herein we describe an oxidative glycosylation method between anomeric stannanes and oxygen nucleophiles resulting in the formation of a C−O bond with consistently high anomeric control for glycosyl donors bearing a free C2-hydroxyl group. These reactions are promoted by hypervalent iodine reagents with catalytic or stoichiometric amounts of Cu or Zn salts. The generality of this transformation is demonstrated in 42 examples. Mechanistic studies indicate that the oxidative glycosylation is initiated by the hydroxyl-guided delivery of the hypervalent iodine and tosylate into the anomeric position, and results in excellent 1,2-trans selectivity. The unique mechanistic paradigm, high selectivities, and mild reaction conditions make this method suitable for the synthesis of oligosaccharides and for integration with other methodologies such as automated synthesis.

The Hydrazine–O2 Redox Couple as a Platform for Organocatalytic Oxidation: Benzo[c]cinnoline‐Catalyzed Oxidation of Alkyl Halides to Aldehydes

AbstractAn organocatalytic oxidation platform that capitalizes on the capacity of hydrazines to undergo rapid autoxidation to diazenes is described. Commercially available benzo[c]cinnoline is shown to catalyze the oxidation of alkyl halides to aldehydes in a novel mechanistic paradigm involving nucleophilic attack, prototropic shift, and hydrolysis. The hydrolysis and reoxidation events occur readily with only adventitious oxygen and water. A survey of the scope of viable substrates is shown along with mechanistic and computational studies that give insight into this mode of catalysis.

The Hydrazine-O2 Redox Couple as a Platform for Organocatalytic Oxidation: Benzo[c]cinnoline-Catalyzed Oxidation of Alkyl Halides to Aldehydes.

An organocatalytic oxidation platform that capitalizes on the capacity of hydrazines to undergo rapid autoxidation to diazenes is described. Commercially available benzo[c]cinnoline is shown to catalyze the oxidation of alkyl halides to aldehydes in a novel mechanistic paradigm involving nucleophilic attack, prototropic shift, and hydrolysis. The hydrolysis and reoxidation events occur readily with only adventitious oxygen and water. A survey of the scope of viable substrates is shown along with mechanistic and computational studies that give insight into this mode of catalysis.

Activation of diverse carbon-heteroatom and carbon-carbon bonds via palladium(II)-catalysed β-X elimination.

Chemists' ability to synthesize structurally complex, high-value organic molecules from simple starting materials is limited by methods to selectively activate and functionalize strong alkyl C(sp3) covalent bonds. Recent activity has focused on the activation of abundant C-O, C-N and C-C bonds via a mechanistic paradigm of oxidative addition of a low-valent, electron-rich transition metal. This approach typically employs nickel(0), rhodium(I), ruthenium(0) and iron catalysts under conditions finely tuned for specific, electronically activated substrates, sometimes assisted by chelating functional groups or ring strain. By adopting a redox-neutral strategy involving palladium(II)-catalysed C-H activation followed by β-heteroatom/carbon elimination, we describe here a catalytic method to activate alkyl C(sp3)-oxygen, nitrogen, carbon, fluorine and sulfur bonds with high regioselectivity. Directed hydrofunctionalization of the resultant palladium(II)-bound alkene leads to formal functional group metathesis. The method is applied to amino acid upgrading with complete regioselectivity and moderate to high retention of enantiomeric excess. Low-strain heterocycles undergo strong-bond activation and substitution, giving ring-opened products.

Theoretical Investigations on the Mechanistic Aspects of O2 Activation by a Biomimetic Dinitrosyl Iron Complex.

Though dinitrosyl-iron complexes (DNICs) are largely believed to act as NO carriers, several experiments on model DNICs have suggested that they can also act as nitrating agents in presence of dioxygen. Oxygen activation by DNICs has been implicated as a possible route for protein tyrosine nitration (PTN), which leads to neurodegenerative disorders. Herein using static and dynamic theoretical techniques we unravel a previously unknown dual state mechanistic paradigm for dioxygen activation of a biomimetic nitrating DNIC complex leading to phenolic nitration. Our computations reveal that the model DNIC, the ground electronic state of which is singlet, has a low-lying triplet state and an inherent singlet-triplet spin-crossover of DNICs can be triggered by fluxional changes in the bite angle of the two NO ligands. The presence of a low-lying triplet state in the DNIC affords an avenue for O2 activation other than a direct O2 activation by O2 -induced spin-crossover of the singlet ground state. These two low-lying channels facilitate the formation of a peroxynitrite species. Nitration of phenolic substrates is facilitated by the release of NO2 . The corresponding minimum energy crossing points (MECP) have been located. Along the reaction path, the changes in the electronic structure scenarios have been studied and interpreted. Our report also sheds light on the plausible mechanistic pathway of PTN by reactive species formed once O2 activation by DNICs have been achieved.

Facilitated Unbinding via Multivalency-Enabled Ternary Complexes: New Paradigm for Protein-DNA Interactions.

Dynamic protein-DNA interactions constitute highly robust cellular machineries to fulfill cellular functions. A vast number of studies have focused on how DNA-binding proteins search for and interact with their target DNA segments and on what cellular cues can regulate protein binding, for which protein concentration is a most obvious one. In contrast, how protein unbinding could be regulated by protein concentration has evaded attention because protein unbinding from DNA is typically a unimolecular reaction and thus concentration independent. Recent single-molecule studies from multiple research groups have uncovered that protein concentration can facilitate the unbinding of DNA-bound proteins, revealing regulation of protein unbinding as another mechanistic paradigm for gene regulation. In this Account, we review these recent in vitro and in vivo single-molecule experiments that uncovered the concentration-facilitated protein unbinding by multiple types of DNA-binding proteins, including sequence-nonspecific DNA-binding proteins (e.g., nucleoid-associated proteins, NAP), sequence-specific DNA-binding proteins (e.g., metal-responsive transcription regulators CueR and ZntR), sequence-neutral single-stranded DNA-binding proteins (e.g., Replication protein A, RPA), and DNA polymerases. For the in vitro experiments, Marko's group investigated the exchange of GFP-tagged DNA-bound NAPs with nontagged NAPs in solution of increasing concentration using single-molecule magnetic-tweezers fluorescence microscopy. The faster fluorescence intensity decrease with higher nontagged NAP concentrations suggests that DNA-bound NAPs undergo faster exchange with higher free NAP concentrations. Chen's group used single-molecule fluorescence resonance energy transfer measurements to study the unbinding of CueR from its cognate oligomeric DNA. The average microscopic dwell times of DNA-bound states become shorter with increasing CueR concentrations in the surroundings, demonstrating that free CueR proteins can facilitate the unbinding of the incumbent one on DNA through either assisted dissociation or direct substitution. Greene's group studied the unbinding of RPAs from single-stranded DNA using total internal reflection fluorescence microscopy and DNA curtain techniques. The fluorescence intensity versus time traces show faster decay with higher wild-type RPA concentrations, indicating that DNA-bound RPAs can undergo a concentration-facilitated exchange when encountering excess free RPA. van Oijen's group investigated the leading/lagging-strand polymerase exchange events in the bacteriophage T7 and E. coli replication systems using a combination of single-molecule fluorescence microscopy and DNA-flow-stretching assay. The processivity was observed to have larger decrease when the concentration of the Y526F polymerase mutant increases, indicating that the unbinding of the polymerase is also concentration-dependent. Using stroboscopic imaging and single-molecule tracking, Chen's group further advanced their study into living bacterial cells. They found CueR, as well as its homologue ZntR, shows concentration-enhanced unbinding from its DNA-binding site in vivo. Mechanistic consensus has emerged from these in vitro and in vivo single-molecule studies that encompass a range of proteins with distinct biological functions. It involves multivalent contacts between protein and DNA. The multivalency enables the formation of ternary complexes as intermediates, which subsequently give rise to concentration-enhanced protein unbinding. As multivalent contacts are ubiquitous among DNA-interacting proteins, this multivalency-enabled facilitated unbinding mechanism thus provides a potentially general mechanistic paradigm in regulating protein-DNA interactions.

Modelling gene regulation: (De)compositional and template-based strategies

Although the interdisciplinary nature of contemporary biological sciences has been addressed by philosophers, historians, and sociologists of science, the different ways in which engineering concepts and methods have been applied in biology have been somewhat neglected. We examine – using the mechanistic philosophy of science as an analytic springboard – the transfer of network methods from engineering to biology through the cases of two biology laboratories operating at the California Institute of Technology. The two laboratories study gene regulatory networks, but in remarkably different ways. The research strategy of the Davidson lab fits squarely into the traditional mechanist philosophy in its aim to decompose and reconstruct, in detail, gene regulatory networks of a chosen model organism. In contrast, the Elowitz lab constructs minimal models that do not attempt to represent any particular naturally evolved genetic circuits. Instead, it studies the principles of gene regulation through a template-based approach that is applicable to any kinds of networks, whether biological or not. We call for the mechanists to consider whether the latter approach can be accommodated by the mechanistic approach, and what kinds of modifications it would imply for the mechanistic paradigm of explanation, if it were to address modelling more generally.

The role of gap junctions in disease and potential treatment approaches

Our research program is engaged in examining the over two dozen distinct human diseases linked to genes that encode the proteins (connexins) used in gap junctional intercellular communication. Mutations in 50% of the 21 connexin gene family members result in conditions ranging from developmental abnormalities that include hearing loss to life-shortening organ failure. We use a multidimensional approach involving organotypic cultures, genetically-modified mice, connexinlinked disease patient cells and human inducible pluripotent stem cells to interrogate the scope of mechanisms that lead to disease in some tissues while other organs are spared. In principal, connexins are linked to disease or injury repair through three different mechanistic paradigms.

Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1

Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responseslinked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 andrestrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.

Reconsidering disaster resilience: a nonlinear systems paradigm in agricultural communities in Southern Africa

Disasters continue to have a dramatic impact on lives, livelihoods and environments communities depend on. In response to these losses, the global community has developed various theories, assessment methodologies and policies aimed at reducing global losses. A contemporary outcome of these interventions is to build the disaster resilience. However, despite the disaster resilience-building endeavours espoused by policies, theories and methodologies, very little progress is being made in reducing disaster losses. This paper argues that a possible reason behind the limitations of current resilience-building policies and methodologies could be that most of these policies are based a mechanistic scientific paradigm that places an emphasis on system components that are perceived to build resilience and not the function of systems as a whole. This often leads to resilience-building initiatives that are based on a ‘one-size-fits-all’ approach. This paper argues for the use of a complex adaptive systems approach to building resilience. This approach argues that contextual factors within different social systems will have a nonlinear affect on disaster resilience-building efforts. Therefore, it is crucial to move away from ‘one-size-fits-all’ approaches to more flexible approaches to building resilience. These hypotheses are tested by means of a correlation statistical analysis of agricultural communities in Southern Africa. Results of this analysis indicate that unique resilience profiles are evident in almost all of the communities studied. This indicates that resilience is not the same for everybody, and that resilience-building endeavours should be flexible enough to be adapted for different contexts.

On the Benefit of a Phenomenological Revision of Problem Solving

AbstractProblem solving has been empirical psychology’s concern for half a century. Cognitive science’s work on this field has been stimulated especially by the computational theory of mind. As a result, most experimental research originates from a mechanistic approach that disregards genuine experience. On the occasion of a review of problem solving’s foundation, a phenomenological description offers fruitful perspectives. Yet, the mechanistic paradigm is currently dominant throughout problem solving’s established patterns of description. The review starts with a critical historical analysis of the state of problem solving in academic psychology. Subsequently, a phenomenological, contrastive approach is proposed. It questions the notion of problems as “goal-driven” behavior by making vivid experience the subject of discussion. As its given compounds, solvability, oppressiveness, and the problem’s horizon are discussed. Ultimately, an experience-based multimodal notion of the problem is elaborated that relates problems to challenges, fatalities and opportunities as different types of situations.

Toward common mechanisms for risk factors in Alzheimer's syndrome

The global strategic goal of reducing health care cost, especially the prospects for massive increases due to expanding markets for health care services demanded by aging populations and/or people with a wide range of chronic disorders-disabilities, is a complex and formidable challenge with many facets. Current projections predict marked increases in the demand for health driven by both the exponential climb in the prevalence of chronic disabilities and the increases in the absolute numbers of people in need of some form of health care. Thus, the looming predicament for the economics of health care systems worldwide mandates the formulation of a strategic goal to foster significant expansion of global R&D efforts to discover and develop wide-ranging interventions to delay and/or prevent the onset of chronic disabling conditions. The rationale for adopting such a tactical objective is based on the premise that the costs and prevalence of chronic disabling conditions will be reduced by half even if a modest delay of 5 years in the onset of disability is obtained by a highly focused multinational research initiative. Because of the recent history of many failures in drug trials, the central thesis of this paper is to argue for the exploration-adoption of novel mechanistic ideas, theories, and paradigms for developing wide range and/or types of interventions. Although the primary focus of our discussion has been on biological approaches to therapy, we recognize the importance of emerging knowledge on nonpharmacological interventions and their potential impact in reducing health care costs. Although we may not find a drug to cure or prevent dementia for a long time, research is starting to demonstrate the potential contributes of nonpharmacological interventions toward the economics of health care in terms of rehabilitation, promoting autonomy, and potential to delay institutionalization, thus promoting healthy aging and reductions in the cost of care.

Neuroendocrine disruption without direct endocrine mode of action: Polychloro-biphenyls (PCBs) and bisphenol A (BPA) as case studies

Endocrine disruption is commonly thought to be restricted to a direct endocrine mode of action i.e. the perturbation of the activation of a given type of hormonal receptor by its natural ligand. Consistent with the WHO definition of an endocrine disrupter, a key issue is the “altered function(s) of the endocrine system”. Such altered functions can result from different chemical interactions, beyond agonistic or antagonistic effect at a given receptor. Based on neuroendocrine disruption by polychlorinated biphenyls and bisphenol A, this paper proposes different mechanistic paradigms that can result in adverse health effects. They are a consequence of altered endocrine function(s) secondary to chemical interaction with different steps in the physiological regulatory processes, thus accounting for a possibly indirect endocrine mode of action.

Synthesis of Complex Glycolates by Enantioconvergent Addition Reactions.

The unique role that stereochemistry plays in molecular recognition events continues to provide a driving force for synthesizing organic compounds in enantioenriched form. The tendency of enantioenriched organic compounds to revert to an entropically favored racemic state in the presence of viable racemization pathways (e.g., the enolization of stereogenic carbonyl derivatives) can sometimes interfere with this objective; however, beginning with Noyori's foundational disclosure of a dynamic kinetic transfer hydrogenation, the ability to channel racemic, configurationally labile starting materials through stereoconvergent reaction pathways has been recognized as a powerful strategy in asymmetric synthesis. Proton transfer, retro-aldol, retro-Michael, reversible redox events, and other processes that can be deleterious to asymmetric synthesis are exploitable in enantioconvergent reactions using chiral small molecules and enzymes as asymmetric catalysts. Enantioselective reduction of configurationally labile carbonyl derivatives bearing a C-H acidic chiral center are particularly common. Because facile racemization is vital to stereocontrol in these transformations, hydrogenations of β-dicarbonyls are commonplace, while less activated substrates have been used less commonly. Our entry into enantioconvergent catalysis evolved from a long-standing interest in the synthesis of complex glycolates and began with the development of a general Noyori-type transfer hydrogenation of α-keto esters. Key innovations in this work include the identification of a new terphenylsulfonamide-Ru(II) complex, which displays unusual preference toward reduction of α-keto esters, and the observation that α-keto esters racemize under mildly basic conditions. This work was extended to the dynamic kinetic hydrogenation of racemic acyl phosphonates. Moreover, the recent recognition that the mechanistic paradigm underlying enantioconvergent hydrogenation chemistry can be extended to diverse carbon-centered nucleophiles has led to advances in the art. Our lab has developed a number of enantioconvergent tertiary alcohol syntheses. In the context of carbon-centered nucleophiles, we have focused on the use of α-keto esters; however, in the latter part of this Account, we will briefly describe our nascent efforts to develop dynamic kinetic additions of carbon-centered nucleophiles to β-oxo acid derivatives. While the enantioconvergent hydrogenation of β-keto acid derivatives is carried out on 100-ton scale annually, non-hydrogenative transformations of these compounds constitute an underexplored subclass of enantioconvergent reactions. With regard to future prospects, a trend toward transformations that afford increasing levels of molecular complexity is apparent. It can be expected that the burgeoning field of asymmetric 1,2-addition chemistry will further drive this chemistry to encompass a wider array of enantioconvergent additions. Additionally, the continued exploration of these chemistries in the context of less conventional electrophiles, as well as identifying novel or overlooked modes of racemization, holds considerable potential.

Catalytic Enantioselective Carbonyl Allylation and Propargylation via Alcohol-Mediated Hydrogen Transfer: Merging the Chemistry of Grignard and Sabatier.

Merging the characteristics of transfer hydrogenation and carbonyl addition, we have developed a new class of catalytic enantioselective C-C bond formations. In these processes, hydrogen transfer between alcohols and π-unsaturated reactants generates carbonyl-organometal pairs that combine to deliver products of addition. On the basis of this mechanistic paradigm, lower alcohols are converted directly to higher alcohols in the absence of premetalated reagents or discrete alcohol-to-carbonyl redox reactions. In certain cases, due to a pronounced kinetic preference for primary versus secondary alcohol dehydrogenation, diols and higher polyols are found to engage in catalytic stereo- and site-selective C-C bond formation-a capability that further enhances efficiency by enabling skeletal construction events without extraneous manipulations devoted to the installation and removal of protecting groups. While this Account focuses on redox-neutral couplings of alcohols, corresponding aldehyde reductive couplings mediated by 2-propanol were developed in parallel for most of the catalytic transformations reported herein. Mechanistically, two distinct classes of alcohol C-H functionalizations have emerged, which are distinguished by the mode of pronucleophile activation, specifically, processes wherein alcohol oxidation is balanced by (a) π-bond hydrometalation or (b) C-X bond reductive cleavage. Each pathway offers access to allylmetal or allenylmetal intermediates and, therefrom, enantiomerically enriched homoallylic or homopropargylic alcohol products, respectively. In the broadest terms, carbonyl addition mediated by premetalated reagents has played a central role in synthetic organic chemistry for well over a century, but the requisite organometallic reagents pose issues of safety, require multistep syntheses, and generate stoichiometric quantities of metallic byproducts. The concepts and catalytic processes described in this Account, conceived and developed wholly within the author's laboratory, signal a departure from the use of stoichiometric organometallic reagents in carbonyl addition. Rather, they reimagine carbonyl addition as a hydrogen autotransfer process or cross-coupling in which alcohol reactants, by virtue of their native reducing ability, drive the generation of transient organometallic nucleophiles and, in doing so, serve dually as carbonyl proelectrophiles. The catalytic allylative and propargylative transformations developed to date display capabilities far beyond their classical counterparts, and their application to the total synthesis of type-I polyketide natural products have evoked a step-change in efficiency. More importantly, the present data suggest that diverse transformations traditionally reliant on premetalated reagents may now be conducted catalytically without stoichiometric metals. This Account provides the reader and potential practitioner with a catalog of enantioselective alcohol-mediated carbonyl additions-a user's guide, 10-year retrospective, and foundation for future work in this emerging area of catalytic C-C bond formation.

Sequence and Functional Diversity Across the Kinesin Superfamily

Members of the kinesin superfamily are defined by the presence a kinesin motor domain containing signature sequences for nucleotide and microtubule binding. A variety of biochemical and biophysical studies of the core kinesin-1 motor domain have illuminated how nucleotide binding and hydrolysis lead to force generation and motility along microtubules. Alternating catalysis by the two motor domains enables processive motility along the microtubule surface. It has been assumed that this is the mechanistic paradigm for all kinesin motors. However, recent work indicates that sequence divergence within the kinesin motor domain endows different kinesin motors with distinct microtubule-based properties. We examined how evolutionary tuning of the core motor domain endowed kinesin-3 motors with a high microtubule on-rate, high velocity, and superprocessivity. We also examined sequence divergence within the kinesin-4 family of motors such that some members of this family lost the ability to undergo processive motility.