Lagrange’s theory of analytical functions and his ideal of purity of method

We reconstruct essential features of Lagrange’s theory of analytical functions by exhibiting its structure and basic assumptions, as well as its main shortcomings. We explain Lagrange’s notions of function and algebraic quantity, and we concentrate on power-series expansions, on the algorithm for derivative functions, and the remainder theorem—especially on the role this theorem has in solving geometric and mechanical problems. We thus aim to provide a better understanding of Enlightenment mathematics and to show that the foundations of mathematics did not, for Lagrange, concern the solidity of its ultimate bases, but rather purity of method—the generality and internal organization of the discipline.     

Structural features underlying the selectivity of the kinase inhibitors NBC and dNBC: role of a nitro group that discriminates between CK2 and DYRK1A

8-hydroxy-4-methyl-9-nitrobenzo(g)chromen-2-one (NBC) has been found to be a fairly potent ATP site-directed inhibitor of protein kinase CK2 (Ki = 0.22 μM). Here, we show that NBC also inhibits PIM kinases, especially PIM1 and PIM3, the latter as potently as CK2. Upon removal of the nitro group, to give 8-hydroxy-4-methyl-benzo(g)chromen-2-one (here referred to as “denitro NBC”, dNBC), the inhibitory power toward CK2 is almost entirely lost (IC₅₀ > 30 μM) whereas that toward PIM1 and PIM3 is maintained; in addition, dNBC is a potent inhibitor of a number of other kinases that are weakly inhibited or unaffected by NBC, with special reference to DYRK1A whose IC₅₀ values with NBC and dNBC are 15 and 0.60 μM, respectively. Therefore, the observation that NBC, unlike dNBC, is a potent inducer of apoptosis is consistent with the notion that this effect is mediated by inhibition of endogenous CK2. The structural features underlying NBC selectivity have been revealed by inspecting its 3D structure in complex with the catalytic subunit of Z. mays CK2. The crucial role of the nitro group is exerted both through a direct electrostatic interaction with the side chain of Lys68 and, indirectly, by enhancing the acidic dissociation constant of the adjacent hydroxyl group which interacts with a conserved water molecule in the deepest part of the cavity. By contrast, the very same nitro group is deleterious for the binding to the active site of DYRK1A, as disclosed by molecular docking. This provides the rationale for preferential inhibition of DYRK1A by dNBC.     

Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor α: when one is better than two

Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB₂) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB₂ and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB₂ and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRβ, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB₂, but not GRα. Overall, our study demonstrates for the first time the existence of a CB₂-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB₂ as a new target for chronic inflammatory and neurodegenerative diseases.     

A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures

We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes.     

Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes

Oligodendrocytes myelinate axons for rapid impulse conduction and contribute to normal axonal functions in the central nervous system. In multiple sclerosis, demyelination is caused by autoimmune attacks, but the role of oligodendroglial cells in disease progression and axon degeneration is unclear. Here we show that oligodendrocytes harbor peroxisomes whose function is essential for maintaining white matter tracts throughout adult life. By selectively inactivating the import factor PEX5 in myelinating glia, we generated mutant mice that developed normally, but within several months showed ataxia, tremor and premature death. Absence of functional peroxisomes from oligodendrocytes caused widespread axonal degeneration and progressive subcortical demyelination, but did not interfere with glial survival. Moreover, it caused a strong proinflammatory milieu and, unexpectedly, the infiltration of B and activated CD8+ T cells into brain lesions. We conclude that peroxisomes provide oligodendrocytes with an essential neuroprotective function against axon degeneration and neuroinflammation, which is relevant for human demyelinating diseases.     

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.     

Design and analysis of the green climate fund

The Green Climate Fund （GCF） has been one of the core issues of the world climate summits under the United Nations Framework Convention on Climate Change （UNFCCC） in recent years. However, the GCF has not progressed smoothly, and currently there are no satisfactory schemes for raising and distributing the fund. This paper first discusses how to finance the GCF among Annex II countries. It introduces the ＇preference score compromises＇ （PSC） approach which is based on environmental responsibility and economic capacity, with historical emissions as an indicator for environmental responsibility and GDP as indicator for economic capacity. The results show that the United States and the European Union are the two largest contributors to the GCF, sponsoring more than 80% of the funds. Second, we discuss how to allocate the funds among non-Annex II parties. The ＇adaptation needs＇ （AN） approach, which takes account of economic strength and climate damages, is proposed to achieve the adaptation purpose of the GCF, and the results reveal that African countries with high levels of climate vulnerability could get most funds, with a share of almost 30%. Regarding the mitigation purpose of the GCF, this research introduces two approaches： the ＇carbon reduction contribution＇ （CC） approach and the ＇incremental cost＇ （IC） approach. Both approaches could achieve significant reductions in carbon emissions in non-Annex II parties, whereas the latter may provide limited adaptation finance but result in more mitigation effects. This paper also develops a method to combine abatement efficiency and adaptation fairness of the GCF, and we find that with an equal split between the AN and CC （or AN and IC） approaches, the amount of USD 100 billion could finance an emissions reduction of 1613 MtCO2 （2477 MtCO2）, while allocating USD 16 （or USD 9） per capita for adaptation in non-Annex II parties. The schemes proposed may be useful for promoting the development of the GCF in the future.     

A Process Model of Collaborative Management Research: The Study of Collective Creativity in the Luxury Industry

This article explores collaborative management research (CMR). As one of the streams within the action research family, CMR is one approach that has been identified as a potent method for advancing scientific knowledge and bringing about change in organizations. The article proposes a hybrid model of the CMR research process in organizations. Following a brief introduction of collaborative management research, we advance an emerging, inductively derived, hybrid process model of CMR. Three critical clusters for achieving the intended outcomes of collaborative management research include: (1) contextual factors, (2) quality of the collaboration, and (3) the development of the collaborative research process itself. Within each cluster, concepts, variables, and processes were identified and linked together to form a hybrid model of CMR process. An illustration of a collaborative management research project that focused on the study of collective creativity with an Italian fashion and design company is followed by a reflective analysis. The discussion provides directions for future research and implications for practice.     

DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1

A single double-strand break (DSB) induced by HO endonuclease triggers both repair by homologous recombination and activation of the Mec1-dependent DNA damage checkpoint in budding yeast. Here we report that DNA damage checkpoint activation by a DSB requires the cyclin-dependent kinase CDK1 (Cdc28) in budding yeast. CDK1 is also required for DSB-induced homologous recombination at any cell cycle stage. Inhibition of homologous recombination by using an analogue-sensitive CDK1 protein results in a compensatory increase in non-homologous end joining. CDK1 is required for efficient 5' to 3' resection of DSB ends and for the recruitment of both the single-stranded DNA-binding complex, RPA, and the Rad51 recombination protein. In contrast, Mre11 protein, part of the MRX complex, accumulates at unresected DSB ends. CDK1 is not required when the DNA damage checkpoint is initiated by lesions that are processed by nucleotide excision repair. Maintenance of the DSB-induced checkpoint requires continuing CDK1 activity that ensures continuing end resection. CDK1 is also important for a later step in homologous recombination, after strand invasion and before the initiation of new DNA synthesis.