Exogenous Ligand-Free Nickel-Catalyzed Carboxylate O-Arylation:Insight into Ni^I/Ni^III Cycles**

Nickel-catalyzed cross-coupling reactions have become a powerful methodology to construct C-heteroatom bonds. However, many protocols suffer from competitive off-cycle reaction pathways and require non-equimolar amounts of coupling partners to suppress them. Here, we report on mechanistic examination of carboxylate O-arylation under thermal conditions, in both the presence and absence of an exogeneous bipyridine-ligand. Furthermore, spectroscopic studies of the novel ligand-free carboxylate O-arylation reaction unveiled the resting state of the nickel catalyst, the crucial role of the alkylamine base and the formation of an off-cycle NiI−NiII dimer upon reduction. This study provides insights into the competition between productive catalysis and deleterious pathways (comproportionation and protodehalogenation) in the commonly proposed self-sustained NiI/NiIII catalytic cycle. Thereby we show that for productive nickel-catalyzed carboxylate O-arylation a choice must be made between either mild conditions or equimolar ratios of substrates

Mechanistic elucidation of monoalkyltin(iv)-catalyzed esterification

Monoalkyltin(iv) complexes are well-known catalysts for esterification reactions and polyester formation, yet the mode of operation of these Lewis acidic complexes is still unknown. Here, we report on mechanistic studies of n-butylstannoic acid in stoichiometric and catalytic reactions, analyzed by NMR, IR and MS techniques. While the chemistry of n-butyltin(iv) carboxylates is dominated by formation of multinuclear tin assemblies, we found that under catalytically relevant conditions only monomeric n-BuSn(OAc)(3) and dimeric (n-BuSnOAc(2)OEt)(2) are present. Density functional theory (DFT) calculations provide support for a mononuclear mechanism, where n-BuSn(OAc)(3) and dimeric (n-BuSnOAc(2)OEt)(2) are regarded as off-cycle species, and suggest that carbon–oxygen bond breaking is the rate-determining step

Protein disulfide isomerases as CSF biomarkers for the neuronal response to tau pathology

Introduction: Cerebrospinal fluid (CSF) biomarkers for specific cellular disease processes are lacking for tauopathies. In this translational study we aimed to identify CSF biomarkers reflecting early tau pathology-associated unfolded protein response (UPR) activation. Methods: We employed mass spectrometry proteomics and targeted immunoanalysis in a combination of biomarker discovery in primary mouse neurons in vitro and validation in patient CSF from two independent large multicentre cohorts (EMIF-AD MBD, n = 310; PRIDE, n = 771). Results: First, we identify members of the protein disulfide isomerase (PDI) family in the neuronal UPR-activated secretome and validate secretion upon tau aggregation in vitro. Next, we demonstrate that PDIA1 and PDIA3 levels correlate with total- and phosphorylated-tau levels in CSF. PDIA1 levels are increased in CSF from AD patients compared to controls and patients with tau-unrelated frontotemporal and Lewy body dementia (LBD). Highlights: Neuronal unfolded protein response (UPR) activation induces the secretion of protein disulfide isomerases (PDIs) in vitro. PDIA1 is secreted upon tau aggregation in neurons in vitro. PDIA1 and PDIA3 levels correlate with total and phosphorylated tau levels in CSF. PDIA1 levels are increased in CSF from Alzheimer's disease (AD) patients compared to controls. PDIA1 levels are not increased in CSF from tau-unrelated frontotemporal dementia (FTD) and Lewy body dementia (LBD) patients

Plangebied Nieuweweg 222-226 te Veenendaal, gemeente Veenendaal; Archeologisch vooronderzoek (bureauonderzoek en inventariserend veldonderzoek; verkennend booronderzoek) en cultuurhistorische analyse

In opdracht van C.V. Nieuwendijk heeft RAAP in de periode april-juni 2021 een archeologisch vooronderzoek in de vorm van een bureauonderzoek en inventariserend veldonderzoek (verkennend booronderzoek) en cultuurhistorische analyse uitgevoerd voor het plangebied Nieuweweg 222-226 te Veenendaal. Het onderzoek vond plaats in het kader van een omgevingsvergunningsaanvraag. Archeologisch bureauonderzoek Op basis van het archeologisch bureauonderzoek en de cultuurhistorische gebiedsontwikkeling bestond de volgende archeologische verwachting. In directe omgeving van het plangebied komen mogelijk gradiëntsituaties voor in het overgangsgebied van delen van de stuwwal naar lager gelegen gebied, terwijl het plangebied in zulke laatstgenoemde relatief natte zones lijkt te hebben gelegen. Voor het plangebied bestond een lage-middelhoge archeologische verwachting voor archeologische resten uit het midden paleolithicum tot het neolithicum B. Voor het plangebied bestond eveneens een lage-middelhoge archeologische verwachting voor archeologische resten uit de periode dat akkerbouw werd bedreven vanaf het neolithicum B tot en met de nieuwe tijd (top van dekzand). Verkennend archeologisch booronderzoek Op basis van het verkennend archeologisch booronderzoek blijkt de bodemopbouw van het dekzand niet intact. Er zijn geen tekenen van bodemvorming in het dekzand waargenomen, terwijl recente verstoringen en mogelijk ook natuurlijke processen zoals verspoeling aan de aangetroffen bodemopbouw hebben bijgedragen. Tijdens het onderzoek zijn geen overduidelijk gestuwde afzettingen aangetroffen en het lijkt waarschijnlijk dat het plangebied deel was van een relatief nat en lager gelegen plateau aan de rand van de stuwwal Groot Venlo. Op basis van deze resultaten kan de archeologische verwachting voor het paleolithicum-nieuwe tijd voor de top van het dekzand in het plangebied als laag worden bestempeld. De lagen die (van boven naar beneden) boven het dekzand zijn aangetroffen (recent opgebrachte grond, verstoorde grond, antropogeen pakket/oude akkerlaag, veen- en/of leemlaag) gaan eveneens gepaard met een lage archeologische verwachting voor bewoningssporen uit deze periode. Cultuurhistorische analyse Op basis van het cultuurhistorisch onderzoek kan worden geconcludeerd dat het plangebied aan een historisch lint ligt dat een oude (middeleeuwse) oorsprong heeft. De Nieuweweg als geheel heeft daarmee een hoge cultuurhistorische waarde. Het plangebied met daarin de twee grootschalige kantoorgebouwen ligt aan een ‘verstoord’ deel van deze Nieuweweg, die is ontstaan door de aanleg van de A12, de aanleg van een stelsel van rondwegen (inclusief de Grote Beer), de invulling van de restruimte tussen stad en snelweg met een bedrijventerrein, en een stedenbouwkundige visie uit de jaren tachtig waarin op deze locatie een markant gebouw moest komen. De bebouwing is de ‘uitkomst’ van deze ontwikkeling, die nog relatief recent is en waar op dit moment een lage/indifferente waardering aan toegekend kan worden. De huidige bebouwing in het plangebied heeft enige waarde als voorbeeld van kantoorbouw uit de jaren tachtig met toepassing van isolerende spiegelbeglazing. Van de architect zijn in het kader van dit onderzoek geen andere werken aangetroffen, over zijn oeuvre is niets bekend

The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity.

The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed picture of how RAG expression is regulated is lacking. In particular the transcriptional targets and specific functions of the various transcription factors are unclear. Jun was the first regeneration-associated transcription factor identified and the first shown to be functionally important. Here we fully define the role of Jun in the RAG expression program in regenerating facial motor neurons. At 1, 4, and 14 days after axotomy, Jun upregulates 11%, 23% and 44% of the RAG program, respectively. Jun functions relevant to regeneration include cytoskeleton production, metabolic functions and cell activation, and the down-regulation of neurotransmission machinery. In silico analysis of promoter regions of Jun targets identifies stronger over-representation of AP1-like sites than CRE-like sites, although CRE sites were also over-represented in regions flanking AP1 sites. Strikingly, in motor neurons lacking Jun, an alternative SRF-dependent gene expression program is initiated after axotomy. The promoters of these newly expressed genes exhibit over-representation of CRE sites in regions near to SRF target sites. This alternative gene expression program includes plasticity-associated transcription factors, and leads to an aberrant early increase in synapse density on motor neurons. Jun thus has the important function in the early phase after axotomy of pushing the injured neuron away from a plasticity response and towards a regenerative phenotype

Catalytic synthesis of 1H-2-benzoxocins; Cobalt(III)-carbene radical approach to 8-membered heterocyclic enol ethers

The metallo-radical activation of ortho-allylcarbonyl-aryl N-arylsulfonylhydrazones with the paramagnetic cobalt(II) porphyrin catalyst [Co^II(TPP)] (TPP = tetraphenylporphyrin) provides an efficient and powerful method for the synthesis of novel 8-membered heterocyclic enol ethers. The synthetic protocol is versatile, practical and enables the synthesis of a wide range of unique 1H-2-benzoxocins in high yields. The catalytic cyclization reactions proceed with excellent chemoselectivities, have a high functional group tolerance, and provide several opportunities for the synthesis of new bioactive compounds. The reactions are shown to proceed via cobalt(III)-carbene radical intermediates, which are in-volved in intramolecular hydrogen transfer (HAT) from the allylic position to the carbene radical, followed by a near barrierless radical rebound step in the coordination sphere of cobalt. The proposed mechanism is supported by experi-mental observations, density functional theory (DFT) calculations and spin trapping experiments

Kinetic studies on Lewis acidic metal polyesterification catalysts - hydrolytic degradation is a key factor for catalytic performance

Kinetic analysis of polyesterification reactions using Lewis-acidic metal catalysts have been performed. While Sn-based catalysts are superior to Ti-based catalysts under neat polycondensation conditions (high [H2O]), the result is inverted under azeotropic conditions (low [H2O]). These findings show that the catalytic activity is crucially determined by the robustness of the catalyst against hydrolytic degradation

Ligand-free Nickel-catalyzed carboxylate O-arylation: Mechanistic in-sight into NiI/NiIII cycles

Nickel-catalyzed cross-coupling reactions have become a powerful methodology to construct C–heteroatom bonds. How-ever, many protocols suffer from competitive off-cycle reaction pathways and require non-equimolar amounts of cou-pling partners to suppress them. Here, we report on mechanistic examination of carboxylate O-arylation under thermal conditions, in both the presence and absence of an exogeneous bipyridine-ligand. Furthermore, spectroscopic studies of the novel ligand-free carboxylate O-arylation reaction unveiled the resting state of the nickel catalyst, the crucial role of the alkylamine base and the formation of a catalytically relevant NiI–NiII dimer upon reduction. This study provides in-sights into the competition between productive catalysis and deleterious pathways (comproportionation and pro-todehalogenation) that exist for all elementary steps in the commonly proposed self-sustained NiI/NiIII catalytic cycle. Thereby we show that for productive nickel-catalyzed carboxylate O-arylation a choice must be made between either mild conditions or equimolar ratios of substrates

No evidence for cell-to-cell transmission of the unfolded protein response in cell culture

The unfolded protein response (UPR) is one of the major cell-autonomous proteostatic stress responses. The UPR has been implicated in the pathogenesis of neurodegenerative diseases and is therefore actively investigated as therapeutic target. In this respect, cell non-autonomous effects of the UPR including the reported cell-to-cell transmission of UPR activity may be highly important. A pharmaca-based UPR induction was employed to generate conditioned media (CM) from CM-donating neuronal (‘donor’) cells (SK-N-SH and primary mouse neurons). As previously reported, upon subsequent transfer of CM to naive neuronal ‘acceptor’ cells, we confirmed UPR target mRNA and protein expression by qPCR and automated microscopy. However, UPR target gene expression was also induced in the absence of donor cells, indicating carry-over of pharmaca. Genetic induction of single pathways of the UPR in donor cells did not result in UPR transmission to acceptor cells. Moreover, no transmission was detected upon full UPR activation by nutrient deprivation or inducible expression of the heavy chain of immunoglobulin M in donor HeLa cells. In addition, in direct co-culture of donor cells expressing the immunoglobulin M heavy chain and fluorescent UPR reporter acceptor HeLa cells, UPR transmission was not observed. In conclusion, carry-over of pharmaca is a major confounding factor in pharmaca-based UPR transmission protocols that are therefore unsuitable to study cell-to-cell UPR transmission. In addition, the absence of UPR transmission in non-pharmaca-based models of UPR activation indicates that cell-to-cell UPR transmission does not occur in cell culture. (Figure presented.)