Regioselective catalytic acetoxylation of limonene

Two efficient strategies for a direct catalytic and regioselective acetoxylation of terpenes are described. Acetoxylated limonene derivatives were synthesized via palladium-catalyzed C-H activation utilizing para-benzoquinone (BQ) as reoxdidation agent and acetic acid as solvent and reactant. Addition of dimethyl sulfoxide (DMSO) to the catalytic system led to highly selective functionalization of the exocyclic double bond of limonene. This catalytic acetoxylation of limonene was further optimized with regard to a more sustainable and environmentally-friendly procedure. On the other hand{,} the use of an aerobic tandem catalytic system using iron(ii) phthalocyanine (Fe(Pc)) as co-catalyst{,} which acts as electron transfer mediator (ETM){,} enabled a highly selective acetoxylation of the endocyclic double bond of limonene with high conversions. Moreover{,} diacetoxylated products were prepared by a reaction sequence applying the aforementioned catalytic systems

The posterior communicating artery: morphometric study in 3D angio-computed tomography reconstruction. The proof of the mathematical definition of the hypoplasia

Background: The aim of this study was to investigate the morphometry of the posterior communicating artery (PCoA), on the basis of angio-computed tomography (CT), and to give proof of the mathematical definition of the term “hypopal sia of the PCoA“.Materials and methods: One hundred 3-dimensional (3D) angio-CT images, performed in adult patients with bilateral reconstruction of the PCoA (200 results) were used tocalculate the morphometry of the vessel.Results: The average length of the vessel on the right side was 14.48 ± 3.47 mm, andon the left side 14.98 ± 4.77 mm (in women 14.75 mm, in men 14.70 mm). The mean of the diameter at the “proximal” point (the junction with P1) on the right side was 1.49 ± 0.51 mm, and on the left 1.46 ± 0.47 mm (in women 1.44 mm and in men 1.51 mm). The mean of the diameter in the “distal” part (the connection with ICA) on the right side was 1.4 ± 0.49 mm, and on the left 1.37 ± 0.41 mm (in women 1.38 mm, and in men 1.39 mm). No statistical correlation between the length and the diameter of the PCoA in relation to the sex and side was shown. On the basis of our measurements, we defined the hypoplasia of the artery as the estimated value less than the average diameter minus the standard deviation. The percentage distribution was as follows: the left artery 15.5%, the right artery 24%, women 11.5%, and the men 9%. Similarly to the above parameters, we have not found any statistical differences. The presence of the foetal origin was noted in 25% of the radiological examinations. The infundibular widening was visualised in 11.5% of cases of 3D reconstructions. The agenesis of PCoA was found in 9% (never bilaterally), and in 1 case the unilateral duplication of the artery was observed. No statistical differences between those parameters in relation to sex and the examined side were revealed.Conclusions: Morphological calculation of the PCoA on the basis of angio-CT from adult patients did not show any statistical differences depending on sex or the investigated side. The presented method of the calculations proved to be useful for the mathematical definition of the term “hypoplasia of the PCoA”

Intracranial region of the vertebral artery: morphometric study in the context of clinical usefulness

Background: The aim of this study was to analyse the morphometry of the intracranial segment of the vertebral artery in the context of clinical usefulness. The results were compared with published data available in full-text archived medical journals. Materials and methods: More than 100 digital subtraction angiography (DSA) and 3-dimensional (3D) angio-computed tomography (CT) examinations were used to measure the following parameters: the whole and partial length of V4 in characteristic anatomical points, the diameter in three places (on the level of foramen magnum, in point of exit to the posterior inferior cerebellar artery, and in the vertebro-basilar junction), the angle of connection to the vertebral arteries, and all anatomical variations including fenestration, duplication, dolichoectasia or absent artery. Results: The left V4 section was predominant over the right artery, which is manifested by length, width, cases of ectasia and fewer cases of hypoplasia. The incidences of V4 ectasia were identified more often than those documented in the accessible literature, and they were found in the natural location of formation of saccular aneurysms. Conclusions: The presented knowledge of anatomical variation and abnormali­ties of vertebral circulation can improve the accuracy and “safety” of the surgical procedures in this region, help to determine the range of surgical approach and avoid associated complications. The radiological examinations using 3D CT, DSA reveal unlimited observation of anatomical structures in contrast to studies based on cadavers, and can complement the morphometry in anatomical preparations

A facile and green route to terpene derived acrylate and methacrylate monomers and simple free radical polymerisation to yield new renewable polymers and coatings

We present new acrylic monomers derived directly from abundant naturally available terpenes via a facile, green and catalytic approach. These monomers can be polymerised to create new polymers with a wide range of mechanical properties that positions them ideally for application across the commodity and specialty plastics landscape; from packaging, cosmetic and medical, through to composites and coatings. We demonstrate their utility through formation of novel renewable polymer coatings

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification

Structural epitope profiling identifies antibodies associated with critical COVID-19 and long COVID

Even within a single protein, antibody binding can have beneficial, neutral, or harmful effects during the response to infection. Resolving a polyclonal antibody repertoire across a pathogen’s proteome to specific epitopes may therefore explain much of the heterogeneity in susceptibility to infectious disease. However, the three-dimensional nature of antibody-epitope interactions makes the discovery of non-obvious targets challenging. We implemented a novel computational method and synthetic biology pipeline for identifying epitopes that are functionally important in the SARS-CoV-2 proteome and identified an IgM-dominant response to an exposed Membrane protein epitope which to our knowledge is the strongest correlate of severe disease identified to date (adjusted OR 72.14, 95% CI: 9.71 – 1300.15), stronger even than the exponential association of severe disease with age. We also identify persistence (> 2 years) of this IgM response in individuals with longCOVID, and a correlation with fatigue and depression symptom burden. The repetitive arrangement of this epitope and the pattern of isotype class switching is consistent with this being a previously unrecognized T independent antigen. These findings point to a coronavirus host-pathogen interaction characteristic of severe virus driven immune pathology. This epitope is a promising vaccine and therapeutic target as it is highly conserved through SARS-CoV-2 variant evolution in humans to date and in related coronaviruses (e.g. SARS-CoV), showing far less evolutionary plasticity than targets on the Spike protein. This provides a promising biomarker for longCOVID and a target to complement Spike-directed vaccination which could broaden humoral protection from severe or persistent disease or novel coronavirus spillovers

Eukaryotic translation initiation factor 4AI: a potential novel target in neuroblastoma

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. Children suffering from high-risk and/or metastatic NB often show no response to therapy, and new therapeutic approaches are urgently needed. Malignant tumor development has been shown to be driven by the dysregulation of eukaryotic initiation factors (eIFs) at the translation initiation. Especially the activity of the heterotrimeric eIF4F complex is often altered in malignant cells, since it is the direct connection to key oncogenic signaling pathways such as the PI3K/AKT/mTOR-pathway. A large body of literature exists that demonstrates targeting the translational machinery as a promising anti-neoplastic approach. The objective of this study was to determine whether eIF4F complex members are aberrantly expressed in NB and whether targeting parts of the complex may be a therapeutic strategy against NB. We show that eIF4AI is overexpressed in NB patient tissue using immunohistochemistry, immunoblotting, and RT-qPCR. NB cell lines exhibit decreased viability, increased apoptosis rates as well as changes in cell cycle distribution when treated with the synthetic rocaglate CR-1-31-B, which clamps eIF4A and eIF4F onto mRNA, resulting in a translational block. Additionally, this study reveals that CR-1-31-B is effective against NB cell lines at low nanomolar doses (≤20 nM), which have been shown to not affect non-malignant cells in previous studies. Thus, our study provides information of the expression status on eIF4AI in NB and offers initial promising insight into targeting translation initiation as an anti-tumorigenic approach for NB.R35 GM118173 - NIGMS NIH HHS; COMET CBmed - Österreichische Forschungsförderungsgesellschaft; 1 - CSRD VAPublished versio

Tissue-specific gene repositioning by muscle nuclear membrane proteins enhances repression of critical developmental genes during myogenesis

Whether gene repositioning to the nuclear periphery during differentiation adds another layer of regulation to gene expression remains controversial. Here, we resolve this by manipulating gene positions through targeting the nuclear envelope transmembrane proteins (NETs) that direct their normal repositioning during myogenesis. Combining transcriptomics with high-resolution DamID mapping of nuclear envelope-genome contacts, we show that three muscle-specific NETs, NET39, Tmem38A, and WFS1, direct specific myogenic genes to the nuclear periphery to facilitate their repression. Retargeting a NET39 fragment to nucleoli correspondingly repositioned a target gene, indicating a direct tethering mechanism. Being able to manipulate gene position independently of other changes in differentiation revealed that repositioning contributes ⅓ to ⅔ of a gene’s normal repression in myogenesis. Together, these NETs affect 37% of all genes changing expression during myogenesis, and their combined knockdown almost completely blocks myotube formation. This unequivocally demonstrates that NET-directed gene repositioning is critical for developmental gene regulation

TMEM120A and B: Nuclear Envelope Transmembrane Proteins Important for Adipocyte Differentiation

<div><p>Recent work indicates that the nuclear envelope is a major signaling node for the cell that can influence tissue differentiation processes. Here we present two nuclear envelope trans-membrane proteins TMEM120A and TMEM120B that are paralogs encoded by the <i>Tmem120A</i> and <i>Tmem120B</i> genes. The TMEM120 proteins are expressed preferentially in fat and both are induced during 3T3-L1 adipocyte differentiation. Knockdown of one or the other protein altered expression of several genes required for adipocyte differentiation, <i>Gata3</i>, <i>Fasn</i>, <i>Glut4</i>, while knockdown of both together additionally affected <i>Pparg</i> and <i>Adipoq</i>. The double knockdown also increased the strength of effects, reducing for example <i>Glut4</i> levels by 95% compared to control 3T3-L1 cells upon pharmacologically induced differentiation. Accordingly, TMEM120A and B knockdown individually and together impacted on adipocyte differentiation/metabolism as measured by lipid accumulation through binding of Oil Red O and coherent anti-Stokes Raman scattering microscopy (CARS). The nuclear envelope is linked to several lipodystrophies through mutations in lamin A; however, lamin A is widely expressed. Thus it is possible that the TMEM120A and B fat-specific nuclear envelope transmembrane proteins may play a contributory role in the tissue-specific pathology of this disorder or in the wider problem of obesity.</p></div

Unexpectedly high barriers to M–P rotation in tertiary phobane complexes : PhobPR behavior that is commensurate with tBu2PR

The four isomers of 9-butylphosphabicyclo[3.3.1]nonane, s-PhobPBu, where Bu = n-butyl, sec-butyl, isobutyl, tert-butyl, have been prepared. Seven isomers of 9-butylphosphabicyclo[4.2.1]nonane (a5-PhobPBu, where Bu = n-butyl, sec-butyl, isobutyl, tert-butyl; a7-PhobPBu, where Bu = n-butyl, isobutyl, tert-butyl) have been identified in solution; isomerically pure a5-PhobPBu and a7-PhobPBu, where Bu = n-butyl, isobutyl, have been isolated. The σ-donor properties of the PhobPBu ligands have been compared using the JPSe values for the PhobP(═Se)Bu derivatives. The following complexes have been prepared: trans-[PtCl2(s-PhobPR)2] (R = nBu (1a), iBu (1b), sBu (1c), tBu (1d)); trans-[PtCl2(a5-PhobPR)2] (R = nBu (2a), iBu (2b)); trans-[PtCl2(a7-PhobPR)2] (R = nBu (3a), iBu (3b)); trans-[PdCl2(s-PhobPR)2] (R = nBu (4a), iBu (4b)); trans-[PdCl2(a5-PhobPR)2] (R = nBu (5a), iBu (5b)); trans-[PdCl2(a7-PhobPR)2] (R = nBu (6a), iBu (6b)). The crystal structures of 1a–4a and 1b–6b have been determined, and of the ten structures, eight show an anti conformation with respect to the position of the ligand R groups and two show a syn conformation. Solution variable-temperature 31P NMR studies reveal that all of the Pt and Pd complexes are fluxional on the NMR time scale. In each case, two species are present (assigned to be the syn and anti conformers) which interconvert with kinetic barriers in the range 9 to >19 kcal mol–1. The observed trend is that, the greater the bulk, the higher the barrier. The magnitudes of the barriers to M–P bond rotation for the PhobPR complexes are of the same order as those previously reported for tBu2PR complexes. Rotational profiles have been calculated for the model anionic complexes [PhobPR-PdCl3]− using DFT, and these faithfully reproduce the trends seen in the NMR studies of trans-[MCl2(PhobPR)2]. Rotational profiles have also been calculated for [tBu2PR-PdCl3]−, and these show that the greater the bulk of the R group, the lower the rotational barrier: i.e., the opposite of the trend for [PhobPR-PdCl3]−. Calculated structures for the species at the maxima and minima in the M–P rotation energy curves indicate the origin of the restricted rotation. In the case of the PhobPR complexes, it is the rigidity of the bicycle that enforces unfavorable H···Cl clashes involving the Pd–Cl groups with H atoms on the α- or β-carbon in the R substituent and H atoms in 1,3-axial sites within the phosphabicycle