Triply Interlocked [2]catenanes: Rational Synthesis, Reversible Conversion Studies and Unprecedented Application in Photothermal Responsive Elastomer.

Triply interlocked [2]catenane complexes featuring two identical, mechanically interlocked units are extraordinarily rare chemical compounds, whose properties and applications remain open to detailed studies. Herein, we introduce the rational design of a new ligand precursor, L1, suitable for the synthesis of six triply interlocked [2]catenanes by coordination-driven self-assembly. The interlocked compounds can be reversibly converted into the corresponding simple triangular prism metallacage by addition of H2O or DMF solvents to their CH3OH solutions, thereby demonstrating the importance of π⋅⋅⋅π stacking and hydrogen bonding interactions in the formation of triply interlocked [2]catenanes. Moreover, extensive studies have been conducted to assess the remarkable photothermal conversion performance. Complex 6 a, exhibiting outstanding photothermal conversion performance (conversion efficiency in solution : 31.82 %), is used to prepare novel photoresponsive elastomer in combination with thermally activated liquid crystal elastomer. The resultant material displays robust response to near-infrared (NIR) laser and the capability of completely reforming the shape and reversible actuation, paving the way for the application of half-sandwich organometallic units in photo-responsive smart materials.

Self-Assembly and Photothermal Conversion of MetallaRussian Doll and Metalla[2]catenanes Induced via Multiple Stacking Interactions.

A variety of organometallic supramolecular architectures have been constructed over the past decades and their properties were also explored via different strategies. However, the synthesis of metalla-Russian doll is still a fascinating challenge. Herein, a series of new coordination supramolecular complexes, including a metalla-Russian doll, metalla[2]catenanes, and metallarectangles, were synthesized by using meticulously selected Cp*Rh (Cp* = η5-C5Me5) building units (E1, E2, and E3) and three rigid anthracylpyridine ligands (L1, L2, and L3) via a self-assembly strategy. While the combination of the short ligand L1 and E1 or E2 generated two metallarectangles, the longer ligand L2 containing an alkynyl group resulted in two new [2]catenanes, most likely due to which the strong electron-donating effect of alkynyl groups causes self-accumulation. Interestingly, an unusual Russian doll assembly was obtained through the reaction of L3 and E3 based on sextuple π···π stacking interactions. Furthermore, the dynamic structural conversion between [2]catenanes and the corresponding metallarectangles could be observed through concentration-, solvent-, and guest-induced effects. The [2]catenane complexes 4b displayed efficient photothermal conversion efficiency in solution (20.2%), in comparison with other organometallic macrocycles. We believe that π···π stacking interactions generate active nonradiative pathways and promote radiative photodeactivation pathways. This study proves the versatility of half-sandwich building units, not only to build complicated supramolecular topologies but also in effective functional materials for various appealing applications.

Selective Synthesis and Structural Transformation of a 4-Ravel Containing Four Crossings and Featuring Cp*Rh/Ir Fragments.

Intricately interwoven topologies are continually being synthesized and are ultimately equally versatile and significant at the nanoscale level; however, reports concerning ravel structures, which are highly entwined new topological species, are extremely rare and fraught with tremendous synthesis challenges. To solve the synthesis problem, a tetrapodontic pyridine ligand L1 with two types of olefinic bond units and two Cp*M-based building blocks (E1, M=Rh; E2, M=Ir) featuring large conjugated planes was prepared to perform the self-assembly. Two unprecedented [5+10] icosanuclear molecular 4-ravels containing four crossings were obtained by parallel-displaced π⋅⋅⋅π interactions in a single-step strategy. Remarkably, reversible structural transformations between the 4-ravel and the corresponding metallocage could be realized by concentration changes and solvent- and guest-induced effects. X-ray crystallographic data and NMR spectroscopy provide full confirmation of these phenomena.

Machine Learning-Based Approach Highlights the Use of a Genomic Variant Profile for Precision Medicine in Ovarian Failure.

Ovarian failure (OF) is a common cause of infertility usually diagnosed as idiopathic, with genetic causes accounting for 10-25% of cases. Whole-exome sequencing (WES) may enable identifying contributing genes and variant profiles to stratify the population into subtypes of OF. This study sought to identify a blood-based gene variant profile using accumulation of rare variants to promote precision medicine in fertility preservation programs. A case-control (n = 118, n = 32, respectively) WES study was performed in which only non-synonymous rare variants <5% minor allele frequency (MAF; in the IGSR) and coverage ≥ 100× were considered. A profile of 66 variants of uncertain significance was used for training an unsupervised machine learning model to separate cases from controls (97.2% sensitivity, 99.2% specificity) and stratify the population into two subtypes of OF (A and B) (93.31% sensitivity, 96.67% specificity). Model testing within the IGSR female population predicted 0.5% of women as subtype A and 2.4% as subtype B. This is the first study linking OF to the accumulation of rare variants and generates a new potential taxonomy supporting application of this approach for precision medicine in fertility preservation.

Biological and clinical significance of dysplastic hematopoiesis in patients with newly diagnosed multiple myeloma.

Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.

Iridium-induced regioselective B-H and C-H activations at azo-substituted m-carboranes: facile access to polynuclear complexes.

Iridium(iii)-induced selective B(2,3)-H and C-H bond activations at mono- and bi-p-methoxybenzeneazo-substituted m-carboranes have been investigated. A powerful methodology is introduced for the preparation of unique polynuclear complexes featuring m-carboranyl ligands in a single step. The experimental results highlight that the base employed in the reaction plays a key role in the formation and the structures of the complexes.

Iridium-Induced Regioselective B-H and C-C Activations at Azo-Substituted o-Carboranes.

p-Methoxybenzeneazo-substituted o-carboranes have been synthesized and their reactivity with half-sandwich iridium and rhodium complexes has been investigated in detail. A variety of solvent- and base-dependent, highly site-selective B-H and C-C σ-bond activations at the C/B cage have been observed. While the use of CH3 OH leads to the formation of metallacarboranes, o-carborane clusters undergo cyclometallation reactions involving B(6)-H, B(4)-H or a rare B(7)-H activation in CH2 Cl2 . The synthesis of a unique pseudo-closo-iridacarborane through a very unconventional metal-mediated Ccage -Ccage activation is described in this contribution.

Preparation of polynuclear NHC complexes by post-synthetic modification of half-sandwich rhodium and iridium complexes bearing C-azolato ligands.

A series of bimetallic and trimetallic complexes has been prepared by N-alkylation of mononuclear half-sandwich rhodium and iridium di-NHC complexes featuring bidentate chelate ligands composed of a classical NHC and a C-azolato donor. The shape and the separation between metal centers in the obtained complexes are highly dependent on the alkylating agent used. While the polynuclear complexes were formed as diastereomeric mixtures according to NMR spectroscopy, X-ray diffraction analysis revealed their remarkable preference to crystallize as meso compounds. The reactivity of the bimetallic, olefin-bridged complexes in electrophilic addition reactions has been investigated.

Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles.

The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.

Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.

Deep sequencing of target linkage assay-identified regions in familial breast cancer: methods, analysis pipeline and troubleshooting.

BACKGROUND: The classical candidate-gene approach has failed to identify novel breast cancer susceptibility genes. Nowadays, massive parallel sequencing technology allows the development of studies unaffordable a few years ago. However, analysis protocols are not yet sufficiently developed to extract all information from the huge amount of data obtained. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we performed high throughput sequencing in two regions located on chromosomes 3 and 6, recently identified by linkage studies by our group as candidate regions for harbouring breast cancer susceptibility genes. In order to enrich for the coding regions of all described genes located in both candidate regions, a hybrid-selection method on tiling microarrays was performed. CONCLUSIONS/SIGNIFICANCE: We developed an analysis pipeline based on SOAP aligner to identify candidate variants with a high real positive confirmation rate (0.89), with which we identified eight variants considered candidates for functional studies. The results suggest that the present strategy might be a valid second step for identifying high penetrance genes.