Cluster dynamics of heterometallic trinuclear clusters during ligand substitution, redox chemistry, and group transfer processes.

Stepwise metalation of the hexadentate ligand tbsLH6 (tbsLH6 = 1,3,5-C6H9(NHC6H4-o-NHSiMe2tBu)3) affords bimetallic trinuclear clusters (tbsL)Fe2Zn(thf) and (tbsL)Fe2Zn(py). Reactivity studies were pursued to understand metal atom lability as the clusters undergo ligand substitution, redox chemistry, and group transfer processes. Chloride addition to (tbsL)Fe2Zn(thf) resulted in a mixture of species including both all-zinc and all-iron products. Addition of ArN3 (Ar = Ph, 3,5-(CF3)2C6H3) to (tbsL)Fe2Zn(py) yielded a mixture of two trinuclear products: (tbsL)Fe3(µ3-NAr) and (tbsL)Fe2Zn(µ3-NAr)(py). The two imido species were separated via crystallization, and outer sphere reduction of (tbsL)Fe2Zn(µ3-NAr)(py) resulted in the formation of a single product, [2,2,2-crypt(K)][(tbsL)Fe2Zn(µ3-NAr)]. These results provide insight into the relationship between heterometallic cluster structure and substitutional lability and could help inform both future catalyst design and our understanding of metal atom lability in bioinorganic systems.

The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities.

The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (ß-catenin dependent) and non-canonical (ß-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

A [CoSiH2] Silylene Synthon Provides Modular Access to Homo- and Heterobimetallic [Co═Si═M] (M = Co, Fe) Silicide Complexes.

Base-stabilized [BP3iPr](H)2CoSiH2(DMAP) (1, [BP3iPr] = PhB(CH2PiPr2)3-; DMAP = 4-dimethylaminopyridine) is a rare instance of a synthon for the simplest "parent" silylene complex (LM═SiH2). Complex 1 was accessed in high yields via double Si-H bond activation in SiH4 by [BP3iPr]Co(DMAP), and in solution, it undergoes rapid exchange between bound and free DMAP by an associative mechanism (as determined by variable-temperature 1H NMR dynamic studies). The DMAP ligand of 1 is readily displaced by metal-based fragments that bind silicon and cleave the Si-H bonds of the SiH2 moiety to produce bimetallic [Co═Si═M] (M = Co, Fe) molecular silicides. Thus, treatment of 1 with 0.5 equiv of (LCoI)2(µ-N2) (L = a tripodal ligand) resulted in the spontaneous formation of [BP3iPr](H)2Co═Si═Co(H)2L (L = [BP2tBuPz], PhB(CH2PtBu2)2(pyrazolyl)- (3); Tp″, HB(3,5-diisopropylpyrazolyl)3- (4)) with the concomitant release of DMAP. The symmetrical silicide [BP3iPr](H)2Co═Si═Co(H)2[BP3iPr] (5) was prepared by treatment of a mixture of 1 and [BP3iPr]Co(DMAP) with 2 equiv of Ph3B, which in this case is required to sequester DMAP as the elimination product Ph3B-DMAP. A heterobimetallic silicide, [BP3iPr](H)2Co═Si═Fe(H)2[SiP3iPr] (7; [SiP3iPr] = PhSi(CH2PiPr2)3), was obtained via in situ KC8 reduction of [SiP3iPr]FeCl and subsequent addition of 1 and Ph3B. These transformations involving a metal-SiH2 derivative demonstrate a fundamentally new type of reactivity for silylene complexes and provide a unique synthetic method for construction of molecular silicide complexes.

Tetracopper σ-Bound µ-Acetylide and -Diyne Units Stabilized by a Naphthyridine-based Dinucleating Ligand.

Reactions of a dicopper(I) tert-butoxide complex with alkynes possessing boryl or silyl capping groups resulted in formation of unprecedented tetracopper(I) µ-acetylide/diyne complexes that were characterized by NMR and UV/Vis spectroscopy, mass spectrometry and single-crystal X-ray diffraction. These compounds possess an unusual µ4 -η1 :η1 :η1 :η1 coordination mode for the bridging organic fragment, enforced by the rigid and dinucleating nature of the ligand utilized. Thus, the central π system remains unperturbed and accessible for subsequent reactivity and modification. This has been corroborated by addition of a fifth copper atom, giving rise to a pentacopper acetylide complex. This work may provide a new approach by which metal-metal cooperativity can be exploited in the transformation of acetylide and diyne groups to a variety of substrates, or as a starting point for the controlled synthesis of copper(I) alkyne-containing clusters.

Niclosamide (NA) overcomes cisplatin resistance in human ovarian cancer.

Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of early diagnosis. The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy, while several targeted therapies have recently been approved for maintenance treatment. The vast majority of OC patients relapse with chemoresistant tumors after an initial response. Thus, there is an unmet clinical need to develop new therapeutic agents to overcome the chemoresistance of OC. The anti-parasite agent niclosamide (NA) has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC. Here, we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant (CR) in human OC cells. To this end, we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer. We showed that NA inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis in both CR lines at a low micromole range. Mechanistically, NA inhibited multiple cancer-related pathways including AP1, ELK/SRF, HIF1, and TCF/LEF, in SKOV3CR and OVCAR8CR cells. NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells. Collectively, our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant human OC, and further clinical trials are highly warranted.

Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases.

Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

Dimetalloylene (M-E-M) Complexes of Heavier Main Group Elements Ge, Sn, Pb, Bi via Cleavage of E-X Bonds (X=N(SiMe3 )2 , OtBu) with an Iridium Hydride.

Reactions of the IrV hydride [Me BDIDipp ]IrH4 {BDI=(Dipp)NC(Me)CH(Me)CN(Dipp); Dipp=2,6-iPr2 C6 H3 } with E[N(SiMe3 )2 ]2 (E=Sn, Pb) afforded the unusual dimeric dimetallotetrylenes ([Me BDIDipp ]IrH)2 (µ2 -E)2 in good yields. Moreover, ([Me BDIDipp ]IrH)2 (µ2 -Ge)2 was formed in situ from thermal decomposition of [Me BDIDipp ]Ir(H)2 Ge[N(SiMe3 )2 ]2 . These reactions are accompanied by liberation of HN(SiMe3 )2 and H2 through the apparent cleavage of an E-N(SiMe3 )2 bond by Ir-H. In a reversal of this process, ([Me BDIDipp ]IrH)2 (µ2 -E)2 reacted with excess H2 to regenerate [Me BDIDipp ]IrH4 . Varying the concentrations of reactants led to formation of the trimeric ([Me BDIDipp ]IrH2 )3 (µ2 -E)3 . The further scope of this synthetic route was investigated with group 15 amides, and ([Me BDIDipp ]IrH)2 (µ2 -Bi)2 was prepared by the reaction of [Me BDIDipp ]IrH4 with Bi(NMe2 )3 or Bi(OtBu)3 to afford the first example of a "naked" two-coordinate Bi atom bound exclusively to transition metals. A viable mechanism that accounts for the formation of these products is proposed. Computational investigations of the Ir2 E2 (E=Sn, Pb) compounds characterized them as open-shell singlets with confined nonbonding lone pairs at the E centers. In contrast, Ir2 Bi2 is characterized as having a closed-shell singlet ground state.

Corrigendum to "Establishment and functional characterization of the reversibly immortalized mouse glomerular podocytes (imPODs)" [Genes & Diseases 5 (2018) 137-149].

[This corrects the article DOI: 10.1016/j.gendis.2018.04.003.].

Corrigendum to 'Modeling colorectal tumorigenesis using the organoids derived from conditionally immortalized mouse intestinal crypt cells (ciMICs)' [Genes Dis 8 (2021) 814-826].

[This corrects the article DOI: 10.1016/j.gendis.2021.01.004.].

Corrigendum to "The development of a sensitive fluorescent protein-based transcript reporter for high throughput screening of negative modulators of lncRNAs" [Genes & Diseases 5 (2018) 62-74].

[This corrects the article DOI: 10.1016/j.gendis.2018.02.001.].

Corrigendum to "Characterization of the essential role of bone morphogenetic protein 9 (BMP9) in osteogenic differentiation of mesenchymal stem cells (MSCs) through RNA interference" [Genes & Diseases 5(2018):172-184].

[This corrects the article DOI: 10.1016/j.gendis.2018.04.006.].

Direct Transformation of SiH4 to a Molecular L(H)2Co═Si═Co(H)2L Silicide Complex.

The synthesis of bimetallic molecular silicide complexes is reported, based on the use of multiple Si-H bond activations in SiH4 at the metal centers of 14-electron LCoI fragments (L = Tp″, HB(3,5-diisopropylpyrazolyl)3-; [BP2tBuPz], PhB(CH2PtBu2)2(pyrazolyl)). Upon exposure of (Tp″Co)2(µ-N2) (1) to SiH4, a mixture of (Tp″Co)2(µ-H) (2) and (Tp″Co)2(µ-H)2 (3) was formed and no evidence for Si-H oxidative addition products was observed. In contrast, [BP2tBuPz]-supported Co complexes led to Si-H oxidative additions with the generation of silylene and silicide complexes as products. Notably, the reaction of ([BP2tBuPz]Co)2(µ-N2) (5) with SiH4 gave the dicobalt silicide complex [BP2tBuPz](H)2Co═Si═Co(H)2[BP2tBuPz] (8) in high yield, representing the first direct route to a symmetrical bimetallic silicide. The effect of the [BP2tBuPz] ligand on Co-Si bonding in 7 and 8 was explored by analysis of solid-state molecular structures and density functional theory (DFT) investigations. Upon exposure to CO or DMAP (DMAP = 4-dimethylaminopyridine), 8 converted to the corresponding [BP2tBuPz]Co(L)x adducts (L = CO, x = 2; L = DMAP, x = 1) with concomitant loss of SiH4, despite the lack of significant Si-H interactions in the starting complex. On heating to 60 °C, 8 underwent reaction with MeCl to produce small quantities of MexSiH4-x (x = 1-3), demonstrating functionalization of the µ-silicon atom in a molecular silicide to form organosilanes.

BAP1 Tumor Predisposition Syndrome Presenting as a Recurrent Ovarian Sex Cord-Stromal Tumor.

The BRCA1-associated protein 1 ( BAP1 ) gene encodes a tumor suppressor that functions as a ubiquitin hydrolase involved in DNA damage repair. BAP1 germline mutations are associated with increased risk of multiple solid malignancies, including mesothelioma, uveal melanoma, renal cell carcinoma, and high-grade rhabdoid meningiomas. Here, we describe the case of a 52-yr-old woman who experienced multiple abdominal recurrences of an ovarian sex cord-stromal tumor that was originally diagnosed at age 25 and who was found to have a germline mutation in BAP1 and a family history consistent with BAP1 tumor predisposition syndrome. Recurrence of the sex cord-stromal tumor demonstrated loss of BAP1 expression by immunohistochemistry. Although ovarian sex cord-stromal tumors have been described in mouse models of BAP1 tumor predisposition syndrome, this relationship has not been previously described in humans and warrants further investigation. The case presentation, tumor morphology, and immunohistochemical findings have overlapping characteristics with peritoneal mesotheliomas, and this case represents a potential pitfall for surgical pathologists.

Expanded [23]-Helicene with Exceptional Chiroptical Properties via an Iterative Ring-Fusion Strategy.

Expanded helicenes are an emerging class of helical nanocarbons composed of alternating linear and angularly fused rings, which give rise to an internal cavity and a large diameter. The latter is expected to impart exceptional chiroptical properties, but low enantiomerization free energy barriers (ΔG‡e) have largely precluded experimental interrogation of this prediction. Here, we report the syntheses of expanded helicenes containing 15, 19, and 23 rings on the inner helical circuit, using two iterations of an Ir-catalyzed, site-selective [2 + 2 + 2] reaction. This series of compounds displays a linear relationship between the number of rings and ΔG‡e. The expanded [23]-helicene, which is 7 rings longer than any known single carbohelicene and among the longest known all-carbon ladder oligomers, exhibits a ΔG‡e that is high enough (29.2 ± 0.1 kcal/mol at 100 °C in o-DCB) to halt enantiomerization at ambient temperature. This enabled the isolation of enantiopure samples displaying circular dichroism dissymmetry factors of ±0.056 at 428 nm, which are ≥1.7× larger than values for previously reported classical and expanded helicenes. Computational investigations suggest that this improved performance is the result of both the increased diameter and length of the [23]-helicene, providing guiding design principles for high dissymmetry molecular materials.

Association of Maternal and Paternal Astigmatism With Child Astigmatism in the Hong Kong Children Eye Study.

Importance: Parental astigmatism is a factor associated with risk for development of child astigmatism; however, the magnitude of the association has not been determined. Objective: To determine the association between parental and child astigmatism. Design, Setting, and Participants: This population-based, cross-sectional study included participants from familial trios, each comprising a child aged 6 to 8 years and both parents, recruited from the Hong Kong Children Eye Study. No restriction criteria were set on the children in terms of refractive status. Data were analyzed from February to June 2022. Exposures: Cycloplegic autorefraction and autokeratometry were conducted on the children, whereas noncycloplegic autorefraction and autokeratometry were conducted on their parents. The children were categorized into 6 groups on the basis of the severity of astigmatism of both parents. Information on parental education, family income, and children's outdoor and near work time were obtained by questionnaires. Main Outcomes and Measures: The primary outcome was the odds of child astigmatism among the 6 categories of children. Associations of factors with child astigmatism were evaluated by logistic regression analyses. Results: A total of 17 124 participants from 5708 trios (2964 boys and 2754 girls) at a mean (SD) age of 7.32 (0.87) years, and 11 416 parents were examined. Astigmatism of 1.0 D or greater in both parents was associated with greater odds of refractive astigmatism (RA) (odds ratio [OR], 1.62; 95% CI, 1.15-2.26) and corneal astigmatism (CA) (OR, 1.94; 95% CI, 1.50-2.50) in the child. The respective ORs increased to 3.10 (95% CI, 1.34-7.21) and 4.31 (95% CI, 1.76-10.55) when both parents had astigmatism 2.0 D or greater. Higher parental astigmatism conferred higher risks for both RA and CA in children (P for trend <.001). Parental astigmatism was significantly associated with greater odds of corresponding child astigmatism (maternal RA: OR, 0.76; 95% CI, 0.68-0.84; paternal RA: OR, 0.82; 95% CI, 0.74-0.91; maternal CA: OR, 1.70; 95% CI, 1.51-1.93; paternal CA: OR, 1.33; 95% CI, 1.19-1.49). Conclusions and Relevance: The findings of this cross-sectional study suggest that parental astigmatism may confer an independent and dose-dependent association with child astigmatism. Children with parents with astigmatism should have early eye examinations for timely detection of astigmatism to facilitate age-appropriate vision correction and visual development.