Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis.

Host-virus protein-protein interactions play key roles in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We conducted a comprehensive interactome study between the virus and host cells using tandem affinity purification and proximity-labeling strategies and identified 437 human proteins as the high-confidence interacting proteins. Further characterization of these interactions and comparison to other large-scale study of cellular responses to SARS-CoV-2 infection elucidated how distinct SARS-CoV-2 viral proteins participate in its life cycle. With these data mining, we discovered potential drug targets for the treatment of COVID-19. The interactomes of two key SARS-CoV-2-encoded viral proteins, NSP1 and N, were compared with the interactomes of their counterparts in other human coronaviruses. These comparisons not only revealed common host pathways these viruses manipulate for their survival, but also showed divergent protein-protein interactions that may explain differences in disease pathology. This comprehensive interactome of SARS-CoV-2 provides valuable resources for the understanding and treating of this disease.

ATR inhibition potentiates ionizing radiation-induced interferon response via cytosolic nucleic acid-sensing pathways.

Mechanistic understanding of how ionizing radiation induces type I interferon signaling and how to amplify this signaling module should help to maximize the efficacy of radiotherapy. In the current study, we report that inhibitors of the DNA damage response kinase ATR can significantly potentiate ionizing radiation-induced innate immune responses. Using a series of mammalian knockout cell lines, we demonstrate that, surprisingly, both the cGAS/STING-dependent DNA-sensing pathway and the MAVS-dependent RNA-sensing pathway are responsible for type I interferon signaling induced by ionizing radiation in the presence or absence of ATR inhibitors. The relative contributions of these two pathways in type I interferon signaling depend on cell type and/or genetic background. We propose that DNA damage-elicited double-strand DNA breaks releases DNA fragments, which may either activate the cGAS/STING-dependent pathway or-especially in the case of AT-rich DNA sequences-be transcribed and initiate MAVS-dependent RNA sensing and signaling. Together, our results suggest the involvement of two distinct pathways in type I interferon signaling upon DNA damage. Moreover, radiation plus ATR inhibition may be a promising new combination therapy against cancer.

Chelating Bis-silylenes As Powerful Ligands To Enable Unusual Low-Valent Main-Group Element Functions.

ConspectusSilylenes are divalent silicon species with an unoccupied 3p orbital and one lone pair of electrons at the SiII center. Owing to the excellent σ-donating ability of amidinato-based silylenes, which stems from the intramolecular imino-N donor interaction with the vacant 3p orbital of the silicon atom, N-heterocyclic amidinato bis(silylenes) [bis(NHSi)s] can serve as versatile strong donating ligands for cooperative stabilization of central atoms in unusually low oxidation states. Herein, we present our recent achievement on the application of bis(NHSi) ligands with electronically and spatially different spacers to main-group chemistry, which has allowed the isolation of a variety of low-valent compounds consisting of monatomic zero-valent group 14 E0 complexes (named "metallylones", E = Si, Ge, Sn, Pb); monovalent group 15 EI complexes (E = N, P, isoelectronic with metallylones); and diatomic low-valent E2 complexes (E = Si, Ge, P) with intriguing electronic structures and chemical reactivities.The role of the SiII···SiII distance was revealed to be crucial in this chemistry. Utilizing the pyridine-based bis(NHSi) (Si···Si distance: 7.8 Å) ligand, germanium(0) complexes with additional Fe(CO)4 protection at the Ge0 site have been isolated. Featuring a shorter Si···Si distance of 4.3 Å, the xanthene-based bis(NHSi) has allowed the realization of the full series of heavy zero-valent group 14 element E0 complexes (E = Si, Ge, Sn, Pb), while the o-carborane-based bis(NHSi) (Si···Si distance: 3.3 Å) has enabled the isolation of Si0 and Ge0 complexes. Remarkably, reduction of the o-carborane-based bis(NHSi)-supported Si0 and Ge0 complexes induces the movement of two electrons into the o-carborane core and provides access to SiI-SiI and GeI-GeI species as oxidation products. Additionally, the o-carborane-based bis(NHSi) reacts with adamantyl azide, leading to a series of nitrogen(I) complexes as isoelectronic species of a carbone (C0 complex). Moreover, cooperative activation of white phosphorus gives bis(NHSi)-supported phosphorus complexes with varying and unexpected electronic structures when employing the xanthene-, o-carborane-, and aniline-based bis(NHSi)s. With the better kinetic protection provided by the xanthene-based bis(NHSi), small-molecule activation and functionalization of the bis(NHSi)-supported central E or E2 atoms (E = Si, Ge, P) are possible and furnish several novel functionalized silicon, germanium, and phosphorus compounds.With knowledge of the ability of chelating bis(NHSi)s in coordinating and functionalizing low-valent group 14 and 15 elements, the application of these ligand systems to other main-group elements such as group 2 and 13 is quite promising. To fully understand the role of the NHSi in a bis(NHSi) ligand, introducing a mixed ligand, i.e., the combination of an NHSi with other functional groups, such as Lewis acidic borane or Lewis basic borylene, in one chelating ligand could lead to new types of low-valent main-group species. Furthermore, the development of a genuine acyclic silylene, without an imino-N interaction with the vacant 3p orbital at the silicon(II) atom, as part of a chelating bis(acyclic silylene) has the potential to form very electronically different main-group element complexes that could achieve even more challenging bond activations such as N2 or unactivated C-H bonds.

Characterization and Flame-Retardant Properties of Cobalt-Coordinated Cyclic Phosphonitrile in Thermoplastic Polyurethane Composites.

Halogen-free organophosphorus flame retardants have promising application prospects due to their excellent safety and environmental protection properties. A cobalt-coordinated cyclic phosphonitrile flame retardant (Co@CPA) was synthesized via a hydrothermal method using hexachlorocyclotriphosphonitrile (HCCP), 5-amino-tetrazolium (5-AT), and cobalt nitrate hexahydrate (Co(NO3)2∙6H2O) as starting materials. The structure was characterized using Fourier transform infrared (FTIR), nuclear magnetic resonance spectroscopy (1H-NMR), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). Thermoplastic polyurethane (TPU) composites were prepared by incorporating 10-(2,5-dihydroxyphenyl)-9,10-dihydro-9-oxa-10-phosphame-10-oxide (ODOPB), Co@CPA, and silicon dioxide (SiO2) via melt blending. The flame-retardant performance and thermal stability of the TPU composites were evaluated through limiting oxygen index (LOI), vertical combustion (UL-94), TG, and cone calorimetric (CCT) tests. SEM and Raman spectroscopy were used to analyze the surface morphology and structure of the residual carbon. A synergistic flame-retardant effect of ODOPB and Co@CPA was observed, with the most effective flame retardancy achieved at a TPU:ODOPB:Co@CPA:SiO2 ratio of 75:16:8:1. This composition exhibited an LOI value of 26.5% and achieved a V-0 rating in the UL-94 test. Furthermore, compared to pure TPU, the composite showed reductions in total heat release, CO production, and CO2 production by 6.6%, 39.4%, and 48.9%, respectively. Our research findings suggest that Co@CPA demonstrates outstanding performance, with potential for further expansion in application areas. Different metal-based cyclic phosphonitrile compounds are significant in enriching phosphorus-based fine chemicals.

Histone chaperone ASF1 acts with RIF1 to promote DNA end joining in BRCA1-deficient cells.

Replication timing regulatory factor 1 (RIF1) acts downstream of p53-binding protein 53BP1 to inhibit the resection of DNA broken ends, which plays critical roles in determining the DNA double-strand break repair pathway choice between nonhomologous end joining and homologous recombination (HR). However, the mechanism by which this choice is made is not yet clear. In this study, we identified that histone chaperone protein ASF1 associates with RIF1 and regulates RIF1-dependent functions in the DNA damage response. Similar to loss of RIF1, we found that loss of ASF1 resulted in resistance to poly (ADP-ribose) polymerase (PARP) inhibition in BRCA1-deficient cells with restored HR and decreased telomere fusion in telomeric repeat-binding protein 2 (TRF2)-depleted cells. Moreover, we showed that these functions of ASF1 are dependent on its interaction with RIF1 but not on its histone chaperone activity. Thus, our study supports a new role for ASF1 in dictating double-strand break repair choice. Considering that the status of 53BP1-RIF1 axis is important in determining the outcome of PARP inhibitor-based therapy in BRCA1- or HR-deficient cancers, the identification of ASF1 function in this critical pathway uncovers an interesting connection between these S-phase events, which may reveal new strategies to overcome PARP inhibitor resistance.

Optimization of optical and structural properties of Al2O3/TiO2 nano-laminates deposited by atomic layer deposition for optical coating.

Optimizing the atomic layer deposition (ALD) process of films is particularly important in preparing multilayer interference films. In this work, a series of Al2O3/TiO2 nano-laminates with a fixed growth cycle ratio of 1:10 were deposited on Si and fused quartz substrates at 300 °C by ALD. The optical properties, crystallization behavior, surface appearance and microstructures of those laminated layers were systematically investigated by spectroscopic ellipsometry, spectrophotometry, X-ray diffraction, atomic force microscope and transmission electron microscopy. By inserting Al2O3 interlayers into TiO2 layers, the crystallization of the TiO2 is reduced and the surface roughness becomes smaller. The TEM images show that excessively dense distribution of Al2O3 intercalation leads to the appearance of TiO2 nodules, which in turn leads to increased roughness. The Al2O3/TiO2 nano-laminate with a cycle ratio 40:400 has relatively small surface roughness. Additionally, oxygen-deficient defects exist at the interface of Al2O3 and TiO2, leading to evident absorption. Using O3 as an oxidant instead of H2O for depositing Al2O3 interlayers was verified to be effective in reducing absorption during broadband antireflective coating experiments.

Genetic vulnerabilities upon inhibition of DNA damage response.

Because of essential roles of DNA damage response (DDR) in the maintenance of genomic integrity, cellular homeostasis, and tumor suppression, targeting DDR has become a promising therapeutic strategy for cancer treatment. However, the benefits of cancer therapy targeting DDR are limited mainly due to the lack of predictive biomarkers. To address this challenge, we performed CRISPR screens to search for genetic vulnerabilities that affect cells' response to DDR inhibition. By undertaking CRISPR screens with inhibitors targeting key DDR mediators, i.e. ATR, ATM, DNAPK and CHK1, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Specifically, we identified YWHAE loss as a key determinant of sensitivity to CHK1 inhibition. We showed that KLHL15 loss protects cells from DNA damage induced by ATM inhibition. Moreover, we validated that APEX1 loss sensitizes cells to DNAPK inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that an ATM inhibitor plus a PARP inhibitor induced dramatic levels of cell death, probably through promoting apoptosis. Our results enhance the understanding of DDR pathways and will facilitate the use of DDR-targeting agents in cancer therapy.

Widely targeted metabolomics analysis of different parts of kudzu.

Pueraria lobata is a traditional medicinal and edible plant. Its root is often used as a nutritional supplement, but its stems and leaves are often discarded. In this study, the types and contents of compounds in roots, stems and leaves of kudzu were studied by ultra-high-performance liquid chromatography electrospray ionization tandem mass spectrometry. A total of 446 metabolites were identified, which were mainly divided into eight categories; 40 unique compounds were detected in roots. Multivariate statistical analysis showed that there were significant differences in the contents of metabolites in the roots, stems and leaves of kudzu, and the most significant differences were found in the roots and stems. Most flavonoids and terpenoids accumulated in roots, while alkaloids, flavonoid glycosides, lignans and coumarins accumulated in stems and leaves. In addition, isoflavones accumulated least in stems and most in roots. These results improved our understanding of the accumulation of metabolites in kudzu and provided a reference for the full study of the medicinal value of different parts of kudzu.

Widely targeted metabolomics analysis reveals the differences in nonvolatile compounds of citronella before and after drying.

Citronella is used as a spice and a traditional herbal medicine. Dried citronella is easy to store and transport, and it is unclear whether dried citronella has more or fewer medicinal components compared to fresh citronella. In the present study, various metabolites in fresh and dry citronella were detected using a widely targeted metabolomics strategy. We identified 712 metabolites and classified them into 31 categories, and we identified 132 flavonoids. After citronella was dried, the quantities of most kinds of flavonoids increased, but the quantities of amino acids, organic acids, and vitamins decreased, and the quantity of quercetin increased significantly. Therefore, the medicinal value of dry citronella may have increased, and the nutritional value of amino acids and vitamins may have decreased. The results of this study can serve as a new theoretical reference to study citronella and promote its nutrition and medicinal chemical composition.

Integrative Analysis of Metabolome and Transcriptome Reveals the Mechanism of Color Formation in Yellow-Fleshed Kiwifruit.

During the development of yellow-fleshed kiwifruit (Actinidia chinensis), the flesh appeared light pink at the initial stage, the pink faded at the fastest growth stage, and gradually changed into green. At the maturity stage, it showed bright yellow. In order to analyze the mechanism of flesh color change at the metabolic and gene transcription level, the relationship between color and changes of metabolites and key enzyme genes was studied. In this study, five time points (20 d, 58 d, 97 d, 136 d, and 175 d) of yellow-fleshed kiwifruit were used for flavonoid metabolites detection and transcriptome, and four time points (20 d, 97 d, 136 d, and 175 d) were used for targeted detection of carotenoids. Through the analysis of the content changes of flavonoid metabolites, it was found that the accumulation of pelargonidin and cyanidin and their respective anthocyanin derivatives was related to the pink flesh of young fruit, but not to delphinidin and its derivative anthocyanins. A total of 140 flavonoid compounds were detected in the flesh, among which anthocyanin and 76% of the flavonoid compounds had the highest content at 20 d, and began to decrease significantly at 58 d until 175 d, resulting in the pale-pink fading of the flesh. At the mature stage of fruit development (175 d), the degradation of chlorophyll and the increase of carotenoids jointly led to the change of flesh color from green to yellow, in addition to chlorophyll degradation. In kiwifruit flesh, 10 carotenoids were detected, with none of them being linear carotenoids. During the whole development process of kiwifruit, the content of ß-carotene was always higher than that of α-carotene. In addition, ß-cryptoxanthin was the most-accumulated pigment in the kiwifruit at 175 d. Through transcriptome analysis of kiwifruit flesh, seven key transcription factors for flavonoid biosynthesis and ten key transcription factors for carotenoid synthesis were screened. This study was the first to analyze the effect of flavonoid accumulation on the pink color of yellow-fleshed kiwifruit. The high proportion of ß-cryptoxanthin in yellow-fleshed kiwifruit was preliminarily found. This provides information on metabolite accumulation for further revealing the pink color of yellow-fleshed kiwifruit, and also provides a new direction for the study of carotenoid biosynthesis and regulation in yellow-fleshed kiwifruit.

Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway.

Etoposide (ETO) is an anticancer drug that targets topoisomerase II (TOP2). It stabilizes a normally transient TOP2-DNA covalent complex (TOP2cc), thus leading to DNA double-strand breaks (DSBs). Tyrosyl-DNA phosphodiesterases two (TDP2) is directly involved in the repair of TOP2cc by removing phosphotyrosyl peptides from 5'-termini of DSBs. Recent studies suggest that additional factors are required for TOP2cc repair, which include the proteasome and the zinc finger protein associated with TDP2 and TOP2, named ZATT. ZATT may alter the conformation of TOP2cc in a way that renders the accessibility of TDP2 for TOP2cc removal. In this study, our genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens revealed that ZATT also has a TDP2-independent role in promoting cell survival following ETO treatment. ZATT KO cells showed relatively higher ETO sensitivity than TDP2-KO cells, and ZATT/TDP2 DKO cells displayed additive hypersensitivity to ETO treatment. The study using a series of deletion mutants of ZATT determined that the N-terminal 1-168 residues of ZATT are required for interaction with TOP2 and this interaction is critical to ETO sensitivity. Moreover, depletion of ZATT resulted in accelerated TOP2 degradation after ETO or cycloheximide (CHX) treatment, suggesting that ZATT may increase TOP2 stability and likely participate in TOP2 turnover. Taken together, this study suggests that ZATT is a critical determinant that dictates responses to ETO treatment and targeting. ZATT is a promising strategy to increase ETO efficacy for cancer therapy.

Sex Differences in Short-Term and Long-Term Outcomes Among Patients With Acute Ischemic Stroke in China.

BACKGROUND: Sex differences in stroke outcomes are crucial to secondary prevention, but previous reports showed inconsistent results. We aimed to explore the sex differences in stroke outcomes in the Third China National Stroke Registry, a prospective multicenter registry study. METHODS: Among the 15 166 patients enrolled between 2015 and 2018, 9038 patients with acute ischemic stroke (AIS) were included. The primary outcomes were stroke recurrence, mortality, and unfavorable functional outcome (modified Rankin Scale > 2) at 3, 6, and 12 months. Cox regression model was used for stroke recurrence and mortality and logistic regression was used for the unfavorable functional outcome, and adjusted as follows: (1) Model 1: without adjustment; (2) Model 2: adjusted for potential risk factors, National Institutes of Health Stroke Scale at admission, prestroke modified Rankin Scale, tPA (tissue-type plasminogen activator) treatment, TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification, and onset-to-door time; (3) Model 3: adjusted for covariates from model 2 in addition to blood pressure and blood serum covariates. Multiple imputation was used for missing values, and sensitivity analyses were conducted to describe sex differences by age groups. RESULTS: One-third (2802/9038) of the patients were women. Women were significantly older than men (64.78±10.84 versus 61.26±11.42, P<0.001). In the fully adjusted model, female patients were more likely to have unfavorable functional outcomes at 3 months (odds ratio, 1.28 [1.09-1.50]), especially among patients aged 65 years or older (odds ratio, 1.39 [1.14-1.70]), but no difference was discovered in patients aged <65 years. There were no sex differences in stroke recurrence and mortality at 3, 6, or 12 months or unfavorable functional outcomes at 6 or 12 months after adjustment. CONCLUSIONS: Compared with men, women with AIS were less likely to have favorable outcomes at 3 months in China, especially among those over 65 years of age. Experts should aim to tailor secondary prevention strategies for high-risk patients.

Cereal grain-based functional beverages: from cereal grain bioactive phytochemicals to beverage processing technologies, health benefits and product features.

Increased consumer awareness of health and wellness has promoted a high demand for foods and beverages with functional and therapeutic properties. Cereals, apart from being important staple crops and primary sources of energy and nutrition, are replete with bioactive phytochemicals with health properties. Cereal grains contain a diverse range of bioactive phytochemicals including phenolic compounds, dietary fibers, carotenoids, tocols, phytosterols, γ-oryzanol, and phytic acid and therefore have great potential for processing into functional beverages. Although there are a variety of cereal grain-based beverages produced world-wide, very little scientific and technological attention has been paid to them. In this review, we have discussed cereal grain-based functional beverages based on 3 main categories: cereal grain-based milk alternatives, roasted cereal grain teas, fermented nonalcoholic cereal grain beverages. The processing techniques, health properties and product features of these beverages are elaborated, and the challenges and future perspectives are proposed. As the food market becomes increasingly diverse, cereal grain-based beverages could be a promising new category of health functional beverages in our daily life.

AMPK Interactome Reveals New Function in Non-homologous End Joining DNA Repair.

Adenosine monophosphate-activated protein kinase (AMPK) is an obligate heterotrimer that consists of a catalytic subunit (α) and two regulatory subunits (ß and γ). AMPK is a key enzyme in the regulation of cellular energy homeostasis. It has been well studied and is known to function in many cellular pathways. However, the interactome of AMPK has not yet been systematically established, although protein-protein interaction is critically important for protein function and regulation. Here, we used tandem-affinity purification, coupled with mass spectrometry (TAP-MS) analysis, to determine the interactome of AMPK and its functions. We conducted a TAP-MS analysis of all seven AMPK subunits. We identified 138 candidate high-confidence interacting proteins (HCIPs) of AMPK, which allowed us to build an interaction network of AMPK complexes. Five candidate AMPK-binding proteins were experimentally validated, underlining the reliability of our data set. Furthermore, we demonstrated that AMPK acts with a strong AMPK-binding protein, Artemis, in non-homologous end joining. Collectively, our study established the first AMPK interactome and uncovered a new function of AMPK in DNA repair.

Improving Research Patient Data Repositories From a Health Data Industry Viewpoint.

Organizational, administrative, and educational challenges in establishing and sustaining biomedical data science infrastructures lead to the inefficient use of Research Patient Data Repositories (RPDRs). The challenges, including but not limited to deployment, sustainability, cost optimization, collaboration, governance, security, rapid response, reliability, stability, scalability, and convenience, restrict each other and may not be naturally alleviated through traditional hardware upgrades or protocol enhancements. This article attempts to borrow data science thinking and practices in the business realm, which we call the data industry viewpoint, to improve RPDRs.

Using an optimized generative model to infer the progression of complications in type 2 diabetes patients.

BACKGROUND: People live a long time in pre-diabetes/early diabetes without a formal diagnosis or management. Heterogeneity of progression coupled with deficiencies in electronic health records related to incomplete data, discrete events, and irregular event intervals make identification of pre-diabetes and critical points of diabetes progression challenging. METHODS: We utilized longitudinal electronic health records of 9298 patients with type 2 diabetes or prediabetes from 2005 to 2016 from a large regional healthcare delivery network in China. We optimized a generative Markov-Bayesian-based model to generate 5000 synthetic illness trajectories. The synthetic data were manually reviewed by endocrinologists. RESULTS: We build an optimized generative progression model for type 2 diabetes using anchor information to reduce the number of parameters learning in the third layer of the model from [Formula: see text] to [Formula: see text], where [Formula: see text] is the number of clinical findings, [Formula: see text] is the number of complications, [Formula: see text] is the number of anchors. Based on this model, we infer the relationships between progression stages, the onset of complication categories, and the associated diagnoses during the whole progression of type 2 diabetes using electronic health records. DISCUSSION: Our findings indicate that 55.3% of single complications and 31.8% of complication patterns could be predicted early and managed appropriately to potentially delay (as it is a progressive disease) or prevented (by lifestyle modifications that keep patient from developing/triggering diabetes in the first place). CONCLUSIONS: The full type 2 diabetes patient trajectories generated by the chronic disease progression model can counter a lack of real-world evidence of desired longitudinal timeframe while facilitating population health management.

Unexpected White Phosphorus (P4 ) Activation Modes with Silylene-Substituted o-Carboranes and Access to an Isolable 1,3-Diphospha-2,4-disilabutadiene.

New types of metal-free white phosphorus (P4 ) activation are reported. While the phosphine-silylene-substituted dicarborane 1, CB-SiP (CB=ortho-C,C'-C2 B10 H10 , Si=PhC(tBuN)2 Si, P=P[N(tBu)CH2 ]2 ), activates white phosphorus in a 2 : 1 molar ratio to yield the P5 -chain containing species 2, the analogous bis(silylene)-substituted compound 3, CB-Si2 , reacts with P4 in the molar ratio of 2 : 1 to furnish the first isolable 1,3-diphospha-2,4-disilabutadiene (Si=P-Si=P-containing) compound 4. For the latter reaction, two intermediates having a CB-Si2 P4 and CB-Si2 P2 core could be observed by multinuclear NMR spectroscopy. The compounds 2 and 4 were characterized including single-crystal X-ray diffraction analyses. Their electronic structures and mechanisms were investigated by density functional theory calculations.

An Isolable 2,5-Disila-3,4-Diphosphapyrrole and a Conjugated Si=P-Si=P-Si=N Chain Through Degradation of White Phosphorus with a N,N-Bis(Silylenyl)Aniline.

White phosphorus (P4 ) undergoes degradation to P2 moieties if exposed to the new N,N-bis(silylenyl)aniline PhNSi2 1 (Si=Si[N(tBu)]2 CPh), furnishing the first isolable 2,5-disila-3,4-diphosphapyrrole 2 and the two novel functionalized Si=P doubly bonded compounds 3 and 4. The pathways for the transformation of the non-aromatic 2,5-disila-3,4-diphosphapyrrole PhNSi2 P2 2 into 3 and 4 could be uncovered. It became evident that 2 reacts readily with both reactants P4 and 1 to afford either the polycyclic Si=P-containing product [PhNSi2 P2 ]2 P2 3 or the unprecedented conjugated Si=P-Si=P-Si=NPh chain-containing compound 4, depending on the employed molar ratio of 1 and P4 as well as the reaction conditions. Compounds 3 and 4 can be converted into each other by reactions with 1 and P4 , respectively. All new compounds 1-4 were unequivocally characterized including by single-crystal X-ray diffraction analysis. In addition, the electronic structures of 2-4 were established by Density Functional Theory (DFT) calculations.

Cancer SIGVAR: A semiautomated interpretation tool for germline variants of hereditary cancer-related genes.

Cancer is one of the most important health issues globally and the accuracy of interpretation of cancer-related variants is critical for the clinical management of hereditary cancer. ClinGen Sequence Variant Interpretation Working Groups have developed many adaptations of American College of Medical Genetics and Genomics and the Association of Molecular Pathologists guidelines to improve the consistency of interpretation. We combined the most recent adaptations to expand the number of the criteria from 28 to 48 and developed a tool called Cancer SIGVAR to help genetic counselors interpret the clinical significance of cancer germline variants. Our tool can accept VCF files as input and realize fully automated interpretation based on 21 criteria and semiautomated interpretation based on 48 criteria. We validated the performance of our tool with the ClinVar and CLINVITAE benchmark databases, achieving an average consistency for pathogenic and benign assessment up to 93.71% and 79.38%, respectively. We compared Cancer SIGVAR with two similar tools, InterVar and PathoMAN, and analyzed the main differences in criteria and implementation. Furthermore, we selected 911 variants from another two in-house benchmark databases, and semiautomated interpretation reached an average classification consistency of 98.35%. Our findings highlight the need to optimize automated interpretation tools based on constantly updated guidelines. Cancer SIGVAR is publicly available at http://cancersigvar.bgi.com/.

New Types of Ge2 and Ge4 Assemblies Stabilized by a Carbanionic Dicarborandiyl-Silylene Ligand.

The first Ge(0)-Ge(II) germylone-germylene-paired Ge2 complex (LSi)2Ge2 (4) and the molecular Ge4 cluster (LSi)2Ge4 (5) supported by the chelating carbanionic ortho-C,C'-dicarborandiyl-silylene ligand LSi [L = C,C'-C2B10H10, Si = PhC(tBuN)2Si] have been synthesized and isolated via reduction of the corresponding precursors chlorogermyl-germyliumylidene chloride (2), [(LSi)2Ge(Cl)Ge]+Cl-, and (LSi)2Ge4Cl4 (3) with C8K, respectively. The latter precursors were obtained from the unexpected outcome of the reaction of the ortho-C,C'-dicarborandiyl phosphine-silylene ligand PLSi (1) {P = P[N(tBu)CH2]2} and GeCl2·dioxane. Compound 2 is formed in higher yields (65% yields) by the salt metathesis reaction of the C-lithium dicarborandiyl-C'-silylene salt LiLSi (6) [Li = Li(OEt2)2] with GeCl2·dioxane. The molecular structures of all these species (1-6) have been established and confirmed spectroscopically and crystallographically. The electronic structures of 4 and 5 were elucidated by density functional theory calculations. While 4 possesses a localized dative Ge(0)→Ge(II) bond, the Ge-Ge σ bonds in 5 are delocalized in the Ge4 cluster core. Featuring a donor-acceptor interaction between two chelating silylenes and the Ge4 core, compound 5 represents a unique molecular model for a Ge4 cluster.