Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress.

Alphaviruses cause severe arthritogenic or encephalitic disease. The E1 structural glycoprotein is highly conserved in these viruses and mediates viral fusion with host cells. However, the role of antibody responses to the E1 protein in immunity is poorly understood. We isolated E1-specific human monoclonal antibodies (mAbs) with diverse patterns of recognition for alphaviruses (ranging from Eastern equine encephalitis virus [EEEV]-specific to alphavirus cross-reactive) from survivors of natural EEEV infection. Antibody binding patterns and epitope mapping experiments identified differences in E1 reactivity based on exposure of epitopes on the glycoprotein through pH-dependent mechanisms or presentation on the cell surface prior to virus egress. Therapeutic efficacy in vivo of these mAbs corresponded with potency of virus egress inhibition in vitro and did not require Fc-mediated effector functions for treatment against subcutaneous EEEV challenge. These studies reveal the molecular basis for broad and protective antibody responses to alphavirus E1 proteins.

The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic results disclosure in diverse families.

Digital solutions are needed to support rapid increases in the application of genetic/genomic tests (GTs) in diverse clinical settings and patient populations. We developed GUÍA, a bilingual digital application that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GTs. The trial evaluated GUÍA's impact on understanding the GT results by randomizing families to results disclosure genetic counseling with GUÍA (intervention) or standard of care (SOC). Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6 months later. Survey measures assessed the primary study outcomes of participants' perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. The analysis included 551 diverse participants, 270 in the GUÍA arm and 281 in SOC. Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR = 2.8, CI[1.004, 7.617], p = 0.049) and maintained higher objective understanding over time (OR = 1.1, CI[1.004, 1.127], p = 0.038) compared to SOC. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR = 3.9, CI[1.603, 9.254], p = 0.003), confidence (OR = 2.7, CI[1.021, 7.277], p = 0.046), and objective understanding (OR = 1.1, CI[1.009, 1.212], p = 0.032) compared to SOC. This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions and builds a case for utilizing GUÍA to deliver complex results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics.

Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region.

The three human pathogenic ebolaviruses: Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) virus, cause severe disease with high fatality rates. Epitopes of ebolavirus glycoprotein (GP) recognized by antibodies with binding breadth for all three ebolaviruses are of major interest for rational vaccine design. In particular, the heptad repeat 2 -membrane-proximal external region (HR2-MPER) epitope is relatively conserved between EBOV, BDBV, and SUDV GP and targeted by human broadly-neutralizing antibodies. To study whether this epitope can serve as an immunogen for the elicitation of broadly-reactive antibody responses, protein design in Rosetta was employed to transplant the HR2-MPER epitope identified from a co-crystal structure with the known broadly-reactive monoclonal antibody (mAb) BDBV223 onto smaller scaffold proteins. From computational analysis, selected immunogen designs were produced as recombinant proteins and functionally validated, leading to the identification of a sterile alpha motif (SAM) domain displaying the BDBV-HR2-MPER epitope near its C terminus as a promising candidate. The immunogen was fused to one component of a self-assembling, two-component nanoparticle and tested for immunogenicity in rabbits. Robust titers of cross-reactive serum antibodies to BDBV and EBOV GPs and moderate titers to SUDV GP were induced following immunization. To confirm the structural composition of the immunogens, solution NMR studies were conducted and revealed structural flexibility in the C-terminal residues of the epitope. Overall, our study represents the first report on an epitope-focused immunogen design based on the structurally challenging BDBV-HR2-MPER epitope.

Potent neutralization of Rift Valley fever virus by human monoclonal antibodies through fusion inhibition.

Rift Valley fever virus (RVFV), an emerging arboviral and zoonotic bunyavirus, causes severe disease in livestock and humans. Here, we report the isolation of a panel of monoclonal antibodies (mAbs) from the B cells of immune individuals following natural infection in Kenya or immunization with MP-12 vaccine. The B cell responses of individuals who were vaccinated or naturally infected recognized similar epitopes on both Gc and Gn proteins. The Gn-specific mAbs and two mAbs that do not recognize either monomeric Gc or Gn alone but recognized the hetero-oligomer glycoprotein complex (Gc+Gn) when Gc and Gn were coexpressed exhibited potent neutralizing activities in vitro, while Gc-specific mAbs exhibited relatively lower neutralizing capacity. The two Gc+Gn-specific mAbs and the Gn domain A-specific mAbs inhibited RVFV fusion to cells, suggesting that mAbs can inhibit the exposure of the fusion loop in Gc, a class II fusion protein, and thus prevent fusion by an indirect mechanism without direct fusion loop contact. Competition-binding analysis with coexpressed Gc/Gn and mutagenesis library screening indicated that these mAbs recognize four major antigenic sites, with two sites of vulnerability for neutralization on Gn. In experimental models of infection in mice, representative mAbs recognizing three of the antigenic sites reduced morbidity and mortality when used at a low dose in both prophylactic and therapeutic settings. This study identifies multiple candidate mAbs that may be suitable for use in humans against RVFV infection and highlights fusion inhibition against bunyaviruses as a potential contributor to potent antibody-mediated neutralization.

Zirconium-Catalyzed C-H Alumination of Polyolefins, Paraffins, and Methane.

C-H/Et-Al exchange in zirconium-catalyzed reactions of saturated hydrocarbons and AlEt3 affords versatile organoaluminum compounds and ethane. The grafting of commercially available Zr(OtBu)4 on silica/alumina gives monopodal ≡SiO-Zr(OtBu)3 surface pre-catalyst sites that are activated in situ by ligand exchange with AlEt3. The catalytic C-H alumination of dodecane at 150 °C followed by quenching in air affords n-dodecanol as the major product, revealing selectivity for methyl group activation. Shorter hydrocarbon or alcohol products were not detected under these conditions. Catalytic reactions of cyclooctane and AlEt3, however, afford ring-opened products, indicating that C-C bond cleavage occurs readily in methyl group-free reactants. This selectivity for methyl group alumination enables the C-H alumination of polyethylenes, polypropylene, polystyrene, and poly-α-olefin oils without significant chain deconstruction. In addition, the smallest hydrocarbon, methane, undergoes selective mono-alumination under solvent-free catalytic conditions, providing a direct route to Al-Me species.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

PURPOSE: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. METHODS: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. RESULTS: A total of 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P < .001). Yield was greater for GS vs TGPs in Hispanic/Latino(a) (17.2% vs 9.5%, P < .001) and White/European American (19.8% vs 7.9%, P < .001) but not in Black/African American (11.5% vs 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. CONCLUSION: GS may yield up to twice as many diagnoses in pediatric patients compared with TGP testing but not yet across all population groups.

A repeated cross-sectional study of intestinal parasites in Texas shelter dogs using fecal flotation and saline sedimentation.

Estimates of intestinal parasite prevalence in canine populations have largely been based on use of fecal flotation methods only. Dogs in animal shelters are likely at higher risk of intestinal parasite infection because of their previous exposure history. Our objectives were to estimate the prevalence of intestinal parasites among Texas shelter dogs using centrifugal fecal flotation and saline sedimentation techniques, to identify risk factors for infection, and to compare proportions of positive samples detected via fecal flotation vs. saline sedimentation for the most common parasites. Using a repeated cross-sectional study design, we collected fecal samples from dogs on three visits to each of seven Texas animal shelters between May 2013 and December 2014. Fecal flotation and/or saline sedimentation were used to identify parasites in samples. Fecal samples were collected from 529 dogs. The most frequently detected parasites were Ancylostoma caninum (26.4% via fecal flotation, 20.7% via saline sedimentation) and Trichuris vulpis (12.0% via fecal flotation, 14.1% via saline sedimentation). Risk factors for certain parasites were identified; for example, dogs with abnormal fecal consistency were more likely to be shedding T. vulpis eggs than dogs with normal fecal consistency (OR = 1.8, p = 0.005). The addition of fecal sedimentation not only added to the number of parasite species detected in this study, but it also increased the number of dogs diagnosed with the common intestinal parasites that are primarily detected using fecal flotation methods. Texas shelter dogs carry a high burden of intestinal parasites, including those of zoonotic importance.

Identification of Driver Epistatic Gene Pairs Combining Germline and Somatic Mutations in Cancer.

Cancer arises from the complex interplay of various factors. Traditionally, the identification of driver genes focuses primarily on the analysis of somatic mutations. We describe a new method for the detection of driver gene pairs based on an epistasis analysis that considers both germline and somatic variations. Specifically, the identification of significantly mutated gene pairs entails the calculation of a contingency table, wherein one of the co-mutated genes can exhibit a germline variant. By adopting this approach, it is possible to select gene pairs in which the individual genes do not exhibit significant associations with cancer. Finally, a survival analysis is used to select clinically relevant gene pairs. To test the efficacy of the new algorithm, we analyzed the colon adenocarcinoma (COAD) and lung adenocarcinoma (LUAD) samples available at The Cancer Genome Atlas (TCGA). In the analysis of the COAD and LUAD samples, we identify epistatic gene pairs significantly mutated in tumor tissue with respect to normal tissue. We believe that further analysis of the gene pairs detected by our method will unveil new biological insights, enhancing a better description of the cancer mechanism.

Ring Contraction of a Tungstacyclopentane Supported on Silica: Direct Conversion of Ethylene to Propylene.

The reaction of W(NAr)(13C4H8)(OSiPh3)2 (1) (NAr = 2,6-diisopropylphenylimido) with silica partially dehydroxylated at 700 °C (SiO2-700) is highly dependent on the reaction conditions. The primary product of this reaction is W(NAr)(13C4H8)(OSiPh3)(OSi(O-)3) (2) when the reaction is carried out in the dark. Grafting 1 onto SiO2-700 in ambient lab light results in the formation of 2, W(NAr)(13CH213CH2)(OSiPh3)(OSi(O-)3) (4), and one isomer of square-pyramidal W(NAr)(13CH213CH(13Me)13CH2)(OSiPh3)(OSi(O-)3) (3). Heating 2 to 85 °C for 6 h results in the formation of 3, 4, W(NAr)(13CH(13Me)13CH213CH2)(OSiPh3)(OSi(O-)3) (5), and W(NAr)((13CH2)213CH(13Me)(13CH2)2)(OSiPh3)(OSi(O-)3) (6). Photolysis of 2 with blue LEDs (λmax = 450 nm) produces 4, both isomers of 3, 5, and free ethylene. In the presence of excess ethylene and blue LED irradiation at 85 °C, 1/SiO2-700 catalyzes the direct conversion of ethylene to propylene.

X-ray absorption spectroscopy insights on the structure anisotropy and charge transfer in Chevrel Phase chalcogenides.

The electronic structure and local coordination of binary (Mo6T8) and ternary Chevrel Phases (MxMo6T8) are investigated for a range of metal intercalant and chalcogen compositions. We evaluate differences in the Mo L3-edge and K-edge X-ray absorption near edge structure across the suite of chalcogenides MxMo6T8 (M = Cu, Ni, x = 1-2, T = S, Se, Te), quantifying the effect of compositional and structural modification on electronic structure. Furthermore, we highlight the expansion, contraction, and anisotropy of Mo6 clusters within these Chevrel Phase frameworks through extended X-ray absorption fine structure analysis. Our results show that metal-to-cluster charge transfer upon intercalation is dominated by the chalcogen acceptors, evidenced by significant changes in their respective X-ray absorption spectra in comparison to relatively unaffected Mo cations. These results explain the effects of metal intercalation on the electronic and local structure of Chevrel Phases across various chalcogen compositions, and aid in rationalizing electron distribution within the structure.

The Intratumor Bacterial and Fungal Microbiome Is Characterized by HPV, Smoking, and Alcohol Consumption in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) tumor phenotypes and clinical outcomes are significantly influenced by etiological agents, such as HPV infection, smoking, and alcohol consumption. Accordingly, the intratumor microbiome has been increasingly implicated in cancer progression and metastasis. However, few studies characterize the intratumor microbial landscape of HNSCC with respect to these etiological agents. In this study, we aimed to investigate the bacterial and fungal landscape of HNSCC in association with HPV infection, smoking, and alcohol consumption. RNA-sequencing data were extracted from The Cancer Genome Atlas (TCGA) regarding 449 tissue samples and 44 normal samples. Pathoscope 2.0 was used to extract the microbial reads. Microbe abundance was compared to clinical variables, oncogenic signatures, and immune-associated pathways. Our results demonstrated that a similar number of dysregulated microbes was overabundant in smokers and nonsmokers, while heavy drinkers were characterized by an underabundance of dysregulated microbes. Conversely, the majority of dysregulated microbes were overabundant in HPV+ tumor samples when compared to HPV- tumor samples. Moreover, we observed that many dysregulated microbes were associated with oncogenic and metastatic pathways, suggesting their roles in influencing carcinogenesis. These microbes provide insights regarding potential mechanisms for tumor pathogenesis and progression with respect to the three etiological agents.

The Association Between Service Connection and Treatment Outcome in Veterans Undergoing Residential PTSD Treatment.

The Department of Veterans Affairs has invested significant time and resources into the treatment of posttraumatic stress disorder (PTSD). Despite concerted efforts, a significant portion of patients do not respond optimally to trauma-focused treatment. One of the factors that has been hypothesized to be associated with treatment response is participation in the Veterans Benefits Administration service-connected disability process. This factor may be particularly relevant in the residential treatment setting, where most participants are engaged in the compensation seeking process. We conducted a retrospective chart review of 105 veterans who completed Cognitive Processing Therapy (CPT) in a residential rehabilitation program. ANCOVAs that adjusted for baseline PTSD severity compared symptom change between those who were and were non-compensation seeking at the time of treatment. Compensation seeking status was associated with significantly less symptom improvement over the course of CPT after adjusting for baseline PTSD severity (F(1, 102) = 4.29, p < .001, η2 = .03). Sensitivity analyses did not detect a similar effect during a prior coping skills phase of treatment. During CPT, clinically significant change was met by 66.7% of non-compensation seeking veterans (M = -15, SD = 14.56) and by 40.1% of the compensation seeking group (M = -7.1, SD = 12.24). Compensation-seeking may be associated with reduced response to trauma-focused treatment in certain settings. Future research is needed to better understand the mechanisms underlying this effect.

Spontaneous verbal repetition in toddler-adult conversations: a longitudinal study with Spanish-speaking two- year-olds.

The role of children's verbal repetition of parents' utterances on vocabulary growth has been well documented (Masur, 1999). Nevertheless, few studies have analyzed adults' and children's spontaneous verbal repetition around the second birthday distinguishing between the types of repetition. We analyzed longitudinally Spanish-speaking parent-child dyads during spontaneous interaction at 21, 24 and 30 months. Linguistic level was measured using the Spanish version of the MacArthur CDI (López-Ornat et al., 2005). Children's and adults' repetitions are about 17% of the speech. Children repeated adults' utterances in a reduced manner whereas adults produced more extended repetitions. Adults' rate of repetition predicted children's linguistic level at 30 months. Children's rate of repetition did not predict linguistic level. These results suggest that parents adapt their speech to children's communicative abilities. Since children's rate of repetition did not predict linguistic level, we suggest that verbal imitation plays an indirect and complex role in communicative development.

The genetic impact of an Ebola outbreak on a wild gorilla population.

BACKGROUND: Numerous Ebola virus outbreaks have occurred in Equatorial Africa over the past decades. Besides human fatalities, gorillas and chimpanzees have also succumbed to the fatal virus. The 2004 outbreak at the Odzala-Kokoua National Park (Republic of Congo) alone caused a severe decline in the resident western lowland gorilla (Gorilla gorilla gorilla) population, with a 95% mortality rate. Here, we explore the immediate genetic impact of the Ebola outbreak in the western lowland gorilla population. RESULTS: Associations with survivorship were evaluated by utilizing DNA obtained from fecal samples from 16 gorilla individuals declared missing after the outbreak (non-survivors) and 15 individuals observed before and after the epidemic (survivors). We used a target enrichment approach to capture the sequences of 123 genes previously associated with immunology and Ebola virus resistance and additionally analyzed the gut microbiome which could influence the survival after an infection. Our results indicate no changes in the population genetic diversity before and after the Ebola outbreak, and no significant differences in microbial community composition between survivors and non-survivors. However, and despite the low power for an association analysis, we do detect six nominally significant missense mutations in four genes that might be candidate variants associated with an increased chance of survival. CONCLUSION: This study offers the first insight to the genetics of a wild great ape population before and after an Ebola outbreak using target capture experiments from fecal samples, and presents a list of candidate loci that may have facilitated their survival.

Nucleophilic Addition to π-Allyl Gold(III) Complexes: Evidence for Direct and Undirect Paths.

π-Allyl complexes play a prominent role in organometallic chemistry and have attracted considerable attention, in particular the π-allyl Pd(II) complexes which are key intermediates in the Tsuji-Trost allylic substitution reaction. Despite the huge interest in π-complexes of gold, π-allyl Au(III) complexes were only authenticated very recently. Herein, we report the reactivity of (P,C)-cyclometalated Au(III) π-allyl complexes toward ß-diketo enolates. Behind an apparently trivial outcome, i.e. the formation of the corresponding allylation products, meticulous NMR studies combined with DFT calculations revealed a complex and rich mechanistic picture. Nucleophilic attack can occur at the central and terminal positions of the π-allyl as well as the metal itself. All paths are observed and are actually competitive, whereas addition to the terminal positions largely prevails for Pd(II). Auracyclobutanes and π-alkene Au(I) complexes were authenticated spectroscopically and crystallographically, and Au(III) σ-allyl complexes were unambiguously characterized by multinuclear NMR spectroscopy. Nucleophilic additions to the central position of the π-allyl and to gold are reversible. Over time, the auracyclobutanes and the Au(III) σ-allyl complexes evolve into the π-alkene Au(I) complexes and release the C-allylation products. The relevance of auracyclobutanes in gold-mediated cyclopropanation was demonstrated by inducing C-C coupling with iodine. The molecular orbitals of the π-allyl Au(III) complexes were analyzed in-depth, and the reaction profiles for the addition of ß-diketo enolates were thoroughly studied by DFT. Special attention was devoted to the regioselectivity of the nucleophilic attack, but C-C coupling to give the allylation products was also considered to give a complete picture of the reaction progress.

Machine Learning Guided Synthesis of Multinary Chevrel Phase Chalcogenides.

The Chevrel phase (CP) is a class of molybdenum chalcogenides that exhibit compelling properties for next-generation battery materials, electrocatalysts, and other energy applications. Despite their promise, CPs are underexplored, with only ∼100 compounds synthesized to date due to the challenge of identifying synthesizable phases. We present an interpretable machine-learned descriptor (Hδ) that rapidly and accurately estimates decomposition enthalpy (ΔHd) to assess CP stability. To develop Hδ, we first used density functional theory to compute ΔHd for 438 CP compositions. We then generated >560 000 descriptors with the new machine learning method SIFT, which provides an easy-to-use approach for developing accurate and interpretable chemical models. From a set of >200 000 compositions, we identified 48 501 CPs that Hδ predicts are synthesizable based on the criterion that ΔHd < 65 meV/atom, which was obtained as a statistical boundary from 67 experimentally synthesized CPs. The set of candidate CPs includes 2307 CP tellurides, an underexplored CP subset with a predicted preference for channel site occupation by cation intercalants that is rare among CPs. We successfully synthesized five of five novel CP tellurides attempted from this set and confirmed their preference for channel site occupation. Our joint computational and experimental approach for developing and validating screening tools that enable the rapid identification of synthesizable materials within a sparse class is likely transferable to other materials families to accelerate their discovery.

GUÍA: a digital platform to facilitate result disclosure in genetic counseling.

PURPOSE: Use of genomic sequencing is increasing at a pace that requires technological solutions to effectively meet the needs of a growing patient population. We developed GUÍA, a web-based application, to enhance the delivery of genomic results and related clinical information to patients and families. METHODS: GUÍA development occurred in five overlapping phases: formative research, content development, stakeholder/community member input, user interface design, and web application development. Development was informed by formative qualitative research involving parents (N = 22) whose children underwent genomic testing. Participants enrolled in the NYCKidSeq pilot study (N = 18) completed structured feedback interviews post-result disclosure using GUÍA. Genetic specialists, researchers, patients, and community stakeholders provided their perspectives on GUÍA's design to ensure technical, cultural, and literacy appropriateness. RESULTS: NYCKidSeq participants responded positively to the use of GUÍA to deliver their children's results. All participants (N = 10) with previous experience with genetic testing felt GUÍA improved result disclosure, and 17 (94%) participants said the content was clear. CONCLUSION: GUÍA communicates complex genomic information in an understandable and personalized manner. Initial piloting demonstrated GUÍA's utility for families enrolled in the NYCKidSeq pilot study. Findings from the NYCKidSeq clinical trial will provide insight into GUÍA's effectiveness in communicating results among diverse, multilingual populations.

Stimuli-Responsive DNA Binding by Synthetic Systems.

DNA is the molecule responsible for the storage and transmission of the genetic information in living organisms. The expression of this information is highly regulated. In eukaryotes, it is achieved mainly at the transcription level thanks to specialized proteins called transcription factors (TFs) that recognize specific DNA sequences, thereby promoting or inhibiting the transcription of particular genes. In many cases, TFs are present in the cell in an inactive form but become active in response to an external signal, which might modify their localization and DNA binding properties or modulate their interactions with the rest of the transcriptional machinery. As a result of the crucial role of TFs, the design of synthetic peptides or miniproteins that can emulate their DNA binding properties and eventually respond to external stimuli is of obvious interest. On the other hand, although the B-form double helix is the most common DNA secondary structure, it is not the only one with an essential biological function. Guanine quadruplexes (GQs) have received considerable attention due to their critical role in the regulation of gene expression, which is usually associated with a change in the GQ conformation. Thus, the development of GQ probes whose properties can be controlled using external signals is also of significant relevance.In this Account, we present a summary of the recent efforts toward the development of stimuli-responsive synthetic DNA binders with a particular emphasis on our own contributions. We first introduce the structure of B and GQ DNAs, and some of the main factors underlying their selective recognition. We then discuss some of the different approaches used for the design of stimulus-mediated DNA binders. We have organized our discussion according to whether the interaction takes place with duplex or guanine quadruplex DNAs, and each section is divided according to the nature of the stimulus (i.e., physical or chemical). Regarding physical stimuli, light (through the incorporation of photolabile protecting groups or photoisomerizable agents) is the most common input for the activation/deactivation of DNA binding events. With respect to chemical signals, the use of metals (through the incorporation of metal-coordinating groups in the DNA binding agent) has allowed the development of a wide range of stimuli-responsive DNA binders. More recently, redox-based systems have also been used to control DNA interactions.This Account ends with a "Conclusions and Outlook" section highlighting some of the general lessons that have been learned and future directions toward further advancing the field.

Ethylene Polymerization Activity of (R3P)Ni(codH)+ (cod = 1,5-cylcooctadiene) Sites Supported on Sulfated Zirconium Oxide.

PAr3 containing o-OMe, o-Me, or o-Et substituents reacts with Brønsted sites on sulfated zirconium oxide (SZO) to form [HPAr3][SZO]. The phosphonium sites on this material react with bis(cyclooctadiene)nickel [Ni(cod)2] to form [Ni(PAr3)(codH)][SZO] that are active in ethylene polymerization reactions. Selective poisoning studies with pyridine show that ∼90% of the Ni(PAr3)(codH)+ sites in this material are active in polymerization reactions.