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Detailed syntheses are reported for the previously reported homoleptic 1-norbornyl complexes [M(norb)4] {M = Ti (1), Zr (3), Hf (4), and Mn (5)}. These compounds were characterized by combustion elemental analysis, NMR spectroscopy, single crystal X-ray diffraction (for 1 and 3), and SQUID magnetometry (for 5). The reaction by-product [{(norb)3Ti}2(μ-O)] (2) was also spectroscopically and structurally characterized. To assess the potential viability of 1 and 3–5 as precursors for thin film deposition by CVD or ALD, their volatility and thermal stability were evaluated by sublimation, thermogravimetric analysis, and in the case of 4, bulk thermolysis.

Mammalian species harbor compositionally distinct gut microbial communities, but the mechanisms that maintain specificity of symbionts to host species remain unclear. Here, we show that natural selection within house mice ( Mus musculus domesticus ) drives deterministic assembly of the house-mouse gut microbiota from mixtures of native and non-native microbiotas. Competing microbiotas from wild-derived lines of house mice and other mouse species ( Mus and Peromyscus spp.) within germ-free wild-type (WT) and Rag1 -knockout ( Rag1 −/− ) house mice revealed widespread fitness advantages for native gut bacteria. Native bacterial lineages significantly outcompeted non-native lineages in both WT and Rag1 −/− mice, indicating home-site advantage for native microbiota independent of host adaptive immunity. However, a minority of native Bacteriodetes and Firmicutes favored by selection in WT hosts were not favored or disfavored in Rag1 −/− hosts, indicating that Rag1 mediates fitness advantages of these strains. This study demonstrates home-site advantage for native gut bacteria, consistent with local adaptation of gut microbiota to their mammalian species.

International audience; Reaction of [(XA2)U(CH2SiMe3)2] (1; XA2 = 4,5-bis(2,6-diisopropylanilido)-2,7-di-tert-butyl-9,9- dimethylxanthene) with 1 equivalent of [Ph3C][B(C6F5)4] in arene solvents afforded the arene-coordinated uranium alkyl cations, [(XA2)U(CH2SiMe3)(hn-arene)][B(C6F5)4] {arene = benzene (2), toluene (3), bromobenzene (4) and fluorobenzene (5)}. Compounds 2, 3, and 5 were crystallographically characterized, and in all cases the arene is π-coordinated. Solution NMR studies of 2-5 suggest that the binding preferences of the [(XA2)U(CH2SiMe3)]+ cation follow the order: toluene ≈ benzene > bromobenzene > fluorobenzene. Compounds 2-4 generated in C6H5R (R = H, Me or Br, respectively) showed no polymerization activity under 1 atm of ethylene. By contrast, 5 and 5-Th (the thorium analogue of 5) in fluorobenzene at 20 and 70 °C achieved ethylene polymerization activities between 16 800 and 139 200 g mol-1 h-1 atm-1, highlighting the extent to which common arene solvents such as toluene can suppress ethylene polymerization activity in sterically open f-element complexes. However, activation of [(XA2) An(CH2SiMe3)2] {M = U (1) or Th (1-Th)} with [Ph3C][B(C6F5)4] in n-alkane solvents did not afford an active polymerization catalyst due to catalyst decomposition, illustrating the critical role of PhX (X = H, Me, Br or F) coordination for alkyl cation stabilization. Gas phase DFT calculations, including fragment interaction calculations with energy decomposition and ETS-NOCV analysis, were carried out on the cationic portion of 2'-Th, 2', 3' and 5' (analogues of 2-Th, 2, 3 and 5 with hydrogen atoms in place of ligand backbone methyl and tert-butyl groups), providing insight into the nature of actinide–arene bonding, which decreases in strength in the order 2'-Th > 2' ≈ 3' > 5'.

Atheromas can be detected incidentally in routine dental cone beam computed tomography (CBCT) images. This study aims to assess prevalence and risk factors associated with these vascular lesions.The maxillofacial CBCT's of 458 subjects were evaluated and divided into 4 groups based on the presence of calcified atheroma: subjects with no calcified atheroma, subjects with intracranial calcified atheroma (ICA), subjects with extracranial calcified atheroma (ECA), and subjects exhibiting combined lesions. Age, sex, medical conditions, family history, and size were documented. ANOVA followed by a multiple comparison test was used for data satisfying parametric test assumptions. Chi Square tests were used to assess categorical data. The Spearman's Rho test was used to assess the correlation between the incidence of calcified atheroma and subjects' medical condition.Of the 458 CBCTs evaluated, 29.90% presented with calcified atheroma. Calcified atheroma prevalence was significantly higher in older patients vs younger patients (p = 0.004) and in males compared to females (p = 0.004). Males were more likely to have the combination of intracranial and extracranial calcified atheroma while females were more likely to have intracranial calcified atheroma alone (p ≤ 0.040). Patients with calcified atheroma were significantly more likely to have a history of hyperlipidemia (p = 0.001), hypertension (p = 0.001), and myocardial infarction/coronary artery diseases (p = 0.001). Overall, patients exhibiting both intracranial and extracranial lesions were more likely to have cardiovascular risk factors (p = 0.001).Incidentally detected calcified atheromas in CBCTs are common. Subjects with combined atheroma lesions are at higher risk for cardiovascular disease. The diagnosis of incidental calcified atheromas in CBCT's warrants early referral to medical specialists, especially if there is no medical history of existing cardiovascular disease. This article is protected by copyright. All rights reserved.

Mammalian species harbor compositionally distinct gut microbial communities, but the mechanisms that maintain specificity of symbionts to host species remain unclear. Here we show that natural selection within house mice (Mus musculus domesticus) drives deterministic assembly of the house-mouse gut microbiota from mixtures of native and non-native microbiotas. Competing microbiotas from wild-derived lines of house mice and other mouse species (Mus and Peromyscus spp.) within germ-free wildtype (WT) and Rag1-knockout (Rag1−/−) house mice revealed widespread fitness advantages for native gut bacteria. Certain native Bacteriodetes and Firmicutes favored by selection in WT hosts were not favored or disfavored in Rag1−/− hosts, which lack adaptive immunity, indicating that Rag1 mediates fitness advantages of these strains. This study demonstrates local adaptation of gut microbiota to a mammalian species.One-Sentence SummaryAdaptive advantages for native bacteria underlie the assembly of the mouse gut microbiota.

Reactions of trans-[(dmpe)2MnH(C2H4)] (1) with BH3(NMe3), 9-BBN, and HBMes2 yielded the manganese(i) borohydride complexes [(dmpe)2Mn(μ-H)2BR2] (3: R = H, 4: R2 = C8H14, 5: R = Mes). The reaction of 1 with BH3(NMe3) proceeds via ethylene substitution. By contrast, a detuerium labelling study indicates that the reaction of 1 with HBMes2 involves initial isomerization of 1 to an unobserved 5-coordinate ethyl intermediate, [(dmpe)2MnEt], which reacts with the hydroborane to afford EtBR2 and [(dmpe)2MnH], followed by reaction with a second equivalent of hydroborane to generate 5 (an analogous pathway is likely followed for other base-free hydroboranes such as 9-BBN). Identification of 3-5 as κ2-borohydride complexes, as opposed to boryl dihydride or hydroborane hydride isomers, is supported by 11B NMR spectroscopy, X-ray diffraction, and Atoms in Molecules calculations. Two byproducts were observed in the syntheses of 3-5: [{(dmpe)2MnH}2(μ-dmpe)] (6) and [(dmpe)2MnH(κ1-dmpe)] (7). These complexes were independently prepared by exposure of 1 to free dmpe under an atmosphere of Ar or H2, and the generality of this synthetic route was demonstrated by the reaction of 1 with PMe3 (under H2) to form [(dmpe)2MnH(PMe3)] (8). Complexes 6-8 can exist as isomers with either a trans or a cis relationship between the hydride and κ1-coordinated phosphine ligands on manganese. trans to cis isomerization of 6-8 is photochemically induced, whereas the reverse reaction occurs under thermal conditions. X-ray crystal structures were obtained for 3-5, trans,trans-6, cis,cis-6, trans-7, and trans-8.

Understanding the mechanism for capacity delivery in conversion/alloying materials (CAM) electrodes, such as ZnO, in lithium-ion batteries (LIBs) requires careful investigation of the electrochemical reactions. Here, we used magic angle spinning (MAS at 60 kHz) 7Li nuclear magnetic resonance (NMR) as a sensitive analytical means to probe the reactions occurring between electrode materials and Li+ ions. The ZnO nanolayer generated on carbon substrate by atomic layer deposition (ALD) enhanced the cyclic capacity of half cell LIB up to 40%. 7Li NMR revealed LixZn alloy formation through an irreversible conversion reaction during discharge. MAS results revealed the dealloying of LixZn at the full charge step which left atomic zinc nanograins that do not undergo the re-oxidation of zinc atoms according to the cyclic voltammetry. An in situ formation of elemental zinc at the initial cycles facilitates uniform lithium deposition on subsequent cycles due to the reduced energy barrier for lithium nucleation on pure zinc as compared to ZnO. X-ray diffraction analysis indicated the crystalline formation of the LixZn alloy while scanning electron microscope showed the uniform morphology for the lithiated discharge products. Cyclic voltammetry and differential capacity functions initially predicted the conversion and alloying reactions.

Rigid thioether- and selenoether-containing pincer proligands H[AS

Manganese silyl dihydride complexes [(dmpe)2MnH2(SiHR2)] {R = Ph (3a), R = Et (3b)} and [(dmpe)2MnH2(SiH2R)] {R = Ph (4a), R = nBu (4b)} were generated by exposure of silylene hydride complexes [(d...

Manganese disilyl hydride complexes [(dmpe)2MnH(SiH2R)2] (4Ph: R = Ph, 4Bu: R = nBu) reacted with ethylene to form silene hydride complexes [(dmpe)2MnH(RHSiCHMe)] (6Ph,H: R = Ph, 6Bu,H: R = nBu). Compounds 6R,H reacted with a second equivalent of ethylene to generate [(dmpe)2MnH(REtSiCHMe)] (6Ph,Et: R = Ph, 6Bu,Et: R = nBu), resulting from apparent ethylene insertion into the silene Si–H bond. Furthermore, in the absence of ethylene, silene complex 6Bu,H slowly isomerized to the silylene hydride complex [(dmpe)2MnH(SiEtnBu)] (3Bu,Et). Reactions of 4R with ethylene likely proceed via low-coordinate silyl {[(dmpe)2Mn(SiH2R)] (2Ph: R = Ph, 2Bu: R = nBu)} or silylene hydride {[(dmpe)2MnH(SiHR)] (3Ph,H: R = Ph, 3Bu,H: R = nBu)} intermediates accessed from 4R by H3SiR elimination. DFT calculations and high temperature NMR spectra support the accessibility of these intermediates, and reactions of 4R with isonitriles or N-heterocyclic carbenes yielded the silyl isonitrile complexes [(dmpe)2Mn(SiH2R)(CNR′)] (7a–d: R = Ph or nBu; R′ = o-xylyl or tBu), and NHC-stabilized silylene hydride complexes [(dmpe)2MnH{SiHR(NHC)}] (8a–d: R = Ph or nBu; NHC = 1,3-diisopropylimidazolin-2-ylidene or 1,3,4,5-tetramethyl-4-imidazolin-2-ylidene), respectively, all of which were crystallographically characterized. Silyl, silylene and silene complexes in this work were accessed via reactions of [(dmpe)2MnH(C2H4)] (1) with hydrosilanes, in some cases followed by ethylene. Therefore, ethylene (C2H4 and C2D4) hydrosilylation was investigated using [(dmpe)2MnH(C2H4)] (1) as a pre-catalyst, resulting in stepwise conversion of primary to secondary to tertiary hydrosilanes. Various catalytically active manganese-containing species were observed during catalysis, including silylene and silene complexes, and a catalytic cycle is proposed.

BDBT interacts with the circadian kinase DBT and accumulates in eye foci during the dark of a light:dark cycle. BDBT is shown here to be constitutively high in the dark and constitutively low in the light. Analysis of circadian photoreceptor cry and visual photoreceptor ninaE mutants showed that disappearance of eye BDBT foci depends upon both the CRY and the RHODOPSIN-1 pathways. The Arr1 and Arr2 mutants which affect rhodopsin quenching eliminated the accumulation of BDBT foci under dark conditions.Arr1 and Arr2 mutants also lead to increased nuclear accumulation of PER protein. Knock-down of BDBT specifically in the eye produced a loss of coupled circadian localization oscillations for both PER and DBT. PER was constitutively nuclear and DBT was constitutively cytosolic. The results show that BDBT is necessary for co-transport of DBT and PER into the nucleus and suggest that this process is regulated by a light dependent mechanism.

INTRODUCTION: Despite viral suppression due to combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND) continue to affect half of people with HIV, suggesting that certain antiretrovirals (ARVs) may contribute to HAND. METHODS: We examined the effects of nucleoside/nucleotide reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) and the integrase inhibitors dolutegravir (DTG) and elvitegravir (EVG) on viability, structure, and function of glutamatergic neurons (a subtype of CNS neuron involved in cognition) derived from human induced pluripotent stem cells (hiPSC-neurons), and primary human neural precursor cells (hNPCs), which are responsible for neurogenesis. RESULTS: Using automated digital microscopy and image analysis (high content analysis, HCA), we found that DTG, EVG, and TDF decreased hiPSC-neuron viability, neurites, and synapses after seven days of treatment. Analysis of hiPSC-neuron calcium activity using Kinetic Image Cytometry (KIC) demonstrated that DTG and EVG also decreased the frequency and magnitude of intracellular calcium transients. Longer ARV exposures and simultaneous exposure to multiple ARVs increased the magnitude of these neurotoxic effects. Using the Microscopic Imaging of Epigenetic Landscapes (MIEL) assay, we found that TDF decreased hNPC viability and changed the distribution of histone modifications that regulate chromatin packing, suggesting that TDF may reduce neuroprogenitor pools important for CNS development and maintenance of cognition in adults. CONCLUSION: This study establishes human preclinical assays that can screen potential ARVs for CNS toxicity to develop safer cART regimens and HAND therapeutics.

Despite viral suppression due to combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND) continue to affect half of people with HIV, suggesting that certain antiretrovirals (ARVs) may contribute to HAND. We examined the effects of nucleoside/nucleotide reverse transcriptase inhibitors tenofovir disproxil fumarate (TDF) and emtricitabine (FTC) and the integrase inhibitors dolutegravir (DTG) and elvitegravir (EVG) on viability, structure, and function of glutamatergic neurons (a subtype of CNS neuron involved in cognition) derived from human induced pluripotent stem cells (hiPSC-neurons), and primary human neural precursor cells (hNPCs), which are responsible for neurogenesis. Using automated digital microscopy and image analysis (high content analysis, HCA), we found that DTG, EVG, and TDF decreased hiPSC-neuron viability, neurites, and synapses after seven days of treatment. Analysis of hiPSC-neuron calcium activity using Kinetic Image Cytometry (KIC) demonstrated that DTG and EVG also decreased the frequency and magnitude of intracellular calcium transients. Longer ARV exposures and simultaneous exposure to multiple ARVs increased the magnitude of these neurotoxic effects. Using the Microscopic Imaging of Epigenetic Landscapes (MIEL) assay, we found that TDF decreased hNPC viability and changed the distribution of histone modifications that regulate chromatin packing, suggesting that TDF may reduce neuroprogenitor pools important for CNS development and maintenance of cognition in adults. This study establishes human preclinical assays that can screen potential ARVs for CNS toxicity to develop safer cART regimens and HAND therapeutics.

Lrig1, an epithelial stem cell marker and tumor suppressor, is uniquely expressed within PDGs in pancreas. PDGs are an epithelial progenitor compartment and likely compartment-of-origin for PDAC. Here, in vivo GFP-lineage tagging of Lrig1 expressing PDG cells identify GFP tagged cells in mesenchyme but not in the main duct epithelium, identifying a cell within a PDG epithelial compartment capable of EMT to regenerate its own micro-environment. Mechanisms regulating this EMT switch results from a loss of Lrig1. Characterization of the GFP-positive mesenchyme and PDG cells confirms EMT. ScRNASeq of epithelial spheroids revealed enhanced mesenchymal features in Lrig1 deficient cells, while Lrig1 overexpression abrogates mesenchymal differentiation. In vivo, in vitro and ex vivo studies reveal the Lrig1 loss within this stem cell compartment results in enhanced EGF and TGF-β signaling, expansion of stem cell, proliferative and mesenchymal markers in addition to the up-regulation of a master regulator of stemness and EMT, PSPC1. In vivo murine models of PDAC (KPC) which tag and lose Lrig1 in the PDG compartment results in the expansion of the PDG stem cell compartment which now resembles low-grade PanINs in addition to the formation of an extensive GFP-positive desmoplasia. In vitro, Lrig1 regulates proliferation and EMT in cancer cell lines. These studies identify Lrig1 as a regulator of stemness and EMT in regeneration and cancer.

Wilkinson’s manganese(I) ethylene hydride complex trans-[(dmpe)2MnH(C2H4)] (1) reacts as a source of a low-coordinate manganese(I) ethyl complex. This is illustrated in the reactivity of 1 toward a variety of reagents. Reactions of 1 with primary silanes RSiH3 (R = Ph, nBu) at 60 °C afforded ethane and the disilyl hydride manganese complexes [(dmpe)2MnH(SiH2R)2] (4a, R = Ph; 4b, R = nBu). Additionally, reaction with H2 at 60 °C afforded ethane and the dihydrogen hydride complex [(dmpe)2MnH(H2)] (5), which has previously been prepared by an alternate route. The proposed low-coordinate intermediate, [(dmpe)2MnEt], was not observed spectroscopically but could be trapped using isonitrile ligands; reaction of 1 with CNR (R = tBu, o-xylyl) afforded the manganese(I) ethyl complexes [(dmpe)2MnEt(CNR)] (6a, R = tBu; 6b, R = o-xylyl). Ethyl complex 6a did not react further with CNtBu at 80 °C. In contrast, complex 6b reacted with excess o-xylyl isonitrile to form 1,1-insertion products, including the iminoacyl comp...

Occasionally, tooth fractures may demonstrate exaggerated pathologic root migration (PRM), often resulting in tooth loss. The early propagation of the root fracture may not be readily identifiable through clinical inspection and conventional radiographic imaging. Ultimately, increased root separation, isolated deep periodontal probing depth, and characteristic radiolucent changes may facilitate the diagnosis. This article describes 3 patients with unusual presentations of PRM in endodontically treated teeth restored with full-coverage crowns. One case illustrates the use of cone beam computed tomography for restorative assessment following root separation. Although it is efficacious to place crowns on most posterior endodontically treated teeth to maintain structural integrity, patients may remain at risk for catastrophic PRM and tooth loss. Timely extraction of teeth with hopeless PRM may minimize underlying bone resorption and the need for osseous regenerative procedures, ultimately improving the dental implant recipient site.

In the early 1980s Jeff Hall and Michael Rosbash at Brandeis University and Mike Young at Rockefeller University set out to isolate the period (per) gene, which was recovered in a revolutionary genetic screen by Ron Konopka and Seymour Benzer for mutants that altered circadian behavioral rhythms. Over the next 15 years the Hall, Rosbash and Young labs made a series of groundbreaking discoveries that defined the molecular timekeeping mechanism and formed the basis for them being awarded the 2017 Nobel Prize in Physiology or Medicine. Here the authors recount their experiences as post-docs in the Hall, Rosbash and Young labs from the mid-1980s to the mid-1990s, and provide a perspective of how basic research conducted on a simple model system during that era profoundly influenced the direction of the clocks field and established novel approaches that are now standard operating procedure for studying complex behavior., Highlights • 2017 Nobel Prize awarded to Hall, Rosbash and Young for circadian clock mechanisms. • Work on fruit flies in the 1980s and 1990s were key to deciphering clock mechanisms. • Authors recount their experiences as postdocs in the Hall, Rosbash and Young labs. • The broad impacts of basic research on fruit fly clock genes.

Under mild conditions (room temperature, 1.1 atm. of CO2), the silyl dihydride complexes [(dmpe)2MnH2(SiHR2)] {R = Ph (1Ph2); Et (1Et2)} reacted rapidly and quantitatively with carbon dioxide to afford [(dmpe)2MnH2{Si(κ1-O2CH)R2)}] {R = Ph (2Ph2); Et (2Et2)}; the products of apparent CO2 insertion into the terminal Si H bond. In addition, room temperature reactions of [(dmpe)2MnH2(SiH2R)] {R = Ph (1Ph); nBu (1Bu)} with CO2 (1.1 atm.) yielded [(dmpe)2MnH2{Si(κ1-O2CH)2R)}] {R = Ph (3Ph); nBu (3Bu)} containing two formate substituents on silicon. The latter reactions proceeded in a stepwise fashion, rapidly forming [(dmpe)2MnH2{SiH(κ1-O2CH)R}] {R = Ph (4Ph); nBu (4Bu)} intermediates, which then slowly converted into 3Ph and 3Bu. During the syntheses of 3Ph and 3Bu, significant amounts of H2 and previously reported [(dmpe)2Mn(CO)(κ1-O2CH)] (5) were also formed. The reaction of [(dmpe)2MnD2(SiH2nBu)] (d2-1Bu) with CO2 was carried out, yielding d2-3Bu as the major reaction product, predominantly (>95%) as [(dmpe)2MnD2{Si(κ1-O2CH)2nBu}] featuring two deuteride ligands. DFT calculations to probe the relative energies of silicate [(dmpe)2Mn(η3-H2SiR3)], trans-hydrosilane/hydride (trans-[(dmpe)2MnH(H–SiR3)]), trans-dihydrogen/silyl (trans-[(dmpe)2Mn(H2)(SiR3)]), and lateral-dihydrogen/silyl (cis-[(dmpe)2Mn(H2)(SiR3)]) isomers of 2Ph2, 3Ph, and 4Ph are also reported; the lowest energy structures of 2Ph2 and 3Ph are those of the silicate isomers, consistent with the NMR spectra obtained for 2R2 and 3R. Also, compound 2Ph2 was isolated, and crystallized as the silicate isomer; the solid state structure of 2Ph2 is qualitatively analogous to that of 1Ph2, but the Mn Si bond in 2Ph2 is significantly shorter {2.2876(7) A vs 2.3176(3) A}.

Reaction of 4,5-bis(2,4,6-triisopropylanilino)-2,7-di-tert-butyl-9,9-dimethylxanthene (H2XN2) with [Zr(NMe2)4], followed by crystallization from O(SiMe3)2, yielded [(XN2)Zr(NMe2)2]·{O(SiMe3)2}0.5 (1·{O(SiMe3)2}0.5). The zirconium dimethyl complex [(XN2)ZrMe2] (2) was subsequently accessed (a) by treatment of 1·(O(SiMe3)2)0.5 with excess AlMe3 or (b) via reaction of 1·(O(SiMe3)2)0.5 with excess Me3SiCl, affording [(XN2)ZrCl2] (3) followed by reaction of 3 with 2 equiv of MeLi. Reaction of [(XN2)ZrMe2] (2) with one equiv of B(C6F5)3 or [CPh3][B(C6F5)4] yielded cationic [(XN2)ZrMe][MeB(C6F5)3] (4) and [(XN2)ZrMe(arene)][B(C6F5)4] {arene = η6-benzene (5a), η6-toluene (5b), or bromobenzene (5c)}, respectively. Both 4 and 5b are active for ethylene polymerization under 1 atm of ethylene at 24 and 80 °C in toluene with activities ranging from 23.5–883 kg mol–1 atm–1 h–1, yielding polymers with weight-average molecular weights (Mw) of 70,800–88,100 g mol–1 and polydispersities (Mw/Mn) of 3.94–4.67.

Postchemotherapy cognitive impairment (PCCI) is commonly exhibited by cancer patients treated with a variety of chemotherapeutic agents, including the endocrine disruptor tamoxifen (TAM). The etiology of PCCI is poorly understood. Our goal was to develop high-throughput assay methods to test the effects of chemicals on neuronal function applicable to PCCI. Rat hippocampal neurons (RHNs) were plated in 96- or 384-well dishes and exposed to test compounds (forskolin [FSK], 17β-estradiol [ES]), TAM or fulvestrant [FUL], aka ICI 182,780) for 6–14 days. Kinetic Image Cytometry™ (KIC™) methods were developed to quantify spontaneously occurring intracellular calcium transients representing the activity of the neurons, and high-content analysis (HCA) methods were developed to quantify the expression, colocalization, and puncta formed by synaptic proteins (postsynaptic density protein-95 [PSD-95] and presynaptic protein Synapsin-1 [Syn-1]). As quantified by KIC, FSK increased the occurrence and synchronization of the calcium transients indicating stimulatory effects on RHN activity, whereas TAM had inhibitory effects. As quantified by HCA, FSK also increased PSD-95 puncta and PSD-95:Syn-1 colocalization, whereas ES increased the puncta of both PSD-95 and Syn-1 with little effect on colocalization. The estrogen receptor antagonist FUL also increased PSD-95 puncta. In contrast, TAM reduced Syn-1 and PSD-95:Syn-1 colocalization, consistent with its inhibitory effects on the calcium transients. Thus TAM reduced activity and synapse formation by the RHNs, which may relate to the ability of this agent to cause PCCI. The results illustrate that KIC and HCA can be used to quantify neurotoxic and neuroprotective effects of chemicals in RHNs to investigate mechanisms and potential therapeutics for PCCI.

Reaction of the ethylene hydride complex trans-[(dmpe)2MnH(C2H4)] (1) with Et2SiH2 at 20 °C afforded the silylene hydride [(dmpe)2MnH(=SiEt2)] (2 a) as the trans-isomer. By contrast, reaction of 1 with Ph2SiH2 at 60 °C afforded [(dmpe)2MnH(=SiPh2)] (2 b) as a mixture of the cis (major) and trans (minor) isomers, featuring a Mn-H-Si interaction in the former. The reaction to form 2 b also yielded [(dmpe)2MnH2(SiHPh2)] (3 b); [(dmpe)2MnH2(SiHR2)] (R=Et (3 a) and Ph (3 b)) were accessed cleanly by reaction of 2 a and 2 b with H2, and the analogous reactions with D2 afforded [(dmpe)2MnD2(SiHR2)] exclusively. Both 2 a and 2 b engaged in unique reactivity with ethylene, generating the silene hydride complexes cis-[(dmpe)2MnH(R2Si=CHMe)] (R=Et (4 a), Ph (4 b)). Compounds trans-2 a, cis-2 b, 3 b, and 4 b were crystallographically characterized, and bonding in 2 a, 2 b, 4 a, and 4 b was probed computationally.

The Muc-1 oncoprotein is a tumor-associated mucin often overexpressed in pancreatic cancer. We report that knockout of Muc-1 reduced the degree of pancreatic inflammation that resulted from infection with Coxsackievirus B3 (CVB3) in a mouse model. CVB3-infected Muc-1-deficient (Muc-1KO) mice had significantly reduced infiltration of macrophages into the murine pancreas. We found that Muc-1 signaling through NF-κB increased expression of ICAM-1, a pro-inflammatory mediator that recruits macrophages. Further investigation revealed that bone marrow derived macrophages (BMDM) from the Muc-1KO mice exhibited defective migration properties, in part due to low expression of the C-C motif chemokine receptor (CCR2) and the integrin Very Late Antigen 4 (VLA-4). The results presented here provide novel insight into the role of Muc-1 in regulating the inflammatory response and the cellular microenvironment in pancreatitis.

Drosophila Double-time (DBT) phosphorylates the circadian protein Period (PER). The period-altering mutation tau, identified in hamster casein kinase I (CKI&epsilon, ) and created in Drosophila DBT, has been shown to shorten the circadian period in flies, as it does in hamsters. Since CKI often phosphorylates downstream of previously phosphorylated residues and the tau amino acid binds a negatively charged ion in X-ray crystal structures, this amino acid has been suggested to contribute to a phosphate recognition site for the substrate. Alternatively, the tau amino acid may affect a nuclear localization signal (NLS) with which it interacts. We mutated the residues that were close to or part of the phosphate recognition site or NLS. Flies expressing DBT with mutations of amino acids close to or part of either of these motifs produced a shortening of period, suggesting that a domain, including the phosphate recognition site or the NLS, can be mutated to produce the short period phenotype. Mutation of residues affecting internally placed residues produced a longer period, suggesting that a specific domain on the surface of the kinase might generate an interaction with a substrate or regulator, with short periods produced when the interaction is disrupted.

Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal health companies in their search for novel pesticides and ectoparasiticides. Herein we report the discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral treatment of flea and tick infestation on dogs.

The solid-state structures and the physical, solution magnetic, solid-state magnetic, and spectroscopic (NMR and UV/vis) properties of a range of oxygen- and nitrogen-free dialkylmanganese(II) complexes are reported, and the solution reactivity of these complexes toward H2 and ZnEt2 is described. The compounds investigated are [{Mn(μ-CH2SiMe3)2}∞] (1), [{Mn(CH2CMe3)(μ-CH2CMe3)2}2{Mn(μ-CH2CMe3)2Mn}] (2), [Mn(CH2SiMe3)2(dmpe)] (3; dmpe = 1,2-bis(dimethylphosphino)ethane), [{Mn(CH2CMe3)2(μ-dmpe)}2] (4), [{Mn(CH2SiMe3)(μ-CH2SiMe3)}2(μ-dmpe)] (5), [{Mn(CH2CMe3)(μ-CH2CMe3)}2(μ-dmpe)] (6), [{Mn(CH2SiMe3)(μ-CH2SiMe3)}2(μ-dmpm)] (7; dmpm = bis(dimethylphosphino)methane), and [{Mn(CH2CMe3)(μ-CH2CMe3)}2(μ-dmpm)] (8). Syntheses for 1–4 have previously been reported, but the solid-state structures and most properties of 2–4 had not been described. Compounds 5 and 6, with a 1:2 dmpe/Mn ratio, were prepared by reaction of 3 and 4 with base-free 1 and 2, respectively. Compounds 7 and 8 were accessed by reaction of 1 and ...