Connected in health: Place-to-place commuting networks and COVID-19 spillovers.

Biweekly county COVID-19 data were linked with Longitudinal Employer-Household Dynamics data to analyze population risk exposures enabled by pre-pandemic, country-wide commuter networks. Results from fixed-effects, spatial, and computational statistical approaches showed that commuting network exposure to COVID-19 predicted an area's COVID-19 cases and deaths, indicating spillovers. Commuting spillovers between counties were independent from geographic contiguity, pandemic-time mobility, or social media ties. Results suggest that commuting connections form enduring social linkages with effects on health that can withstand mobility disruptions. Findings contribute to a growing relational view of health and place, with implications for neighborhood effects research and place-based policies.

Perceived risk, political polarization, and the willingness to follow COVID-19 mitigation guidelines.

OBJECTIVE: Risk assessment and response is important for understanding human behavior. The divisive context surrounding the coronavirus pandemic inspires our exploration of risk perceptions and the polarization of mitigation practices (i.e., the degree to which the behaviors of people on the political "Left" diverge from those on the "Right"). Specifically, we investigate the extent to which the political polarization of willingness to comply with mitigation behaviors changes with risk perceptions. METHOD: Analyses use data from two sources: an original dataset of Twitter posts and a nationally-representative survey. In the Twitter data, negative binomial regression models are used to predict mitigation intent measured using tweet counts. In the survey data, logit models predict self-reported mitigation behavior (vaccination, masking, and social distancing). RESULTS: Findings converged across both datasets, supporting the idea that the links between political orientation and willingness to follow mitigation guidelines depend on perceived risk. People on the Left are more inclined than their Right-oriented colleagues to follow guidelines, but this polarization tends to decrease as the perceived risk of COVID-19 intensifies. Additionally, we find evidence that exposure to COVID-19 infections sends ambiguous signals about the risk of the virus while COVID-19 related deaths have a more consistent impact on mitigation behaviors. CONCLUSIONS: Pandemic-related risks can create opportunities for perceived "common ground," between the political "Right" and "Left." Risk perceptions and politics interact in their links to intended COVID-19 mitigation behavior (as measured both on Twitter and in a national survey). Our results invite a more complex interpretation of political polarization than those stemming from simplistic analyses of partisanship and ideology.

Saving Grace? Religious ecology and deaths of despair.

Since the late 1990s, deaths related to drug and alcohol abuse and suicide have increased substantially in the United States. Religious ecology is an important community attribute with theoretical links to these "deaths of despair." This study uses spatial autoregressive models to explore the relationship between religious ecology and deaths of despair, analyzing 2,992 US counties. Analyses focus on the effects of four American religious traditions (Mainline Protestant, Evangelical Protestant, Black Protestant, and Catholic), and how religious ecological effects interact with structural community disadvantage. Mainline Protestantism is protective in communities of low to medium disadvantage, while Black Protestantism is protective at high levels of disadvantage. Catholicism is positively associated with death rate at high levels of disadvantage. These denominational differences are likely linked to social processes of organizational support and norms about alcohol, which vary in efficacy and salience by community disadvantage. Overall, findings highlight the importance of religious ecology to understanding community health and mortality, as well as nuance in where and how religious ecology matters.

Electronic and Combustible Cigarette Use in Adolescence: Links With Adjustment, Delinquency, and Other Substance Use.

PURPOSE: The purpose of the study was to identify proximal links between electronic cigarette (e-cigarette) use and numerous indicators of adjustment, delinquency, and other substance use in adolescence, beyond prior levels and confounders. METHODS: The ongoing Millennium Cohort Study is a nationally representative, intergenerational, longitudinal study of children born 2000-2001 in the United Kingdom followed from birth to age 14 years (n = 11,564 adolescents and their parents). A series of ordinary least squares and logistic regressions compared 14-year-old e-cigarette only users to never users and to combustible/dual users on 10 measures of adjustment (school engagement, well-being, and self-esteem), delinquency (theft, vandalism, disorderly conduct, and graffitiing), and other substance use (frequent alcohol use, heavy drinking, and marijuana use). Controls included each outcome variable measured at age 11 years and prospectively assessed parent and child confounders (e.g., parent education, child externalizing and internalizing behaviors, cognitive test scores, gender, and race/ethnicity). RESULTS: At age 14 years, e-cigarette only users (approximately 7% of youth) had a higher risk of adolescent adjustment problems, delinquent behavior, and substance use relative to nonusers (75% of youth), but lower risk relative to combustible cigarette/dual users (18% of youth), even after controlling for a host of childhood confounders. CONCLUSIONS: Positive links shown here between e-cigarette use and poor adjustment, delinquency, and other substance use in adolescence, coupled with accumulating evidence that e-cigarettes substantially increase youths' likelihood of combustible smoking, indicate that e-cigarettes are part of an emerging pattern of health-risk behaviors and poor adjustment for some youth.

Self-Assembly of Nanoparticles into Two-Dimensional Arrays for Catalytic Applications.

Self-assembly of nanoparticles (NPs) is at the heart of nanotechnology, and has shown many potential applications in fabricating nanodevices with highly controlled functionality. Two-dimensional (2D) arrays of NPs can provide a thin and uniform NP array with each NP being exposed on the surface to maximize NP catalysis. This minireview summarizes the recent progress on the fabrication and application of 2D NP arrays. It conveys the important message to readers that creation of libraries of NP arrays with varying catalytic strengths is an exciting direction in catalysis. This approach can be used to solve complicated catalytic problems in which multiple chemical reactions need to be catalyzed in a single reaction vessel.

Rational design of novel irreversible inhibitors for human arginase.

Parasites have developed a variety of strategies for invading hosts and escaping their immune response. A common mechanism by which parasites escape nitric oxide (NO) toxicity is the activation of host arginase. This activation leads to a depletion of l-arginine, which is the substrate for NO synthase, resulting in lower levels of NO and increased production of polyamines that are necessary for parasite growth and differentiation. For this reason, small molecule inhibitors for arginase show promise as new anti-parasitic chemotherapeutics. However, few arginase inhibitors have been reported. Here, we describe the discovery of novel irreversible arginase inhibitors, and their characterization using biochemical, kinetic, and structural studies. Importantly, we determined the site on human arginase that is labeled by one of the small molecule inhibitors. The tandem mass spectra data show that the inhibitor occupies the enzyme active site and forms a covalent bond with Thr135 of arginase. These findings pave the way for the development of more potent and selective irreversible arginase inhibitors.

Hydrodehalogenation of Polyhalogenated Aromatics Catalyzed by NiPd Nanoparticles Supported on Nitrogen-Doped Graphene.

Ni30 Pd70 nanoparticles supported on nitrogen-doped graphene (NG) acts as a catalyst for the hydrodehalogenation of halogenated aromatics under mild reaction conditions. It reduces mono- or dichloroarenes to the corresponding dehalogenated arenes in >90 % yield in 10 % aqueous isopropanol solvent at or below 50 °C within 5 h. Tests on a variety of substrates containing various functional groups show that the catalyst is selective for reduction of C-Cl and C-Br bonds. In addition, this catalyst completely hydrodehalogenates high-concentration solutions of dioxin, polychlorinated biphenyls, chloroaromatic constituents of the defoliant agent orange, and polybrominated diphenyl ethers in 12 h. The catalyst is reusable and shows no morphological or compositional changes after 5 cycles. This methodology offers a powerful, low-cost, and safe technology for the degradation of polyhalogenated aromatics, and may be useful for preventing proliferation of these toxins in the environment from causing serious health issues.

Maximizing the Catalytic Activity of Nanoparticles through Monolayer Assembly on Nitrogen-Doped Graphene.

We report a facile method for assembly of a monolayer array of nitrogen-doped graphene (NG) and nanoparticles (NPs) and the subsequent transfer of two layers onto a solid substrate (S). Using 3 nm NiPd NPs as an example, we demonstrate that NiPd-NG-Si (Si=silicon wafer) can function as a catalyst and show maximum NiPd catalysis for the hydrolysis of ammonia borane (H3 NBH3 , AB) with a turnover frequency (TOF) of 4896.8 h-1 and an activation energy (Ea ) of 18.8 kJ mol-1 . The NiPd-NG-S catalyst is also highly active for catalyzing the transfer hydrogenation from AB to nitro compounds, leading to the green synthesis of quinazolines in water. Our assembly method can be extended to other graphene and NP catalyst materials, providing a new 2D NP catalyst platform for catalyzing multiple reactions in one pot with maximum efficiency.

AgPd Nanoparticles Deposited on WO2.72 Nanorods as an Efficient Catalyst for One-Pot Conversion of Nitrophenol/Nitroacetophenone into Benzoxazole/Quinazoline.

We report a seed-mediated growth of 2.3 nm AgPd nanoparticles (NPs) in the presence of 40 × 5 nm WO2.72 nanorods (NRs) for the synthesis of AgPd/WO2.72 composites. The strong interactions between AgPd NPs and WO2.72 NRs make the composites, especially the Ag48Pd52/WO2.72, catalytically active for dehydrogenation of formic acid (TOF = 1718 h-1 and Ea = 31 kJ/mol) and one-pot reactions of formic acid, 2-nitrophenol, and aldehydes into benzoxazoles in near quantitative yields under mild conditions. The catalysis can also be extended to the one-pot reactions of ammonium formate, 2-nitroacetophenone, and aldehyde for high yield syntheses of quinazolines. Our studies demonstrate a new catalyst design to achieve a green chemistry approach to one-pot reactions for the syntheses of benzoxazoles and quinazolines.

Description of the cytotoxic effect of a novel drug Abietyl-Isothiocyanate on endometrial cancer cell lines.

The objective of the present study was to determine the in-vitro effect of Abietyl-Isothiocyanate (ABITC), a representative of a new class of anti-cancer drugs, on endometrial cancer (EC) cell lines. ABITC at concentrations ≥1 µM displayed dose-dependent and selective cytotoxicity to EC cell lines (ECC-1, AN3CA, RL95-2) in comparison to other cancer cell lines. After treatment with ABITC, ECC-1 unlike control cells displayed hallmark features of apoptosis including chromatin condensation and nuclear fragmentation. At concentrations below the IC50, ABITC exerted anti-proliferative effects by blocking cell-cycle progression through G0/G1 and S-phase. In addition, cells attempted to counteract drug treatment by pro-survival signaling such as deactivation of JNK/SAPK and p38 MAPK and activation of AKT and ErK1/2. ABITC also altered EGF-receptor phosphorylation. At a concentration of 5 µM ABITC generated an excess amount of reactive oxygen species (ROS) and displayed pro-apoptotic signaling such as activation of caspase-8, JNK-SAPK and deactivation of PARP-1. Co-treatment with an antioxidant blocked the drug effects by reducing ROS generation, cytotoxicity and pro-apoptotic signaling. In summary, novel isothiocyanate ABITC is an anti-proliferative and selectively cytotoxic drug to EC cells in-vitro. Key mechanisms during cell death are predominantly correlated to excess generation of ROS. We suggest the further development of ABITC as a potential therapeutic by studying the drug efficacy in EC in-vivo models.

Kinetic delay of cyclization/elimination-coupled enzyme assays: analysis and solution.

A kinetic analysis of an enzyme assay employing a synthetic substrate that produces a detectable signal through a spontaneous organic cyclization/elimination reaction following the enzymatic reaction was conducted. The results from the calculation were used to predict the lag period and provide accurate measurements of the activity of alkaline phosphatase using the fluorogenic substrate (1).

A focused library of protein tyrosine phosphatase inhibitors.

Protein tyrosine phosphatases such as PTP1B and YopH are potential targets for the development of therapeutic agents against a variety of pathological conditions including diabetes, obesity, and infection by the bacterium Yersinia pestis. A focused library of bidentate α-ketoacid-based inhibitors has been screened against several tyrosine phosphatases. Compound 2a has IC(50) values of 43 and 220 nM against YopH and PTP1B, respectively, and shows a 30-fold selectivity for PTP1B over the closely related phosphatase TCPTP.

The binding site of zinc and indium metal to amino acid derivatized squarate complexes - Implications in inhibitor and mediator designs.

Three novel metal squaric acid-peptide complexes, SQI-SQIII were prepared by addition of indium triflate or zinc chloride to the previously reported compounds [1], 3-(hydroxymethylamino)-4-(l-isoleucine methyl ester)-3-cyclobutene-1,2-dione (squarate 1), and 3-(hydroxymethylamino)-2-(l-isoleucine methyl ester)-4-thioxo-2-cyclobuten-1-one (squarate 2). The structures of SQI-SQIII were elucidated using NMR analysis. The electrochemical applications of two of these metal-squaric acid systems (SQI and SQII) were also investigated. Incorporation of SQII as a mediator, in the previously optimized Pt/p(HEMA)/p(pyrrole)/GOx electrode using the ionic liquid [bmim][BF(4)] as the solvent medium, produced a biosensor with enhanced properties, namely a sensitivity of 175.9mA/M d-glucose, working potential of +200mV, large linear range (0-12mM) and a detection limit of 1x10(-6)M.

Enantioselective synthesis of 1-aryltetrahydroisoquinolines.

1-Aryltetrahydroisoquinolines (1-arylTHIQs) are important structural motifs in many alkaloids and biologically active compounds. Ligand 2a promotes the enantioselective addition of arylzinc reagents to 3,4-dihydroisoquinoline N-oxide to yield (S)-1-arylTHIQs in 97-99% ee. Pinacol arylboronic esters are the optimal precursors for the arylzinc reagents. This method is applied to the enantioselective synthesis of Solifenacin.

Fluorogenic peptide substrates for serine and threonine phosphatases.

A new fluorescent assay for Ser/Thr protein phosphatases has been developed. Hydrolysis of a phosphoSer residue liberates the Ser hydroxyl group, which induces a cyclization reaction on the N-terminal carbamate and releases a fluorescent reporter. Sequence selectivity is observed using several peptide substrates against alkaline phosphatase (ALP), bacteriophage lambda protein phosphatase (lambda-PPase), and vaccinia H1 related phosphatase (VHR). These studies suggest that the assay could be a useful tool for profiling the substrate specificities of medicinally important phosphatases.

Macrocyclic inhibitors for the serine protease plasmin.

Macrocyclic inhibitors for the serine protease plasmin were synthesized and evaluated. The inhibitors were constructed starting from a cyclohexanone core. This core was linked to either the C- or N-terminus of a peptide so that the inhibitors were designed to interact with the non-primed or primed binding sites of the protease. Macrocycles were prepared by connecting the side chain of Tyr or Trp, via a short linker, to one end of the peptide. The activities of the macrocyclic inhibitors, while modest, were up to 10-fold more potent than a related non-cyclic analog.

Development of a specific inhibitor for the placental protease, cathepsin P.

Gene duplications in rodents have given rise to a family of proteases that are expressed exclusively in placenta. To define the biological role of these enzymes specific inhibitors are needed to differentiate their activities from other more ubiquitously expressed proteases, such as cathepsins B and L. Libraries of peptidyl inhibitors based upon a 4-cyclohexanone pharmacophore were screened for inhibition of cathepsins P, L, and B. The tightest binding dipeptidyl inhibitor for cathepsin P contained Tyr in P(2) and Trp in P(2)('), consistent with the specificity of this enzyme for hydrophobic amino acids at these sites in synthetic substrates. An inhibitor containing Trp in both P(2) and P(2)(') provided better discrimination between cathepsin P and cathepsins B and L. Extension of the inhibitors to include P(3), and P(3)(') amino acids identified an inhibitor with Trp in P(2), P(2)('), and P(3), and Phe in P(3)(') that bound to cathepsin P with a K(i) of 32 nM. This specificity for inhibitors with hydrophobic aromatic amino acids in these four positions is unique among the lysosomal cysteine proteases. This inhibitor bound to cathepsin P an order of magnitude tighter than to mouse and human cathepsin L and two orders of magnitude tighter than to human cathepsin B. Cbz-Trp-Trp-4-cyclohexanone-Trp-Phe-OMe can discriminate cathepsin P from cathepsins B and L and consequently can be used to specifically inhibit and identify cathepsin P in cellular systems.

A two stage click-based library of protein tyrosine phosphatase inhibitors.

Protein tyrosine phosphatases (PTPs) are important regulators of signal transduction pathways. Potent and selective PTP inhibitors are useful for probing these pathways and also may serve as drugs for the treatment of a variety of diseases including type 2 diabetes and infection by the bacterium Yersinia pestis. In this report Cu(I)-catalyzed 'click' cycloaddition reactions between azides and alkynes were employed to generate two sequential libraries of PTP inhibitors. In the first round library methyl 4-azidobenzoylformate was reacted with 56 mono- and diynes. After hydrolysis of the methyl esters, the resulting alpha-ketocarboxylic acids were assayed in crude form against the Yersinia PTP and PTP1B. Four compounds were selected for further evaluation, and one compound was chosen as the lead for generation of the second round library. This lead compound was modified by conversion of an alcohol into an azide group, and the resulting azide was reacted with the same 56 mono- and diynes that were used in the first generation library. After screening the crude inhibitors against the Yersinia PTP and PTP1B, four compounds were selected and evaluated in pure form against the Yersinia PTP, PTP1B, TCPTP, LAR, and CD45. The best bis(alpha-ketocarboxylic acid) inhibitor 34 had an IC(50) value of 550nM against the Yersinia PTP and an IC(50) value of 710nM against TCPTP. The most potent inhibitor containing a single alpha-ketocarboxylic acid group 32 had IC(50) values of 2.1, 5.7, and 2.6 microM against the Yersinia PTP, PTP1B, and TCPTP, respectively.

Structure-activity studies of cyclic ketone inhibitors of the serine protease plasmin: design, synthesis, and biological activity.

Three series of cyclic ketone inhibitors were synthesized and evaluated against the serine protease plasmin. Peptide inhibitors that incorporated 3-oxotetrahydrofuran and 3-oxotetrahydrothiophene 1,1-dioxide groups had the highest activities. Alkylamino substituents, which were designed to bind in the S1 subsite of plasmin, were attached to the inhibitors. Compounds 5c and 5g, which incorporated 6-aminohexyl substituents, were found to be optimal and demonstrated IC(50) values in the low micromolar range. Incorporating conformationally constrained peptide segments into the inhibitors did not improve their activities.

Enantioselective addition of vinylzinc reagents to 3,4-dihydroisoquinoline N-oxide.

Ligand 2a promotes the enantioselective addition of vinylzinc reagents to 3,4-dihydroisoquinoline N-oxide to yield chiral allylic hydroxylamines. With 0.1 equiv of the ligand, the product is obtained in up to 84% ee, whereas with 1.2 equiv of the ligand, the ee is increased to the 90-95% range with a variety of aliphatic, cyclic, and aromatic vinylzinc reagents. This method was used to synthesize the protected unnatural amino acid N-Cbz-d-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid in three steps from the allylic hydroxylamine.