Ostrich eggshell bead strontium isotopes reveal persistent macroscale social networking across late Quaternary southern Africa.

Hunter-gatherer exchange networks dampen subsistence and reproductive risks by building relationships of mutual support outside local groups that are underwritten by symbolic gift exchange. Hxaro, the system of delayed reciprocity between Ju/'hoãn individuals in southern Africa's Kalahari Desert, is the best-known such example and the basis for most analogies and models of hunter-gatherer exchange in prehistory. However, its antiquity, drivers, and development remain unclear, as they do for long-distance exchanges among African foragers more broadly. Here we show through strontium isotope analyses of ostrich eggshell beads from highland Lesotho, and associated strontium isoscape development, that such practices stretch back into the late Middle Stone Age. We argue that these exchange items originated beyond the macroband from groups occupying the more water-stressed subcontinental interior. Tracking the emergence and persistence of macroscale, transbiome social networks helps illuminate the evolution of social strategies needed to thrive in stochastic environments, strategies that in our case study show persistence over more than 33,000 y.

Do Antarafacial Cycloadditions Occur? Cycloaddition of Heptafulvalene with Tetracyanoethylene.

The cycloaddition of heptafulvalene (1) with tetracyanoethylene (TCNE) was previously described as an example of an antarafacial cycloaddition, a [π14 a +π2 s ] process that afforded only the trans cycloadduct by virtue of the edge-to-face approach of TCNE, facilitated by the S shape of 1. The reaction has been investigated in depth and found not to be a concerted antarafacial process. At low temperature, the reaction is observed to give a mixture of cis and trans cycloadducts as well as a [4+2] cycloadduct. The mixture of products is converted to the trans cycloadduct by equilibration upon warming to room temperature. Studies with diethyl 2,3-dicyanofumarate and -maleate confirmed the formation of cis cycloadducts. DFT studies at the M06-2X/6-311+G(2d,p) SCRF=acetone level of theory show that the originally proposed edge-to-face approach of TCNE to 1 is highly disfavored, whereas a stepwise mechanism involving the addition of TCNE at C2 to form a zwitterion followed by collapse at either C2' or C7' is energetically accessible. The Diels-Alder adduct is also formed in a stepwise reaction by competitive addition of TCNE at C4 of 1. These studies suggest that edge-to-face interactions are prohibitive in even the most favorable cases.

Dual-function antiandrogen/HDACi hybrids based on enzalutamide and entinostat.

The combination of androgen receptor antagonists with histone deacetylase inhibitors (HDACi) has been shown to be more effective than antiandrogens alone in halting growth of prostate cancer cell lines. Here we have designed, synthesized and assessed a series of antiandrogen/HDACi hybrids by combining structural features of enzalutamide with either SAHA or entinostat. The hybrids are demonstrated to maintain bifunctionality using a fluorometric HDAC assay and a bioluminescence resonance energy transfer (BRET) antiandrogen assay. Antiproliferative assays showed that hybrids bearing o-aminoanilide-based HDACi motifs outperformed hydroxamic acid based HDACi's. The hybrids demonstrated selectivity for epithelial cell lines vs. stromal cell lines, suggesting a potentially useful therapeutic window.

Mechanism of an Organocatalytic Cope Rearrangement Involving Iminium Intermediates: Elucidating the Role of Catalyst Ring Size.

The mechanism of the organocatalytic Cope rearrangement is elucidated through a combined computational and experimental approach. As reported previously, hydrazides catalyze the Cope rearrangement of 1,5-hexadiene-2-carboxaldehydes via iminium ion formation, and seven- and eight-membered ring catalysts are more active than smaller ring sizes. In the present work, quantum mechanical computations and kinetic isotope effect experiments demonstrate that the Cope rearrangement step, rather than iminium formation, is rate-limiting. The computations further explain how the hydrazide catalyst lowers the free-energy barrier of the Cope rearrangement via an associative transition state that is stabilized by enehydrazine character. The computations also explain the catalyst ring size effect, as larger hydrazide rings are able to accommodate optimal transition-state geometries that minimize the unfavorable lone-pair repulsion between neighboring nitrogen atoms and maximize the favorable hyperconjugative donation from each nitrogen atom into neighboring electron-poor sigma bonds, with the seven-membered catalyst achieving a nearly ideal transition-state geometry that is comparable to that of an unconstrained acyclic catalyst. Experimental kinetics studies support the computations, showing that the seven-membered and acyclic hydrazide catalysts react 10 times faster than the six-membered catalyst. Unraveling the mechanism of this reaction is an important step in understanding other reactions catalyzed by hydrazides, and explaining the ring size effect is critical because cyclic catalysts provide a constrained scaffold, enabling the development of asymmetric variants of these reactions.

Hydrazide-Catalyzed Polyene Cyclization: Asymmetric Organocatalytic Synthesis of cis-Decalins.

Polyene cyclizations offer rapid entry into terpenoid ring systems. Although enantioselective cyclizations of (E)-polyenes to form trans-decalin ring systems are well precedented, highly enantioselective cyclizations of (Z)-polyenes to form the corresponding cis-decalins have not been reported. Here, we describe the first application of iminium catalysis to the initiation of polyene cyclizations. Ethyl 1,2-diazepane-1-carboxylate catalyzes the cyclization of polyenes bearing enal initiators. Moreover, chiral bicyclic hydrazides catalyze the cyclizations of (Z)-polyene substrates to form cis-decalins with enantioselectivities of up to 97:3 er. DFT calculations suggest the catalysts promote the reaction by stabilizing positive charge as it develops during the bicyclization.

Incorporation of histone deacetylase inhibitory activity into the core of tamoxifen - A new hybrid design paradigm.

Hybrid antiestrogen/histone deacetylase (HDAC) inhibitors were designed by appending zinc binding groups to the 4-hydroxystilbene core of 4-hydroxytamoxifen. The resulting hybrids were fully bifunctional, and displayed high nanomolar to low micromolar IC50 values against both the estrogen receptor α (ERα) and HDACs in vitro and in cell-based assays. The hybrids were antiproliferative against ER+ MCF-7 breast cancer cells, with hybrid 28b possessing an improved activity profile compared to either 4-hydroxytamoxifen or SAHA. Hybrid 28b displayed gene expression patterns that reflected both ERα and HDAC inhibition.

Pulmonary Artery Dimensions as a Prognosticator of Transplant-Free Survival in Scleroderma Interstitial Lung Disease.

BACKGROUND: Systemic sclerosis is a chronic debilitating autoimmune disease characterized by endothelial dysfunction and multi-organ fibrosis. Interstitial lung disease, a common manifestation of SSc, is termed scleroderma-related interstitial lung disease (SSc-ILD) and along with pulmonary hypertension contributes to a majority of deaths in SSc. SSc-ILD patients frequently develop pulmonary hypertension, which prognosticates a poorer outcome. We investigated pulmonary artery dimensions as an outcome predictor in patients with SSc-ILD. METHODS: A retrospective chart review abstracting data from SSc-ILD patients evaluated at a large tertiary care center was performed. HRCT imaging was reviewed and pulmonary artery (PA) and ascending aorta (Ao) diameters were measured for calculation of the PA:Ao ratio. Additionally, demographics, vital signs, spirometric parameters, comorbidities, and mean pulmonary artery pressures were collected when available. Outcome analysis with lung transplant or death events within 4 years based on pulmonary artery size as well as PA:Ao ratio was performed. RESULTS: 70 SSc-ILD patients were identified. Mean pulmonary artery diameter and PA:Ao ratio was 31.17 and 1.07 mm, respectively. Patients with a pulmonary artery diameter ≥32 mm had higher risk of lung transplantation or death (p < 0.001) within 4 years. Patients with a PA:Ao ratio ≥1.1 also had higher risk of lung transplantation or death (p < 0.001) within 4 years. Unadjusted outcomes analyses also identified PA:Ao ratio ≥1.1 as an independent outcome predictor (hazard ratio 3.30, p < 0.001). CONCLUSIONS/CLINICAL IMPLICATIONS: In SSc-ILD patients, a PA:Ao ratio ≥1.1 is associated with higher risk of lung transplant or death. These data suggest that PA:Ao dimension may be used for prognostication in SSc-ILD.

A Concise Enantioselective Total Synthesis of (-)-Virosaine†A.

The total synthesis of (-)-virosaine A (1) was achieved in ten steps starting from furan and 2-bromoacrolein. A one-pot Diels-Alder cycloaddition/organolithium addition initiated an efficient sequence to access a key oxime/epoxide intermediate. Heating this intermediate in acetic acid resulted in an intramolecular epoxide opening/nitrone [3+2] cycloaddition cascade to construct the caged core of 1 in a single step. Several methods of C-H functionalization were assessed on the cascade product, and ultimately, a directed lithiation/bromination effected selective C14 functionalization, enabling the synthesis of 1.

Including Youth with Intellectual Disabilities in Health Promotion Research: Development and Reliability of a Structured Interview to Assess the Correlates of Physical Activity among Youth.

BACKGROUND: The input of youth with intellectual disabilities in health promotion and health disparities research is essential for understanding their needs and preferences. Regular physical activity (PA) is vital for health and well-being, but levels are low in youth generally, including those with intellectual disabilities. Understanding the perceptions of and barriers to PA as reported by youth with intellectual disabilities themselves is important for designing effective interventions. MATERIALS AND METHODS: We developed a structured interview that queried youth with intellectual disabilities and typically developing youth (ages 13-21 years) about their enjoyment, preferences and perceived barriers to PA. We describe the development of this interview and present its test-retest reliability on 15 youth with intellectual disabilities and 20 typically developing youth. RESULTS: Twenty-three of 33 questions were reliable in both groups. The results suggest that youth with intellectual disabilities can reliably report activities that they do or do not enjoy, as well as their beliefs and perceived benefits of PA. CONCLUSIONS: Self-reported information on the experiences, preferences, beliefs and perceptions about among youth with intellectual disabilities is key for research efforts in health promotion and health disparities.

An Organocatalytic Cope Rearrangement.

The first example of an organocatalytic Cope rearrangement is reported. Acyclic and cyclic acyl hydrazides catalyze the rearrangement of 1,5-hexadiene-2-carboxaldehydes via iminium ion formation. A correlation between ring size and catalyst activity was observed for the cyclic hydrazides, with seven- and eight-membered-ring catalysts being the most active. Diazepane carboxylate 5 c (10 mol %) catalyzed the rearrangement of a range of dienes at room temperature in acetonitrile using triflic acid as a co-catalyst. Preliminary proof of principle for asymmetric catalysis was provided by rearrangement of 3,3-dimethyl-7-phenyl-1,5-heptadiene-2-carboxaldehyde in the presence of a novel 7-substituted diazepane carboxylate.

A robust synthesis of N-glycolyl muramyl dipeptide via azidonitration/reduction.

A novel synthetic route leading to N-glycolyl muramyl dipeptide (MDP), a bacterial glycopeptide of particular interest in studies of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), is described. The synthetic strategy hinges on the alkylation of benzylidene-protected glucal with 2-bromopropionic acid and thus circumvents a challenging and non-reproducible SN2 step at the C-3 position of glucosamine derivatives. The subsequent sequence includes an azidonitration and an unusual azide reduction/acylation step via an aza ylide/oxaphospholidine intermediate. This approach generates a protected N-glycolyl MDP that can be either subjected to a one-step global deprotection or differentially deprotected to obtain further derivatives.

Optimization of histone deacetylase inhibitor activity in non-secosteroidal vitamin D-receptor agonist hybrids.

The combination of (1α,25)-dihydroxyvitamin D3 (1,25D) and histone deacetylase inhibitor (HDACi) trichostatin A is highly antiproliferative in numerous cancer cell lines. We have previously prepared novel non-secosteroidal hybrid molecules which simultaneously act as both vitamin D receptor (VDR) agonists and HDACi. These molecules function as cytostatic and cytotoxic agents in 1,25D-resistant SCC4 squamous carcinoma cells. Here we have extended the scope of the hybrids by making several modifications to the diarylpentane core and to the aliphatic spacer unit to develop molecules with increased potency towards HDACs while maintaining VDR agonist activity. Notably, hybrid DK-366 (33a), a direct analog of first-generation hybrids but lacking a methyl group on one aryl ring possesses low micromolar potency for HDAC3 and HDAC6 and is a highly effective antiproliferative agent in SCC4 cells. Chain extended hybrids such as DK-367 (33c) possess even greater HDAC potency and are also highly antiproliferative. These results show that we can optimize HDACi potency in hybrid molecules without sacrificing VDR agonism.

Design, synthesis and evaluation of antiestrogen and histone deacetylase inhibitor molecular hybrids.

The combination of antiestrogens and histone deacetylase inhibitors (HDACi) has been found to be antiproliferative in breast cancer models. We designed and synthesized hybrid structures which combined structural features of the pure antiestrogen ICI-164,384 and HDACi's SAHA and entinostat in a single bifunctional molecule. The hybrids retained antiestrogenic and HDACi activity and, in the case of benzamide hybrids, were selective for Class I HDAC3 over Class II HDAC6. The hybrids possessed low micromolar to high nanomolar activity against both ER+ MCF-7 and ER- MDA-MB-231 breast cancer cell models.

Docking ligands into flexible and solvated macromolecules. 6. Development and application to the docking of HDACs and other zinc metalloenzymes inhibitors.

Metalloenzymes are ubiquitous proteins which feature one or more metal ions either directly involved in the enzymatic activity and/or structural properties (i.e., zinc fingers). Several members of this class take advantage of the Lewis acidic properties of zinc ions to carry out their various catalytic transformations including isomerization or amide cleavage. These enzymes have been validated as drug targets for a number of diseases including cancer; however, despite their pharmaceutical relevance and the availability of crystal structures, structure-based drug design methods have been poorly and indirectly parametrized for these classes of enzymes. More specifically, the metal coordination component and proton transfers of the process of drugs binding to metalloenzymes have been inadequately modeled by current docking programs, if at all. In addition, several known issues, such as coordination geometry, atomic charge variability, and a potential proton transfer from small molecules to a neighboring basic residue, have often been ignored. We report herein the development of specific functions and parameters to account for zinc-drug coordination focusing on the above-listed phenomena and their impact on docking to zinc metalloenzymes. These atom-type-dependent but atomic charge-independent functions implemented into Fitted 3.1 enable the simulation of drug binding to metalloenzymes, considering an acid-base reaction with a neighboring residue when necessary with good accuracy.

Driving tert-butyl axial: the surprising cyclopropyl effect.

The presence of a small spirocyclic ring at an adjacent position alters the conformational preference for equatorial substitution in six-membered rings. DFT calculations and low-temperature 1H NMR experiments demonstrate that alkyl groups larger than methyl possess negative A-values when geminal to a spirocyclopropane, with larger groups such as isopropyl and tert-butyl being exclusively axial at -78 °C. Similar effects are found for heteroatoms, including halogens, and for a range of other electron-withdrawing substituents. Similar effects are observed for other strained rings (epoxide, cyclobutane, oxetane) and the concepts extend to acyclic models as well as heterocycles such as piperidines and piperazines. The origin of the effect is traced to an increase in torsional strain in combination with hyperconjugative effects in the case of electron-poor groups.

Design, synthesis and antiproliferative activity of raloxifene/histone deacetylase inhibitor hybrids in breast cancer.

Antiestrogen/histone deacetylase inhibitor (HDACi) hybrids were designed by merging structures of raloxifene with suberoylanilide hydroxamic acid, incorporating the HDACi unit into the phenolic ring of the antiestrogen. These hybrids were synthesized with a range of HDACi chain lengths and assessed for bifunctionality. Four hybrids, 21 (YW471), 22 (YW490), 27(YW486), and 28 (YW487) showed good potency both as antiestrogens in a BRET assay and in a fluorometric HDACi assay. The antiproliferative activity of the hybrids was demonstrated in both ER+ MCF7 and ER- MDA-MB-231 breast cancer cell lines.

Bifunctionality and Antitumor Efficacy of ZG-126, a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule.

Analogues of hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D), signal through the nuclear vitamin D receptor (VDR). They have potential in combination therapies with other anticancer agents such as histone deacetylase inhibitors (HDACi's). Here, we characterize the ZG series of hybrid compounds that combine HDACi within the backbone of a VDR agonist. All display improved solubility, with ZG-126 being the most robustly bifunctional molecule in multiple cell lines. ZG-126 is well tolerated and strongly induces VDR target gene expression in vivo at therapeutic doses. Its antitumor efficacy is superior to 1,25D and the HDACi SAHA, separately or together, in mouse models of melanoma and triple-negative breast cancer (TNBC). Notably, ZG-126 treatment reduces metastases almost 4-fold in an aggressive TNBC model. ZG-126 also reduces total macrophage infiltration and the proportion of immunosuppressive M2-polarized macrophages in TNBC tumors by 2-fold. ZG-126 thus represents a bifunctional and efficacious anticancer agent with improved physicochemical properties.

Parent support improves weight loss in adolescents and young adults with Down syndrome.

OBJECTIVE: To assess whether parent training in behavioral intervention, combined with a 16-session nutrition and activity education program, would improve weight loss relative to nutrition and activity education alone in adolescents and young adults with Down syndrome. STUDY DESIGN: Twenty-one patients with Down syndrome aged 13-26 years with a body mass index ≥ 85 th percentile were enrolled and randomized to a 6-month nutrition and activity education intervention (n = 10) or to a nutrition and activity education+behaviorial intervention (n = 11), and followed for 6 months after the active intervention period (1-year follow-up). The primary outcome measure was body weight; secondary outcomes included percentage body fat by bioelectric impedance; intake of fruits, vegetables, and energy-dense low-nutrient snack food (treats) by 3-day food record; and moderate/vigorous physical activity by accelerometry. RESULTS: At 6 months, mean body weight in the nutrition and activity education+behavioral intervention group was 3.2 kg lower than that in the nutrition and activity education group (95% CI, 1.0-5.5 kg; P = .005). Mean group differences were sustained at 1 year (3.6 kg; 95% CI, 1.4-5.9 kg; P = .002). At 6 months, moderate/vigorous physical activity time increased by an average of 18 minutes/day compared with baseline in the nutrition and activity education+behavioral intervention group (P = .01) and decreased by 7 minutes/day in the nutrition and activity education group (P = .30). These changes were largely maintained at 1 year, but were not statistically significant. Vegetable intake in the nutrition and activity education+behavioral intervention group exceeded that in the nutrition and activity education group by a mean of 1.6 servings at 1 year (P = .009), but not at 6 months. No between-group differences were observed for percentage body fat or consumption of fruits or treats. CONCLUSION: Parent-supported behavioral intervention appears to be a successful adjunct to a 6-month nutrition education intervention in achieving weight loss in adolescents and young adults with Down syndrome.

Mimicking enzymatic cation-π interactions in hydrazide catalyst design: access to trans-decalin frameworks.

Chiral bicyclic hydrazide organocatalysts have previously been shown to catalyze the cyclization of (Z)-polyene substrates with high enantioselectivity, but with poor selectivity for the corresponding (E)-polyenes. Here we demonstrate that diazapane carboxylates bearing terphenyl groups efficiently catalyze (E)-polyene bicyclization with enantioselectivities up to 94 : 6 er and with high diastereoselectivity for trans-decalin formation. The catalysts function by simultaneously initiating the cyclization via iminium ion formation and stabilizing intermediates/transition states by cation-π interactions.

An Organocatalytic Oxy-Cope/Michael Cascade Reaction.

Ethyl diazepane carboxylate catalyzes the oxy-Cope rearrangement of 4-hydroxy- and 4-alkoxy-1,5-hexadiene-2-carboxaldehydes via iminium ion activation. The resulting intermediate undergoes an intramolecular Michael reaction to furnish cyclopentane-containing products. The reaction proceeds with a range of substrates, including both cyclic and acyclic substrates, and tolerates substitution on the vinyl substituent. Substrates fused on a cycloalkane framework undergo net ring expansion/cyclopentannulation with a high degree of stereocontrol via chairlike transition states. The reaction extends iminium organocatalysis to the oxy-Cope rearrangement, embedded within a complexity-generating cascade transformation.