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Synthetic ion channels based on benzo(crown-ether) compounds have been previously reported to function as ion-selective channels in planar lipid bilayers, with hydrogen bonding networks implicated in the formation of self-aggregated complexes. Herein, we report the synthesis and characterization of two new families of benzo(crown-ether) compounds, termed monoacylated and monoalkylated benzo(crown-ethers) (MABCE), both of which lack hydrogen bond donors. Depending on the length of alkyl chain substituent and the size of macrocycle, MABCE compounds inhibit bacterial growth and transport ions across biological membranes. Single-channel recordings show that the activity is higher in the presence of K

The formation processes of metal–organic frameworks are becoming more widely researched using in situ techniques, although there remains a scarcity of NMR studies in this field. In this work, the synthesis of framework MFM-500(Ni) has been investigated using an in situ NMR strategy that provides information on the time-evolution of the reaction and crystallization process. In our in situ NMR study of MFM-500(Ni) formation, liquid-phase 1H NMR data recorded as a function of time at fixed temperatures (between 60 and 100 °C) afford qualitative information on the solution-phase processes and quantitative information on the kinetics of crystallization, allowing the activation energies for nucleation (61.4 ± 9.7 kJ mol−1) and growth (72.9 ± 8.6 kJ mol−1) to be determined. Ex situ small-angle X-ray scattering studies (at 80 °C) provide complementary nanoscale information on the rapid self-assembly prior to MOF crystallization and in situ powder X-ray diffraction confirms that the only crystalline phase present during the reaction (at 90 °C) is phase-pure MFM-500(Ni). This work demonstrates that in situ NMR experiments can shed new light on MOF synthesis, opening up the technique to provide better understanding of how MOFs are formed., A new in situ NMR methodology for studying the formation processes of MOFs is reported, supported by SAXS and PXRD experiments. Synthesis of a phosphonate-based MOF is described, from molecular aggregation through to nucleation and crystallisation.

While neurodegenerative diseases affect millions of patients worldwide, there are insufficient available therapeutics to halt or slow down the progression of these diseases. A key pathological feature of several neurodegenerative diseases is the oligomerization and aggregation of specific intrinsically disordered proteins (IDPs) creating neuronal deposits, such as Lewy bodies in Parkinson's disease. Clearance of these pathogenic, aggregation-prone IDPs is mediated by the 20S isoform of the human proteasome. Thus, enhancing the 20S proteasome-mediated proteolysis could be a very useful therapeutic pathway to prevent neurotoxicity. Here, we report the successful development of sub-microM 20S proteasome activators based on a phenothiazine scaffold. This class of compounds prevented the accumulation of pathologically relevant IDPs, such as the pathogenic A53T mutated α-synuclein

An industry survey representing approximately 310 million (M) market weight pigs was conducted with 20 U.S. slaughter facilities over the calendars years of 2012 to 2015 to determine the incidence, seasonal patterns, and estimated economic impact of dead and non-ambulatory pigs. Each plant entered daily totals in a secure online database for the following variables: 1) pigs slaughtered, 2) dead on arrival (DOA; dead on the truck), 3) euthanized on arrival (EOA; non-ambulatory pig with an injury that required euthanasia), 4) dead in pen (DIP; died after unloading), and 5) non-ambulatory (pig unable to move or keep up with the rest of the group from unloading to stunning). Total dead pigs were calculated as DOA + EOA + DIP, and total losses were calculated as non-ambulatory + total dead. The economic impact was estimated based on the 4-yr weighted averages from USDA annual reports for market swine slaughtered (108,470,550 pigs), live market weight (126.9 kg), and live market price ($1.44/kg). The 4-yr weighted averages for total dead, non-ambulatory, and total losses were 0.26%, 0.63%, and 0.88%, respectively. Total dead consisted of 0.15% DOA, 0.05% EOA, and 0.05% DIP. The months with the highest rates of total dead were July (0.29%), August (0.32%), and September (0.30%), while the lowest incidence rates occurred in February (0.22%), March (0.22%), and April (0.22%). The months with the highest rates of non-ambulatory pigs were observed during the months of October (0.70%), November (0.71%), and December (0.70%), whereas the lowest rates of non-ambulatory pigs were observed during the months of April (0.57%), May (0.53%), and June (0.54%). The following assumptions were used in the economic analysis: 1) dead pigs received no value and 2) non-ambulatory pigs were discounted 30%. Based on these assumptions, the annual cost to the industry for dead and non-ambulatory pigs was estimated to be $52 M ($0.48 per pig marketed) and $37 M ($0.35 per pig marketed), respectively. Therefore, total losses represent approximately $89 M in economic losses or $0.83 per pig marketed. This is the first industry-wide survey on the incidence of transport losses in market weight pigs at U.S. slaughter facilities, and this information is important for establishing an industry baseline and benchmark for transport losses that can be used for measuring industry improvements.

Allosteric regulators of clinically important enzymes are gaining popularity as alternatives to competitive inhibitors. This is also the case for the proteasome, a major intracellular protease and a target of anti-cancer drugs. All clinically used proteasome inhibitors bind to the active sites in catalytic chamber and display a competitive mechanism. Unfortunately, inevitable resistance associated with this type of inhibition drives the search for non-competitive agents. The multisubunit and multicatalytic "proteolytic machine" such as the proteasome is occasionally found to be affected by agents with other primary targets. For example the immunosuppressive agent rapamycin has been shown to allosterically inhibit the proteasome albeit at levels far higher than its mTOR related efficacy. As part of an ongoing program to search for novel proteasome-targeting pharmacophores, we identified the binding domain of rapamycin as required for proteasome inhibition even without the macrocyclic context of the parent compound. By subsequent structure-activity relationship studies, we generated a pipecolic ester derivative compound 3 representing a new class of proteasome inhibitors. Compound 3 affects the core proteasome activities and proliferation of cancer cells with low micromolar/high nanomolar efficacy. Molecular modeling, atomic force microscopy imaging and biochemical data suggest that compound 3 binds into one of intersubunit pockets in the proteasomal α ring and destabilizes the α face and the gate. The α face is used as a docking area for proteasome-regulating protein modules and the gate is critical for controlling access to the catalytic chamber. Thus, the pipecolic ester template elicits a new and attractive mechanism for proteasome inhibition distinct from classical competitive drugs.

OBJECTIVE The objective of this article was to assess the impact on behavioral and socioemotional development, 2 to 6 years postintervention (depending on the curriculum), of Legacy for Children, a public health approach to improve child developmental outcomes among families living in poverty. METHODS Mothers who were recruited prenatally or at the time of childbirth participated in a set of Legacy parallel design randomized control trials between 2001 and 2009 in Miami, Florida, or Los Angeles, California. Of the initial 574 mother-child dyads, 364 completed at least 1 behavioral or socioemotional outcome measure at the third-grade follow-up. Intention-to-treat analyses compared Legacy and comparison groups on behavioral and socioemotional outcomes. RESULTS Children of Legacy mothers in Los Angeles were at lower risk for externalizing behaviors and poor adaptive skills than children whose mothers did not participate in the intervention. No significant outcome differences by group assignment were found in Miami. CONCLUSION Group-based positive parenting interventions such as Legacy may have a sustained impact on children's behavioral and socioemotional development several years after intervention completion.

The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S–20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.

The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disorders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity. Chemical manipulation of chlorpromazine abrogated its D2R receptor binding affinity while retaining its ability to enhance 20S mediated proteolysis at low micromolar concentrations. The resulting small molecule enhancers of 20S proteasome activity induced the degradation of intrinsically disordered proteins, α-synuclein, and tau but not structured proteins. These small molecule 20S agonists can serve as leads to explore the therapeutic potential of 20S activation or as new tools to provide insight into the yet unclear mechanics of 20S-gate regulation.

Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called “intrinsically disordered proteins” (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.

CdZnTe single crystals grown with the traveling heater method have been specifically engineered to support high-flux x-ray photon counting applications. Pixelated detector devices absorb hardened $120~\mathrm {kV}_{\mathrm {p}}$ fluxes up to $10^{8}~\mathrm {photons}/(\mathrm {mm}^{2.}\mathrm {sec})$ without any sign of electric field polarization at room temperature (23-28) °C. It is shown that detector functionality can be verified using photon counting electronics even under conditions of strong pulse pile-up. A non-paralyzable counting model satisfactory describes the average output count rate of the detector-electronics system as a function of the absorbed flux. Good pixel-to-pixel count rate uniformity can be achieved.

Metal–organic frameworks (MOFs) have emerged over the past two decades as highly promising materials in the gas storage and separation arenas, with the potential to act as rapid uptake/rapid release sorbents for CO2, CH4 and H2 that may have significant impact in energy and sustainability technologies. However, a small but growing subset of the MOF community have been developing alternative, light-induced applications of MOFs. This review briefly outlines some of these exciting diversions from the ‘traditional’ applications of MOFs and focusses particularly on the design strategies of those frameworks that undergo photoinduced structural change. These strategies are classified as either (i) the imposition of photoresponsivity by a photoresponsive guest; (ii) post-synthetic modification (PSM) of frameworks to add in photoresponsive groups; (iii) synthesis of MOFs with linkers that support pendant photoresponsive groups; and, perhaps the most challenging, (iv) synthesis of MOFs from linkers that themselves have intrinsic structural photoresponsivity such that their structure is altered on illumination. Examples are given of each approach, future applications are proposed, and strategic pathways to next-generation photoresponsive frameworks are discussed.

A series of new group 2 coordination polymers, MgL ={MgL(H 2 O)(DMF) 0.75 } ∞ , CaL = {CaL(DMF) 2 } ∞ , SrL = {SrL(H 2 O) 0.5 } ∞ and BaL = {BaL(H 2 O) 0.5 } ∞ , were synthesized using a flexible benzimidazolone diacetic acid linker ( H 2 L ) in which the two carboxylic acid binding sites are connected to a planar core via {–CH 2 –} spacers that can freely rotate in solution. In a ‘curiosity-led' diversion from group 2 metals, the first row transition metal salts Mn 2+ , Cu 2+ and Zn 2+ were also reacted with L to yield crystals of MnL = {MnL(DMF)(H 2 O) 3.33 } ∞ , Cu 3 L 2 = {Cu 3 L 2 (DMF) 2 (CHO 2 ) 2 } ∞ and ZnL = {ZnL(DMF)} ∞ . Crystal structures were obtained for all seven materials. All structures form as two-dimensional sheets and contain six-coordinate centres, with the exception of ZnL, which displays tetrahedrally coordinated metal centres, and Cu 3 L 2 , which contains square planar coordinated metal centres and Cu paddle-wheels. In each structure, the linker adopts one of two distinct conformations, with the carboxylate groups either cis or trans with respect to the planar core. All materials were also characterized by powder X-ray diffraction and thermogravimetric analysis.

The hydroxyamination reagent Br-N-(CO2Me)2 underwent Markovnikov addition to various olefins in the presence of catalytic BF3·OEt2 and provides efficient access to aminoalcohols. The reaction provided the trans-1-bromo, 2-N-bis-carbamate adduct stereoisomer in all cases. The resulting adduct underwent cyclization to give an oxazolidinone, which could be readily hydrolyzed to an oxazolidin-2-one or an amino alcohol.

The hydroxyamination reagent Br-N-(CO2Me)2 underwent Markovnikov addition to various olefins in the presence of catalytic BF3·OEt2 and provides efficient access to aminoalcohols. The reaction provided the trans-1-bromo, 2-N-bis-carbamate adduct stereoisomer in all cases. The resulting adduct underwent cyclization to give an oxazolidinone, which could be readily hydrolyzed to an oxazolidin-2-one or an amino alcohol.

e23066 Background: Proteasome as a hub protease of the ubiquitin proteasome pathway is an established anticancer drug target. Several drugs that inhibit proteasome are currently used to successfully treat aggressive blood cancers. These drugs are based on their competition with protein substrates of proteasome. However, efficacy of these drugs toward solid cancers is inadequate. Besides, the side effects and developing drug resistance are increasingly hampering the therapy. Therefore, there is an unmet challenge to develop new types of proteasome targeting compounds that are efficient against solid cancers and utilize other mechanisms to stop proteasome. Here we present a compound with a novel molecular mechanism, potentially bypassing limitations of the available drugs. Methods: We rationally designed and synthesized a series of small molecule “B” compounds, derivatives of a binding domain of seco-rapamycin that noncompetitively interfere with peptidase activities of proteasome. We tested effects of the compounds in vitro on purified proteasome, in cellulo with selected cancer cell lines and in a xenograft mouse model of prostate cancer. Results: We found that compound B1 binds to the catalytic core of proteasome far from the catalytic sites, destabilizes assembly of the 26S proteasome responsible for digest of polyUb substrates and allosterically inhibits its proteolytic activities. Molecularly, B1 impedes the gating mechanism responsible for substrate uptake as found with AFM. Tryptophan fluorescence indicates that B1 changes proteasome fold and the binding mode of competitive inhibitors. B1 substantially decreases viability of selected cancer cell lines and shifts their mechanical phenotype toward noncancerous status. B1 synergizes with bortezomib decreasing the IC50 5-10 fold. In a xenograft hormone resistant prostate cancer model, B1 treatment leads to shrinkage of the tumor size, decreases enumeration of aggressive, EpCAM+ CTCs and shifts the macrophage profile toward predator M1 type. Conclusions: B1 compounds constitute a new class of noncompetitive allosteric inhibitors of proteasome that could be useful to develop to treat aggressive prostate cancers alone or in synergy with competitive inhibitors.

The authors' clinical impression that homosexual gender-dysphoric males are physically smaller than nonhomosexual gender-dysphoric males was tested. Subjects were 176 homosexual and 246 nonhomosexual male outpatients, ages 16 to 65, who complained of discontent with their biological sex. Compared with the nonhomosexual male gender dysphorics, the homosexual gender dysphorics were shorter, lighter, and lighter in proportion to their height. The homosexual gender dysphorics were also shorter than men in the general population, whereas the nonhomosexual gender dysphorics were not. The smaller physiques of homosexual gender-dysphoric men may partly explain the clinical observation that these patients are somewhat more successful in passing as women.