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Conformer-RL is an open-source Python package for applying deep reinforcement learning (RL) to the task of generating a diverse set of low-energy conformations for a single molecule. The library features a simple interface to train a deep RL conformer generation model on any covalently bonded molecule or polymer, including most drug-like molecules. Under the hood, it implements state-of-the-art RL algorithms and graph neural network architectures tuned specifically for molecular structures. Conformer-RL is also a platform for researching new algorithms and neural network architectures for conformer generation, as the library contains modular class interfaces for RL environments and agents, allowing users to easily swap components with their own implementations. Additionally, it comes with tools to visualize and save generated conformers for further analysis. Conformer-RL is well-tested and thoroughly documented with tutorials for each of the functionalities mentioned above, and is available on PyPi and Github: https://github.com/ZimmermanGroup/conformer-rl.

Stereochemistry can have a profound impact on polymer and materials properties. Unfortunately, straightforward methods for realizing high levels of stereocontrolled polymerizations are often challenging to achieve. In a departure from traditional metal-mediated ring-opening metathesis polymerization (ROMP), we discovered a remarkably simple method for controlling alkene stereochemistry in photoredox mediated metal-free ROMP. Ion-pairing, initiator sterics, and solvation effects each had profound impact on the stereochemistry of polynorbornene (PNB). Simple modifications to the reaction conditions produced PNB with trans alkene content of 25 to >98 %. High cis content was obtained from relatively larger counterions, toluene as solvent, low temperatures (-78 °C), and initiators with low Charton values. Conversely, smaller counterions, dichloromethane as solvent, and enol ethers with higher Charton values enabled production of PNB with high trans content. Data from a combined experimental and computational investigation are consistent with the stereocontrolling step of the radical cationic mechanism proceeding under thermodynamic control.

Infectious diseases have the potential to extirpate populations of great apes. As the interface between humans and great apes expands, zoonoses pose an increasingly severe threat to already endangered great ape populations. Despite recognition of the threat posed by human pathogens to great apes, health monitoring is only conducted for a small fraction of the world's wild great apes (and mostly those that are habituated) meaning that outbreaks of disease often go unrecognized and therefore unmitigated. This lack of surveillance (even in sites where capacity to conduct surveillance is present) is the most significant limiting factor in our ability to quickly detect and respond to emerging infectious diseases in great apes when they first appear. Accordingly, we must create a surveillance system that links disease outbreaks in humans and great apes in time and space, and enables veterinarians, clinicians, conservation managers, national decision makers, and the global health community to respond quickly to these events. Here, we review existing great ape health surveillance programs in African range habitats to identify successes, gaps, and challenges. We use these findings to argue that standardization of surveillance across sites and geographic scales, that monitors primate health in real-time and generates early warnings of disease outbreaks, is an efficient, low-cost step to conserve great ape populations. Such a surveillance program, which we call "Great Ape Health Watch" would lead to long-term improvements in outbreak preparedness, prevention, detection, and response, while generating valuable data for epidemiological research and sustainable conservation planning. Standardized monitoring of great apes would also make it easier to integrate with human surveillance activities. This approach would empower local stakeholders to link wildlife and human health, allowing for near real-time, bidirectional surveillance at the great ape-human interface.

Natural antibodies (NAbs) are polyreactive, have low avidity, and are a product of B-1 cells. Evidence suggests that NAbs may play a key role in immune defense in turtles, as increased total mucosal antibodies are associated with a decreased number of extracellular intestinal parasites. However, it is unknown if this trend extends to other types of pathogens and if avidity of the NAb to the pathogen is a factor in protection. We examined the relationship between a common intracellular bacteria in turtles-Salmonella-and NAbs. Plasma and mucosal samples were taken from red-eared slider turtles. We measured levels and avidity of antibodies that bound to lipopolysaccharide (LPS), a component of Salmonella cell wall. We examined the relationship between these measures and the ability of plasma to kill Salmonella as well as infection status. Higher mucosal antibody levels were significantly associated with a decrease in likelihood of infection with Salmonella; however, plasma antibody levels were not. There was a trend for bactericidal ability of the plasma to be positively correlated with plasma antibody levels bound to LPS, but not mucosal antibody levels. Avidity was not significantly related to either killing capacity or likelihood of infection suggesting that only increased quantity and not better binding is responsible for the decreased likelihood of infection. These findings suggest that NAb regulation was sufficient to isolate the infection to the gastrointestinal tract of the turtles, allowing it to be cleared with the mucus layer. Our results add further evidence that turtles use a general, nonspecific NAb response to combat pathogens.

Block copolymers containing both insulating and conducting segments have been shown to exhibit improved charge transport properties and air stability. Nevertheless, their syntheses are challenging, relying on multiple post-polymerization functionalization reactions and purifications. A simpler approach would be to synthesize the block copolymer in one pot using the same catalyst to enchain both monomers via distinct mechanisms. Such multitasking polymerization catalysts are rare, however, due to the challenges of finding a single catalyst that can mediate living, chain-growth polymerizations for each monomer under similar conditions. Herein, a diimine-ligated Ni catalyst is evaluated and optimized to produce block copolymer containing both 1-pentene and 3-hexylthiophene. The reaction mixture also contains both homopolymers, suggesting catalyst dissociation during and/or after the switch in mechanisms. Experimental and theoretical studies reveal a high energy switching step coupled with infrequent catalyst dissociation as the culprits for the low yield of copolymer. Combined, these studies highlight the challenges of identifying multitasking catalysts, and suggest that further tuning the reaction conditions (e.g., ancillary ligand structure and/or metal) is warranted for this specific copolymerization. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017

Marizomib (MRZ) is an irreversible, pan-subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low-dose dexamethasone (Lo-DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0·3–0·5 mg/m(2)) was administered over 2 h on days 1, 4, 8, 11; POM (3–4 mg) on days 1–21; and Lo-DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1–10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities (DLTs) were observed and 0·5 mg/m(2) MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients.

Reptiles tend to have a broad innate immune response followed by a more moderate adaptive response, and as an ectotherm, their immune response is strongly affected by temperature. The innate immune responses in reptiles encompass a diverse group of molecules and cells that includes non-specific leukocytes, lysozymes, antimicrobial peptides, the complement pathway and fever. The adaptive response involves both T and B cells; however, reptile humoral responses are much less robust than mammalian responses. Thus, reptiles may rely more heavily on a natural antibody response. The slower adaptive response may be because reptiles lack lymph nodes and do not form germinal centres. Phagocytic B cells have also been identified in reptiles. Studies of the reptilian immune system may contribute to our understanding of the evolution of the immune system as well as to the fields of conservation biology, ecological immunology and human medicine. Key Concepts Reptiles have a broad innate immune response able to encompass a variety of pathogens followed by a specific adaptive response. Because reptiles are ectothermic, temperature has a strong effect on immune responses. Seasonal variation in structure and function of the immune system in reptiles is common. As the only ectothermic amniotes, reptiles provide vital information on the evolution of the immune systems. Keywords: ecological immunology; ectotherm; reptile; innate immunity; adaptive immunity; phagocytosis

Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We designed the current phase 1/2 trial to determine the maximum tolerated doses (MTD) of bendamustine that can be safely combined with lenalidomide and dexamethasone and to assess the safety and efficacy of the combination. Patients with relapsed MM following at least 1 prior therapy, but no more than four lines of prior therapy and with measurable disease were enrolled. Bendamustine 75 mg/m(2) given on days 1 and 2, lenalidomide 25 mg given days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22, was the recommended Phase 2 dose. Seventy-one patients were accrued: 21 on Phase 1 and 50 on Phase 2. The median age was 62.3 years; patients had a median of three prior lines of therapy (range 1-4), with over 70% of the patients having received prior lenalidomide, bortezomib, and/or peripheral blood stem cell transplant. Thirty-four of 70 (49%) patients had a confirmed partial response or better, including 20 patients (29%) with a very good partial response or better. An additional 4 patients had a minor response, translating to an overall 55% clinical benefit rate. Grade 3 or higher toxicity was seen in 96% of patients, with ≥grade 3 hematologic in 94% and nonhematologic in 50%. The median progression free survival was 11.8 months and the median duration of response was 23 months. The combination of bendamustine, lenalidomide, and dexamethasone is very effective in relapsed multiple myeloma with high response rates and durable responses

The area of reaction mechanism discovery simulation has taken considerable strides in recent years. Novel methods that make hypotheses for elementary steps and complementary means for reaction path and transition state (TS) optimization are lowering the amount of chemical intuition and user effort required to explore reaction networks. The resulting networks lead from reactants to reactive intermediates and products, and are becoming closer representations of physical mechanisms involved in experiments. This review describes several of these approaches, which are categorized based on their overarching TS finding strategies. Future advances are discussed that may revolutionize the ability of simulation to fully predict not just the reaction mechanism but reaction outcomes. For further resources related to this article, please visit the WIREs website.

An enantioselective intramolecular chiral phosphoric acid-catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two-step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S(N)2'-like displacement to yield the product with stereoselectivity in agreement with experimental observations.

The authors hypothesized that an interprofessional workshop would improve geriatrics trainees' medication management. The workshop was based on a needs assessment and comprised an interactive session with pharmacists on managing medications in elderly adults. Participants were trainees in their geriatrics rotation at a tertiary care medical center. Trainees completed a medication appropriateness survey for three patients, one of which was their own. After the workshop, trainees reviewed medications of the three patients. Trainees completed online surveys after their rotation and 3 months later. Of 95 trainees rotating through geriatrics, 76 (80%) attended the workshop and completed the worksheet. Trainees' scores on reviewing medication lists improved significantly, from 6.7 ± 2.3 to 7.7 ± 2.0 out of 11 for standardized patient 1 (P < .001) and from 5.7 ± 1.8 to 6.4 ± 1.5 out of 11 for standardized patient 2 (P = .009). Trainees' scores on their own patients' lists also improved significantly, from 5.6 ± 1.5 to 6.6 ± 1.5 out of 10 (P < .001). After the workshop, 95% (71/75) planned to change the medication regimen of the patient they presented, and 93% (68/73) planned to change other patients' medications based on information learned during the workshop. Three months later, 35% (12/34) had made changes to the regimen of the patient they discussed during the workshop, and 71% (15/21) had made changes to other patients' regimens. Seventy-eight percent (18/23) rated the workshop as the top nonclinical experience of their geriatrics rotation. In conclusion, this interprofessional medication management workshop improved trainees' ability to perform medication reviews accurately and led to change in self-reported prescribing behavior.

Aging is associated with a large number of both phenotypic and molecular changes, but for most of these, it is not known whether these changes are detrimental, neutral, or protective. We have identified a conserved Caenorhabditis elegans GATA transcription factor/MTA-1 homolog egr-1 (lin-40) that extends lifespan and promotes resistance to heat and UV stress when overexpressed. Expression of egr-1 increases with age, suggesting that it may promote survival during normal aging. This increase in expression is dependent on the presence of the germline, raising the possibility that egr-1 expression is regulated by signals from the germline. In addition, loss of egr-1 suppresses the long lifespan of insulin receptor daf-2 mutants. The DAF-16 FOXO transcription factor is required for the increased stress resistance of egr-1 overexpression mutants, and egr-1 is necessary for the proper regulation of sod-3 (a reporter for DAF-16 activity). These results indicate that egr-1 acts within the insulin signaling pathway. egr-1 can also activate the expression of its paralog egl-27, another factor known to extend lifespan and increase stress resistance, suggesting that the two genes act in a common program to promote survival. These results identify egr-1 as part of a longevity-promoting circuit that changes with age in a manner that is beneficial for the lifespan of the organism.

Pesticide concentration data for waters from selected carbonate-rock aquifers in agricultural areas of Pennsylvania were collected in 1993-2009 for occurrence and distribution assessments. A set of 30 wells was visited once in 1993-1995 and again in 2008-2009 to assess concentration changes. The data include censored matched pairs (nondetections of a compound in one or both samples of a pair). A potentially improved approach for assessing concentration changes is presented where (i) concentrations are adjusted with models of matrix-spike recovery and (ii) area-wide temporal change is tested by use of the paired Prentice-Wilcoxon (PPW) statistical test. The PPW results for atrazine, simazine, metolachlor, prometon, and an atrazine degradate, deethylatrazine (DEA), are compared using recovery-adjusted and unadjusted concentrations. Results for adjusted compared with unadjusted concentrations in 2008-2009 compared with 1993-1995 were similar for atrazine and simazine (significant decrease; 95% confidence level) and metolachlor (no change) but differed for DEA (adjusted, decrease; unadjusted, increase) and prometon (adjusted, decrease; unadjusted, no change). The PPW results were different on recovery-adjusted compared with unadjusted concentrations. Not accounting for variability in recovery can mask a true change, misidentify a change when no true change exists, or assign a direction opposite of the true change in concentration that resulted from matrix influences on extraction and laboratory method performance. However, matrix-based models of recovery derived from a laboratory performance dataset from multiple studies for national assessment, as used herein, rather than time- and study-specific recoveries may introduce uncertainty in recovery adjustments for individual samples that should be considered in assessing change.

edu † Previous presentations are given in Appendix I. Summary The combination of lenalidomide–dexamethasone is active in multiple myeloma (MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to lenalidomide and dexamethasone, providing the rationale for this Phase I, multicentre, single-arm study to assess the safety and determine the maximum-tolerated dose (MTD) of perifosine–lenalidomide–dexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50–100 mg daily and lenalidomide 15–25 mg once daily on days 1–21 of each 28-d cycle, plus dexamethasone 20–40 mg weekly thereafter, as indicated. Thirty-two patients were enrolled across four dose cohorts. MTD was not reached, with 31 patients evaluable for safety/tolerability. The most common all-causality grade 1-2 adverse events were fatigue (48%) and diarrhoea (45%), and grade 3–4 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57·5–89·2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression-free survival was 10·8 months and median overall survival 30·6 months. Response was associated with phospho-Akt in pharmacodynamic studies. Perifosine–lenalidomide–dexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM.

SUMMARY 1. Global climate change is predicted to raise water temperatures and alter flow regimes in northern river systems. Climate-related factors might have profound impacts on survival, reproduction and distribution of freshwater species such as red-listed noble crayfish (Astacus astacus) in its northern limit of distribution. 2. In this study, noble crayfish capture data over 27 years from the River Ljungan, Sweden, were examined. Time series of catch per unit effort (CPUE) were analysed in relation to the North Atlantic Oscillation (NAO) index, regional weather factors and water flow. CPUE was assumed to reflect differences in population size. Two models were constructed to explore the relative impact of different climate factors and density dependence on variability of catch sizes. 3. The most parsimonious model for CPUE time series, explaining 72% of the variance in CPUE, included density-dependent population dynamics of the crayfish and climate or weather factors. The specific effect from density dependence in the model was 37%, while climate ⁄weather factors contributed with 35% of the variation. The most important climate ⁄weather factors are variations in NAO index and water flow. Temperature did not improve the model fit to capture data. 4. The best model was evaluated using independent data sets that gave correlations between model predictions and data ranging from 0.44 to 0.53. The density dependence shows a time lag of 1 year, while climate variables show time lags from 2 to 6 years in relation to CPUE, indicating effects on different cohorts of the crayfish population. 5. Both density dependence and climatic factors play a significant role in population fluctuations of noble crayfish. A 6-year time lag for NAO index is puzzling but indicates that some as yet unidentified factors related to NAO might act on the juvenile stages of the population. Water flow shows a 2-year lag to the CPUE, and high flow in the river may affect adult survival. The reasons for fluctuation of crayfish catches in response to climate need to be identified, and fishing quotas should consider the different cohort sizes because of variation in environment. Reintroduction programmes for crayfish need to consider effects of climate change when designing management strategies.

Although the correlation between peer delinquency and delinquency is one of the most consistently demonstrated findings in delinquency research, researchers have focused primarily on the direct, linear, and additive effects of peers in statistical models, rather than on empirically modeling mediating, nonlinear, and moderating processes that are specified by theory. To address these issues, we measure respondent delinquency and peer delinquency with illegal substance use and then decompose the effect of peer substance use on self-reported substance use. Logistic hierarchical models on a sample of adolescents from the Project on Human Development in Chicago Neighborhoods (PHDCN) indicate that the effect of peer substance use on self-reported substance use is partially mediated by perceptions of the health risks of substance use. In addition, the direct statistical effect of peers is nonlinear: On average, the peer effect decreases at higher values of peer substance use, which is consistent with a “saturation” effect. We also find that the functional form of the peer substance use/substance use relationship is dependent on the neighborhood context. In neighborhoods with more opportunities for crime, the peer effect is initially strong but decreases as peer substance use increases, which is consistent with a saturation effect. Conversely, in neighborhoods with fewer opportunities for crime, the effect of peers is initially small, but as delinquent peer associations increase, the peer effect increases multiplicatively.

This study investigated differences in parent and child estimates of the child's exposure to violence. Using data (N = 1,517) from the Project on Human Development in Chicago Neighborhoods, analyses related differences between parent and child reports of the child's exposure to violence to the child's psychosocial functioning. Most parents (66%) underestimated their children's exposure to violence. Further, parental underestimation was associated with the child's internalizing and externalizing problems and delinquent behaviors but parental overestimation was not. Family support partially mediated these associations. Parental underestimation of the child's exposure to violence, therefore, reflected lower levels of family support, which in turn led to more internalizing and externalizing problems and delinquency for the child.

Objective Pulmonary arterioles respond to hypoxia with constriction that raises vascular resistance and pulmonary artery blood pressure. The response is sustained indefinitely by the chronic hypoxia of high-altitude residence among highlanders of European and Andean descent, but not Tibetans. The objective of this study was to identify the consequences of lifelong hypoxia exposure for the pulmonary vasculature among Amhara high-altitude natives from Ethiopia. Methods A three-way static group comparison tested for the effect of Amhara ancestry and high residence altitude on pulmonary hemodynamics measured using echocardiography in samples of 76 healthy adult Amhara lifelong residents at 3700 m, 54 Amhara lifelong residents at 1200 m, and 46 U.S. low-altitude residents at 282 m. Results Amhara at 3700 m had average Doppler-estimated pulmonary artery systolic pressure (tricuspid regurgitant gradient) of 27.9 ± 8.4 (SD) mm Hg as compared with 21.9 ± 4.0 among Amhara at low altitude and 16.5 ± 3.6 in the U.S. low-altitude reference sample. However, there was no residence altitude effect on pulmonary blood flow or vascular resistance. Amhara ancestry was associated with greater pulmonary artery systolic pressure and pulmonary blood flow, yet lower pulmonary vascular resistance. Conclusions The Amhara at 3700 m had elevated pulmonary artery pressure, but without the elevated pulmonary vascular resistance characteristic of the classic model of the response to long-term hypoxia by the pulmonary vasculature. The elevated pressure among Amhara may be a consequence of high pulmonary blood flow regardless of altitude and represent a newly identified pattern of response. Am. J. Hum. Biol., 2011. © 2010 Wiley-Liss, Inc.

Summary In mammals, somatic hypermutation (SHM) of immunoglobulin (Ig) genes is critical for the generation of high-affinity antibodies and effective immune responses. Knowledge of sequence-specific biases in the targeting of somatic mutations can be useful for studies aimed at understanding antibody repertoires produced in response to infections, B-cell neoplasms, or autoimmune disease. To evaluate potential nucleotide targets of somatic mutation in zebrafish (Danio rerio), an enriched IgL cDNA library was constructed and > 250 randomly selected clones were sequenced and analysed. In total, 55 unique VJ-C sequences were identified encoding a total of 125 mutations. Mutations were most prevalent in VL with a bias towards single base transitions and increased mutation in the complementarity-determining regions (CDRs). Overall, mutations were overrepresented at WRCH/DGYW motifs suggestive of activation-induced cytidine deaminase (AID) targeting which is common in mice and humans. In contrast to mammalian models, N and P addition was not observed and mutations at AID hotspots were largely restricted to palindromic WRCH/DGYW motifs. Mutability indexes for di- and trinucleotide combinations confirmed C/G targets within WRCH/DGYW motifs to be statistically significant mutational hotspots and showed trinucleotides ATC and ATG to be mutation coldspots. Additive mutations in VJ-C sequences revealed patterns of clonal expansion consistent with affinity maturation responses seen in higher vertebrates. Taken together, the data reveal specific nucleotide targets of SHM in zebrafish and suggest that AID and affinity maturation contribute to antibody diversification in this emerging immunological model.

We developed a spreadsheet-based model for the use of managers, conservationists, and biologists for projecting the effects of climate change on coral reefs at local-to-regional scales. The COMBO (Coral Mortality and Bleaching Output) model calculates the impacts to coral reefs from changes in average SST and CO 2 concentrations, and from high temperature mortality (bleaching) events. The model uses a probabilistic assessment of the frequency of high temperature events under a future climate to address scientific uncertainties about potential adverse effects. COMBO offers data libraries and default factors for three selected regions (Hawai’i, Great Barrier Reef, and Caribbean), but it is structured with user-selectable parameter values and data input options, making possible modifications to reflect local conditions or to incorporate local expertise. Preliminary results from sensitivity analyses and simulation examples for Hawai’i demonstrate the relative importance of high temperature events, increased average temperature, and increased CO 2 concentration on the future status of coral reefs; illustrate significant interactions among variables; and allow comparisons of past environmental history with future predictions.

Kainate is a potent neuroexcitatory agent; its neurotoxicity is thought to be mediated by an ionotropic receptor with a nanomolar affinity for kainate. In this report, we describe the cloning of a cDNA encoding a human glutamate ionotropic receptor subunit protein from a human hippocampal library. This cDNA, termed humEAA1, is most closely related to rat and human cDNAs for kainate receptor proteins and, when expressed in COS or Chinese hamster ovary cells, is associated with high-affinity kainate receptor binding. We have successfully established cell lines stably expressing humEAA1. This is the first report of establishment of stable cell lines expressing a glutamate receptor subunit. The relative potency of compounds for displacing [3H] kainate binding of humEAA1 receptors expressed in these stable cell lines was kainate > quisqualate > domoate > L-glutamate > (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid > dihydro-kainate > 6, 7-dinitroquinoxaline-2, 3-dione > 6-cyano-7-nitroquinoxaline-2, 3-dione. Homooligomeric expression of humEAA1 does not appear to elicit ligand-gated ion channel activity. Nevertheless, the molecular structure and pharmacological characterization of high-affinity kainate binding of the humEAA1 expressed in the stable cell line (ppEAA1–16) suggest that the humEAA1 is a subunit protein of a human kainate receptor complex.

The protozoan, Tetrahymena pyriformis GL, was used as a model system for studying polysomal mRNA during the cell cycle and during cilia regeneration. Our previous work has shown a substantial induction of tubulin synthesis following deciliation and during G2 of the synchronous cell cycle. In the present study, the abundance of tubulin mRNA on polysomes was examined in order to determine whether more tubulin mRNA was being translated during the periods of peak tubulin synthesis. Polysomes isolated at sequential times following deciliation and during the synchronous cell cycle were translated in a cell-free translation system derived from wheat germ. The abundance of tubulin mRNA on polysomes was inferred from the amount of tubulin translated in vitro. Following deciliation and prior to the peak period of tubulin synthesis, the abundance of tubulin mRNA (at 140 min post-deciliation) increases to 25 times the initial value observed (at 20 min post-deciliation). Since the increase in tubulin mRNA abundance precedes the peak in tubulin synthesis, induction of tubulin synthesis appears to be mRNA-dependent. A similar analysis of tubulin mRNA abundance on polysomes during the synchronous cell cycle revealed a peak of tubulin mRNA prior to each peak of tubulin synthesis. These studies suggest that the periodic fluctuations in the synthesis of tubulin are dependent upon fluctuating levels of tubulin mRNA on polysomes.

A highly enantioselective intramolecular cyclization of unsaturated acetals (I) and (III) is utilized for the synthesis of chiral piperidines (II) and (IV), respectively.

Confocal microscopy, in association with three-dimensional reconstruction, revealed that microtubules and microfilaments in differentiating PC-12 cells were disrupted in a dose-dependent manner following pressure treatment. Hydrostatic pressure caused cell rounding, microtubule and microfilament disorganization, neurite retraction and the formation of a microtubule ring adjacent to the cell surface. Volume analysis from computer-generated reconstructed cells, at atmospheric pressure, showed that the apparent volume of microtubules and microfilaments, normalized to 100 units, was 22 and 11 respectively. At 4000 and 8000 psi, the apparent microtubule volume was reduced to 16 and 12 units, respectively, and the apparent microfilament volume was reduced to 8 and 5 units, respectively. Thus, the apparent microtubule and microfilament volumes in PC-12 cells decreased as pressure increased. In the presence of taxol and phalloidin which stabilize the cytoarchitecture, cells resist the effects of hydrostatic pressure. In the presence of colchicine and cytochalasin D compounds which destabilize the cytoarchitecture, cells are more susceptible to the disrupting effects of hydrostatic pressure. The effects of hydrostatic pressure on cell morphology were reversible.

A study was conducted to investigate methods of improving a near-infrared transmittance spectroscopy (NITS) amylose calibration that could serve as a rapid, nondestructive alternative to traditional methods for determining amylose content in corn. Calibrations were developed using a set of genotypes possessing endosperm mutations in single- and double-mutant combinations ranging in starch-amylose content (SAC) from -8.5 to 76%, relative to a standard curve. The influence of three factors were examined including comparing calibrations made against SAC versus grain amylose content (GAC), developing calibrations using partial least squares (PLS) analysis versus artificial neural networking (ANN), and using all samples in the calibrations set versus using progressively narrower ranges of SAC or GAC in the calibration set. Grain samples were divided into calibration and validation sets for PLS analysis while samples used in ANN were assigned to a training set, test set, and validation set. Performance...

Despite efforts by the membrane community to develop polymeric materials with improved O2/N2 separation performance, limited progress has occurred for almost a decade. Molecular sieving media, which can exhibit gas separation properties superior to polymers, tend to be brittle and uneconomical to produce for large-scale membrane separation processes. Considering this, the polymer structures investigated in this work were designed to mimic aspects of the structure of molecular sieving media such as zeolites and carbon molecular sieves while maintaining the processability associated with polymers. Significantly attractive gas separation material properties were obtained using hyper rigid polypyrrolone copolymers with controlled packing disruptions between flat, packable segments. The gas transport properties in the materials changed dramatically as a result of different average interchain spacing. Moreover, all of the polypyrrolones studied in this work exhibited performance lying on or above the existing O2/N2 upper bound trade-off line between permselectivity and permeability. These results, therefore, may point the way to a new cycle of membrane materials improvements for gas separations. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 1235–1249, 1999

The temperature dependence of the gas permeability and sorption coefficients of a series of ladder-type polypyrrolones, 6FDA–TAB and 6FDA/PMDA–TAB copolymers, is reported at temperatures up to 80°C. Knowledge of gas transport and sorption behavior at higher temperatures provides insights into these unusual systematically varied high-performance polymers. Activation energies for permeation and diffusion as well as heats of sorption for He, CO2, O2, N2, and CH4 are reported for the four polypyrrolones. These gas transport properties are interpreted in terms of the polypyrrolone structures, which possess different average interchain spacings. In addition, the activation energy for diffusion is shown to be dominant in influencing the activation energy for permeation. The so-called “dual mode” sorption behavior, especially of highly sorbing gases like CO2, is shown to affect the calculation of the apparent heat of sorption. The individual heats of sorption associated with the Henry's law and Langmuir environments provide a more complete description of the temperature dependence of sorption in these glassy materials. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 1251–1265, 1999

A subgroup of patients with refractory Hodgkin's (HD) or non-Hodgkin's (NHL) lymphoma may be cured with high-dose chemotherapy and peripheral blood progenitor cell rescue. To investigate the relationship of adequate leukapheresis yield and time course of platelet recovery after mobilization chemotherapy, we retrospectively analyzed the leukapheresis yields in seven patients with Hodgkin's disease and fifteen patients with non-Hodgkin's lymphoma undergoing high-dose chemotherapy. Our goal was to develop a rule to determine when to initiate leukapheresis and then to prospectively validate this rule. All patients were mobilized with cyclophosphamide and G-CSF (granulocyte-colony stimulating factor). A total of 144 leukaphereses were completed and analyzed. Based on the CD34 content in the initial harvest product, fifteen patients were defined as poor mobilizers (CD34 < 0.15 × 106/kg) and seven were good mobilizers. The platelet count on the first day of harvesting was significantly associated with the poor mobilizers (P = .03). Age, sex, marrow involvement, disease (HD vs. NHL), prior radiation, time since last chemotherapy, and total number of cycles of prior chemotherapy were not predictive of poor mobilizers. By using a platelet count cut off of 35 × 109/L, we retrospectively analyzed 144 individual leukapheresis products, to test whether CD34 yield was predicted by the peripheral blood platelet count on the day of leukapheresis. This rule had an excellent sensitivity, 91%, and a specificity of 67%. Subsequently, we validated this rule with the next twenty-four patients undergoing leukapheresis of which there were 143 leukaphereses. The prediction rule exhibited a sensitivity of 72% and a specificity of 68% in the validation set. There does appear to be utility in using the platelet count to guide the initiation of leukapheresis after chemotherapy and G-CSF mobilization. J. Clin. Apheresis 14:31–34, 1999.© 1999 Wiley-Liss, Inc.

Typically, materials with high-performance transport properties such as zeolites, carbon molecular sieves, or hyper rigid polymers are inherently difficult or impossible to characterize by steady-state membrane permeation experiments used for conventional polymers. Diffusion coefficients determined by transient sorption, a measurement easily performed on brittle media, are analyzed here and compared to those determined by steady-state permeation/sorption and transient permeation for a glassy polymer and a carbon molecular sieve. Average and local diffusion coefficients are extrapolated to zero upstream partial pressure to eliminate effects caused by concentration dependence. Good agreement between the techniques was observed for the glassy polymer. On the other hand, carbon molecular sieves, possessing a more complex morphology, exhibit a greater difference in diffusion coefficients determined by the various techniques. Nevertheless, comparison of the analysis techniques is shown to provide potentially valuable insights into the morphological features of such carbon molecular sieves. © 1998 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 36: 1747–1755, 1998

Designer stimulants are rapidly emerging as drugs of abuse. Marketed as “bath salts” or “plant food,” these commercial products typically contain cathinone analogues such as 3,4-methylenedioxypyrov...

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A 10-mG, 50 to 60-Hz magnetic field is in the intensity and frequency range that people worldwide are often exposed to in homes and in the workplace. Studies about the effects of 50- to 100-Hz electromagnetic fields on various species of animal embryos (fish, chick, fly, sea urchin, rat, and mouse) indicate that early stages of embryonic development are responsive to fluctuating magnetic fields. Chick, sea urchin, and mouse embryos are responsive to magnetic field intensities of 10-100 mG. Results from studies on sea urchin embryos indicate that exposure to conditions of rotating 60-Hz magnetic fields, e.g., similar to those in our environment, interferes with cell proliferation at the morula stage in a manner dependent on field intensity. The cleavage stages, prior to the 64-cell stage, were not delayed by this rotating 60-Hz magnetic field suggesting that the ionic surges, DNA replication, and translational events essential for early cleavage stages were not significantly altered. Studies of histone synthesis in early sea urchin embryos indicated that the rotating 60-Hz magnetic field decreased zygotic expression of "early" histone genes at the morula stage and suggests that this decrease in early histone production was limiting to cell proliferation. Whether these comparative observations from animal development studies will be paralleled by results from studies of human embryogenesis, as suggested by some epidemiology studies, has yet to be established.