Environmental Sustainability of Fluid Milk Delivery Systems in the United States

Beverage producers in the United States choose packaging based on cost and consumer preference. Monolayer high‐density polyethylene (HDPE) and gable‐top carton containers have long dominated the U.S. fluid milk market, but pressure for more sustainable packaging is increasing. We present a broad discussion on environmental sustainability of 18 fluid milk containers through life cycle assessment. Because different container types require unique milk processing, distribution, and disposal and incur or avoid milk losses, fluid milk delivery systems (FMDSs) are evaluated, rather than containers in isolation. By assessing FMDSs, a complete measure of containers’ environmental sustainability was obtained. Despite conservative assumptions about milk losses, differences in container size, milk processing, distribution, and container recycling, pair‐wise cradle‐to‐grave comparisons of FMDSs show there are no superior FMDSs. But, 500‐ to 1,000‐milliliter FMDSs are potentially superior to ≥half gallon if they prevent milk losses. Thus, the future of FMDSs in the United States depends on the industry's ability to prevent distribution (12%) and consumption milk losses (20% to 35%). Farm‐gate‐to‐grave comparisons showed that chilled HDPE FMDSs are superior to other plastic and chilled paperboard FMDSs for climate‐change impact, but the result is inconclusive for chilled HDPE to ambient (unrefrigerated) paperboard or plastic pouch FMDS comparisons. Plastic pouch FMDSs show potential to reduce nonrenewable fossil energy, but need to be recyclable. Ambient FMDSs are superior to chilled FMDSs for water depletion. Eight‐ounce paperboard FMDSs are superior to 8‐ounce plastic FMDSs. Thus, alternative FMDSs may improve environmental sustainability of the U.S. postfarm fluid milk supply chain.     

b-Annulated 1,4-dihydropyridines as Notch inhibitors

The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal cancer, pancreatic cancer, breast cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 (1) is an inhibitor of the Notch pathway with an EC50?≈?2.5?μM prompted us to screen a library of related analogs. After structure activity studies were conducted, racemic compound 7 was identified with an EC50?=?0.36?μM. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50?=?0.13?μM, or about 20-fold the potency of 1.     

Greenhouse Gas and Energy Life Cycle Assessment of Pine Chemicals Derived from Crude Tall Oil and Their Substitutes

Pine chemicals are co‐products of papermaking that are upgraded into diverse products from inks to adhesives. They can also be utilized for energy purposes. This research investigates the carbon and energy life cycle assessment (LCA) of pine chemicals derived from crude tall oil (CTO). The study goals are to determine the cradle‐to‐gate carbon and energy footprint for CTO‐derived chemicals, compare CTO‐derived chemicals to their likely substitutes, and calculate the carbon and energy effects of shifting CTO resources from current chemical production to biodiesel production. The data collected represent 100% of the U.S. and 90% of the European CTO distillation industry for 2011. This analysis is the first industry‐level LCA of pine chemicals. The carbon footprint for CTO‐derived pine chemical products is 50% lower than the likely mix of alternative products, including hydrocarbon resins for rubber, ink, and adhesive, alkyl succinic anhydride for paper size, and heavy fuel oil for heat. Current and proposed European policies could result in CTO being classified as renewable biomass for energy production, creating incentive to convert CTO into fuel rather than chemicals. The differences in the carbon and energy footprints of utilizing CTO for biodiesel versus chemicals are not meaningful when comparing European CTO biodiesel, which displaces conventional diesel, to European CTO‐derived chemicals, which displace the previously discussed substitutes. Therefore, there is no additional carbon or energy benefit that accrues by diverting CTO from current chemical feedstock applications to use for biodiesel production in Europe.     

Induction of PrPSc-specific systemic and mucosal immune responses in white-tailed deer with an oral vaccine for chronic wasting disease

The ongoing epidemic of chronic wasting disease (CWD) within cervid populations indicates the need for novel approaches for disease management. A vaccine that either reduces susceptibility to infection or reduces shedding of prions by infected animals, or a combination of both, could be of benefit for disease control. The development of such a vaccine is challenged by the unique nature of prion diseases and the requirement for formulation and delivery in an oral format for application in wildlife settings. To address the unique nature of prions, our group targets epitopes, termed disease specific epitopes (DSEs), whose exposure for antibody binding depends on disease-associated misfolding of PrP^C into PrP^Sc. Here, a DSE corresponding to the rigid loop (RL) region, which was immunogenic following parenteral vaccination, was translated into an oral vaccine. This vaccine consists of a replication-incompetent human adenovirus expressing a truncated rabies glycoprotein G recombinant fusion with the RL epitope (hAd5:tgG-RL). Oral immunization of white-tailed deer with hAd5:tgG-RL induced PrP^Sc-specific systemic and mucosal antibody responses with an encouraging safety profile in terms of no adverse health effects nor prolonged vector shedding. By building upon proven strategies of formulation for wildlife vaccines, these efforts generate a particular PrP^Sc-specific oral vaccine for CWD as well as providing a versatile platform, in terms of carrier protein and biological vector, for generation of other oral, peptide-based CWD vaccines.     

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.     

Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression

Multi-target compounds where more than one functional activity is incorporated into the same molecule may have advantages in treating disease states. Selective serotonin re-uptake inhibitors (SSRIs)^a (i.e., (R)- and (S)-norfluoxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual PDE4 inhibitor/SSRIs (i.e., (R)-8 and (S)-8) showed moderately potent but highly selective serotonin re-uptake inhibition (IC₅₀ values of 173 and 42 nM, respectively) in vitro. The dual PDE4 inhibitor/SSRIs (R)-8 and (S)-8 also inhibited PDE4D2 (i.e., K_i values of 106 and 253 nM, respectively). Due to the synergistic functional activity, PDE4 inhibitor/SSRIs may be effective in treating diseases such as depression.     

Relative and regional stabilities of the hamster, mouse, rabbit, and bovine prion proteins toward urea unfolding assessed by nuclear magnetic resonance and circular dichroism spectroscopies

The residue-specific urea-induced unfolding patterns of recombinant prion proteins from different species (bovine, rabbit, mouse, and Syrian hamster) were monitored using high-resolution (1)H nuclear magnetic resonance (NMR) spectroscopy. Protein constructs of different lengths, and with and without a His tag attached at the N-terminus, were studied. The various species showed different overall sensitivities toward urea denaturation with stabilities in the following order: hamster ≤ mouse < rabbit < bovine protein. This order is in agreement with recent circular dichroism (CD) spectroscopic measurements for several species [Khan, M. Q. (2010) Proc. Natl. Acad. Sci. U.S.A.107, 19808-19813] and for the bovine protein presented herein. The [urea](1/2) values determined by CD spectroscopy parallel those of the most stable residues observed by NMR spectroscopy. Neither the longer constructs containing an additional hydrophobic region nor the His tag influenced the stability of the structured domain of the constructs studied. The effect of the S174N mutation in rabbit PrP(C) was also investigated. The rank order of the regional stabilities within each protein remained the same for all species. In particular, the residues in the β-sheet region in all four species were more sensitive to urea-induced unfolding than residues in the α2 and α3 helical regions. These observations indicate that the regional specific unfolding pattern is the same for the four mammalian prion proteins studied but militate against the idea that PrP(Sc) formation is linked with the global stability of PrP(C).     

N-acetyl-beta-hexosaminidase B deficiency in cultured fibroblasts from a patient with progressive motor neuron disease

A patient with a 20-year history of progressive motor neuron disease was previously found to have profoundly low levels of N-acetyl-beta-hexosaminidase (Hex) in serum and leukocytes; Hex activity in cultured skin fibroblasts was in the low normal range. By thermal inactivation and cellulose acetate electrophoresis, the residual activity appeared to be Hex A. In the present study, the residual activity in cultured skin fibroblasts was further characterized as Hex A by thermal inactivation at reduced temperatures and ion exchange chromatography; no evidence was obtained for a diffusible inhibitor of Hex activity. After labeling with [3H]leucine, immunoprecipitation with polyclonal antibody to Hex B, and SDS-polyacrylamide gel electrophoresis, both alpha and beta polypeptide chains were visualized, confirming the presence of Hex A. The results suggest that, in the patient's fibroblasts, a defect in beta-chain synthesis or processing precludes the self-association of beta-chains to form Hex B, but does not prevent the association of alpha- and beta-chains to form Hex A.     

General practitioner obstetrics in the Northern region in 1983.

In late 1983 a four page questionnaire on general practitioner obstetrics was sent to a 50% random sample of general practitioners in the Northern region of England; 84% responded. Half of them said that they had access to general practitioner facilities for delivery, and half of these used them. A quarter of all respondents had provided intranatal care previously but had given it up, most of them during the late 1970s. Younger general practitioners were more highly qualified in obstetrics than older ones but did not do more intranatal work. Isolated general practitioner maternity units were much more likely to be used than those that were alongside consultant units or integrated with them. Ninety per cent of respondents provided antenatal care, 77% of these at special clinics and 88% with midwives in attendance. Teamwork, however, was not well developed. Increasing general practitioner participation in obstetric care seems feasible but depends heavily on more appropriate training and intranatal facilities being provided for general practitioners in association with specialist units.     

Similarities in Restriction Fragment Patterns of Mitochondrial DNAs of PhytophthoraSpecies Strongly Depend on the Restriction Enzyme Used Due to Heterogeneous Base Distribution and Sequence Conservation

Mitochondrial DNAs of six morphologically different Phytophthora species were digested with 15 restriction enzymes. The numbers of restriction fragments obtained differed considerably from those theoretically expected for random base distribution. Enzymes with relatively many G and C in their recognition sequences produced significantly larger numbers of fragments. Moreover, fragments generated by most of these enzymes were more often shared by two or more species than those from enzymes with more A and T in their recognition sequence. It is concluded that base distribution in mitochondrial DNA of Phytophthora is heterogeneous,AT-rich stretches occurring scattered over the mitochondrial genome and GC-rich regions present in conserved sequences, presumably genes. A practical consequence for taxonomic RFLP studies is that optimal enzymes can be selected, depending on the desired level of resolution.