Proteomic basis of the antibody response to monkeypox virus infection examined in cynomolgus macaques and a comparison to human smallpox vaccination

Monkeypox is a zoonotic viral disease that occurs primarily in Central and West Africa. A recent outbreak in the United States heightened public health concerns for susceptible human populations. Vaccinating with vaccinia virus to prevent smallpox is also effective for monkeypox due to a high degree of sequence conservation. Yet, the identity of antigens within the monkeypox virus proteome contributing to immune responses has not been described in detail. We compared antibody responses to monkeypox virus infection and human smallpox vaccination by using a protein microarray covering 92-95% (166-192 proteins) of representative proteomes from monkeypox viral clades of Central and West Africa, including 92% coverage (250 proteins) of the vaccinia virus proteome as a reference orthopox vaccine. All viral gene clones were verified by sequencing and purified recombinant proteins were used to construct the microarray. Serum IgG of cynomolgus macaques that recovered from monkeypox recognized at least 23 separate proteins within the orthopox proteome, while only 14 of these proteins were recognized by IgG from vaccinated humans. There were 12 of 14 antigens detected by sera of human vaccinees that were also recognized by IgG from convalescent macaques. The greatest level of IgG binding for macaques occurred with the structural proteins F13L and A33R, and the membrane scaffold protein D13L. Significant IgM responses directed towards A44R, F13L and A33R of monkeypox virus were detected before onset of clinical symptoms in macaques. Thus, antibodies from vaccination recognized a small number of proteins shared with pathogenic virus strains, while recovery from infection also involved humoral responses to antigens uniquely recognized within the monkeypox virus proteome.     

Regional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction

The hippocampus is critical for cognition and memory formation and is vulnerable to age‐related atrophy and loss of function. These phenotypes are attenuated by caloric restriction (CR), a dietary intervention that delays aging. Here, we show significant regional effects in hippocampal energy metabolism that are responsive to age and CR, implicating metabolic pathways in neuronal protection. In situ mitochondrial cytochrome c oxidase activity was region specific and lower in aged mice, and the impact of age was region specific. Multiphoton laser scanning microscopy revealed region‐ and age‐specific differences in nicotinamide adenine dinucleotide (NAD)‐derived metabolic cofactors. Age‐related changes in metabolic parameters were temporally separated, with early and late events in the metabolic response to age. There was a significant regional impact of age to lower levels of PGC‐1α, a master mitochondrial regulator. Rather than reversing the impact of age, CR induced a distinct metabolic state with decreased cytochrome c oxidase activity and increased levels of NAD(P)H. Levels of hippocampal PGC‐1α were lower with CR, as were levels of GSK3β, a key regulator of PGC‐1α turnover and activity. Regional distribution and colocalization of PGC‐1α and GSK3β in mouse hippocampus was similar in monkeys. Furthermore, the impact of CR to lower levels of both PGC‐1α and GSK3β was also conserved. The studies presented here establish the hippocampus as a highly varied metabolic environment, reveal cell‐type and regional specificity in the metabolic response to age and delayed aging by CR, and suggest that PGC‐1α and GSK3β play a role in implementing the neuroprotective program induced by CR.     

Some physical,chemical, and microbiological characteristics of two beaches of anglesey

Observations during 1971 and 1972 of some of the physical, chemical, and microbiological characteristics of contrasting Anglesey beaches, Newborough and Llanddona, are reported. The fine sandy beach at Newborough was observed to be very unstable and topographical changes were recorded. In particular, the movement of a sand wave across the intertidal zone from low water to extinction at the foot of the dune system was observed. The more extensive fine sandy beach at Llanddona had greater stability.Chemically, each beach was variable both spatially and temporally, with ill-defined patterns of concentration changes. Sand from Newborough beach was low in organic carbon (0.07–0.40 mg C/g dry sand) and well aerated, and the soluble inorganic nitrogen in the ground water (up to 30 μg-at. N/l) was dominated by nitrate form (up to 22 μg NO₃-N/l). By contrast, Llanddona sand had a more variable organic carbon content (0.22–2.25 mg C/g dry sand), was wetter, and poorly aerated with consequent sulphide lenses; its dissolved inorganic nitrogen (over 70 μg-at. N/l) was completely dominated by the ammonium form.Microbiologically, the beaches possessed dissimilar bacterial floras, and sediment from Llanddona gave higher bacterial counts than that from Newborough. For both beaches it is shown that estimated bacterial numbers decreased with depth as well as down the intertidal zone.     

When is coercive methadone therapy justified?

Heroin use poses a significant health and economic burden to society, and individuals with heroin dependence are responsible for a significant amount of crime. Owing to its efficacy and cost‐effectiveness, methadone maintenance therapy (MMT) is offered as an optional alternative to imprisonment for drug offenders in several jurisdictions. Some object to such ‘MMT offers’ on the basis that they involve coercion and thus invalidate the offender's consent to MMT. While we find these arguments unpersuasive, we do not attempt to build a case against them here. Instead, we explore whether administration of MMT following acceptance of an MMT offer might be permissible even on the assumption that MMT offers are coercive, and in such a way that the resulting MMT is non‐consensual. We argue that non‐consensual MMT following an MMT offer is typically permissible. We first offer empirical evidence to demonstrate the substantial benefits to the offender and society of implementing non‐consensual MMT in the criminal justice system. We then explore and respond to potential objections to such uses of MMT. These appeal respectively to harm, autonomy, bodily and mental interference, and penal theoretic considerations. Finally, we introduce and dismiss a potential response to our argument that takes a revisionist position, rejecting prevailing incarceration practices.     

Analogues of dealanylalahopcin are inhibitors of human HIF prolyl hydroxylases

Analogues of the naturally occurring cyclic hydroxamate dealanylalahopcin, which is an inhibitor of procollagen prolyl-4-hydroxylase, were synthesised and shown to be inhibitors of the human hypoxia-inducible factor prolyl hydroxylases.