Selective p38α MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction

Maladaptive responses to stress adversely affect human behavior, yet the signaling mechanisms underlying stress-responsive behaviors remain poorly understood. Using a conditional gene knockout approach, the α isoform of p38 mitogen-activated protein kinase (MAPK) was selectively inactivated by AAV1-Cre-recombinase infection in specific brain regions or by promoter-driven excision of p38α MAPK in serotonergic neurons (by Slc6a4-Cre or ePet1-Cre) or astrocytes (by Gfap-CreERT2). Social defeat stress produced social avoidance (a model of depression-like behaviors) and reinstatement of cocaine preference (a measure of addiction risk) in wild-type mice, but not in mice having p38α MAPK selectively deleted in serotonin-producing neurons of the dorsal raphe nucleus. Stress-induced activation of p38α MAPK translocated the serotonin transporter to the plasma membrane and increased the rate of transmitter uptake at serotonergic nerve terminals. These findings suggest that stress initiates?a cascade of molecular and cellular events in which p38α MAPK induces a hyposerotonergic state underlying depression-like and drug-seeking behaviors.     

A historical synopsis of farm animal disease and public policy in twentieth century Britain

The diseases suffered by British livestock, and the ways in which they were perceived and managed by farmers, vets and the state, changed considerably over the course of the twentieth century. This paper documents and analyses these changes in relation to the development of public policy. It reveals that scientific knowledge and disease demographics cannot by themselves explain the shifting boundaries of state responsibility for animal health, the diseases targeted and the preferred modes of intervention. Policies were shaped also by concerns over food security and the public's health, the state of the national and livestock economy, the interests and expertise of the veterinary profession, and prevailing agricultural policy. This paper demonstrates how, by precipitating changes to farming and trading practices, public policy could sometimes actually undermine farm animal health. Animal disease can therefore be viewed both as a stimulus to, and a consequence of, twentieth century public policy.     

Engineering cell surfaces via liposome fusion

In this study, we have rewired cell surfaces with ketone and oxyamine molecules based on liposome fusion for applications in cell-surface engineering. Lipid vesicles, functionalized with ketone and oxyamine molecules, display complementary chemistry and undergo recognition, docking, and subsequent fusion upon covalent oxime bond formation. Liposome fusion was characterized by several techniques including matrix-assisted laser-desorption/ionization mass spectrometry (MALDI-MS), light scattering, fluorescence resonance energy transfer (FRET), and transmission electron microscopy (TEM). When cultured with cells, ketone- and oxyamine-containing liposomes undergo spontaneous membrane fusion to present the respective molecules from cell surfaces. Ketone-functionalized cell surfaces serve as sites for chemoselective ligation with oxyamine-conjugated molecules. We tailored and fluorescently labeled cell surfaces with an oxyamine-conjugated rhodamine dye. As an application of this cell-surface engineering strategy, ketone- and oxyamine-functionalized cells were patterned on oxyamine- and ketone-presenting surfaces, respectively. Cells adhered, spread, and proliferated in the patterned regions via interfacial oxime linkage. The number of ketone molecules on the cell surface was also quantified by flow cytometry.     

Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis

Fibrotic interstitial pneumonias are more prevalent in males of advancing age, although little is known about the underlying mechanisms. To evaluate the contributions of age and sex to the development of pulmonary fibrosis, we intratracheally instilled young (8-12 wk) and aged (52-54 wk) male and female mice with bleomycin and assessed the development and severity of fibrotic lung disease by measurements of lung collagen levels, static compliance, leukocyte infiltration, and stereological quantification of fibrotic areas in histological sections. We also quantified proinflammatory and profibrotic chemokine and cytokine levels in the bronchoalveolar lavage fluid. Aged male mice developed more severe lung disease, indicated by increased mortality, increased collagen deposition, and neutrophilic alveolitis compared with aged female mice or young mice of either sex. Aged male mice also exhibited increased levels of transforming growth factor-β, IL-17A, and CXCL1 in their bronchoalveolar lavage fluid. Young male mice developed a more fibrotic disease after bleomycin instillation compared with female mice, regardless of age. There was no difference in fibrosis between young and aged female mice. Taken together, these findings suggest that the variables of advanced age and male sex contribute to the severity of pulmonary fibrosis in this model. Our findings also emphasize the importance of stratifying experimental groups on the basis of age and sex in experimental and epidemiological studies of this nature.     

Synthesis and characterization of dendron cross-linked PEG hydrogels as corneal adhesives

In pursuit of a wound-specific corneal adhesive, hydrogels formed by the reaction of propionaldehyde, butyraldehyde, or 2-oxoethyl succinate-functionalized poly(ethylene glycol) (PEG) with a peptide-based dendritic cross-linker (Lys(3)Cys(4)) were characterized. These macromers react within minutes of mixing to form transparent and elastic hydrogels with in vitro degradation times that range from hours to months based on the type of bonds formed during the cross-linking reaction, either thiazolidine or pseudoproline. The mechanical properties of these materials, determined via parallel plate rheology, were dependent on the polymer concentration, as was the hydrogel adhesive strength, which was determined by lap shear adhesive testing. In addition, these hydrogels were efficacious in closing ex vivo 4.1 mm central corneal lacerations: wounds closed with these hydrogel adhesives were able to withstand intraocular pressure values equivalent to, or in excess of, those obtained by closing the wounds with suturing.     

Cross-species transmission of a novel adenovirus associated with a fulminant pneumonia outbreak in a new world monkey colony

Adenoviruses are DNA viruses that naturally infect many vertebrates, including humans and monkeys, and cause a wide range of clinical illnesses in humans. Infection from individual strains has conventionally been thought to be species-specific. Here we applied the Virochip, a pan-viral microarray, to identify a novel adenovirus (TMAdV, titi monkey adenovirus) as the cause of a deadly outbreak in a closed colony of New World monkeys (titi monkeys; Callicebus cupreus) at the California National Primate Research Center (CNPRC). Among 65 titi monkeys housed in a building, 23 (34%) developed upper respiratory symptoms that progressed to fulminant pneumonia and hepatitis, and 19 of 23 monkeys, or 83% of those infected, died or were humanely euthanized. Whole-genome sequencing of TMAdV revealed that this adenovirus is a new species and highly divergent, sharing <57% pairwise nucleotide identity with other adenoviruses. Cultivation of TMAdV was successful in a human A549 lung adenocarcinoma cell line, but not in primary or established monkey kidney cells. At the onset of the outbreak, the researcher in closest contact with the monkeys developed an acute respiratory illness, with symptoms persisting for 4 weeks, and had a convalescent serum sample seropositive for TMAdV. A clinically ill family member, despite having no contact with the CNPRC, also tested positive, and screening of a set of 81 random adult blood donors from the Western United States detected TMAdV-specific neutralizing antibodies in 2 individuals (2/81, or 2.5%). These findings raise the possibility of zoonotic infection by TMAdV and human-to-human transmission of the virus in the population. Given the unusually high case fatality rate from the outbreak (83%), it is unlikely that titi monkeys are the native host species for TMAdV, and the natural reservoir of the virus is still unknown. The discovery of TMAdV, a novel adenovirus with the capacity to infect both monkeys and humans, suggests that adenoviruses should be monitored closely as potential causes of cross-species outbreaks.     

The antiviral efficacy of HIV-specific CD8⁺ T-cells to a conserved epitope is heavily dependent on the infecting HIV-1 isolate

A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef_90–97 epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A–H) could activate antiviral activity in FL8-specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate. Only 23% of Nef proteins, expressed by HIV-1 isolates or as recombinant vaccinia-Nef, were optimally recognised by CTL. Recognition of the HIV-1 isolates by CTL was independent of clade-grouping but correlated with virus-specific polymorphisms in the epitope flanking region, which altered immunoproteasomal cleavage resulting in enhanced or impaired epitope generation. The finding that the majority of virus isolates failed to present this conserved epitope highlights the importance of viral variance in CTL epitope flanking regions on the efficiency of antigen processing, which has been considerably underestimated previously. This has important implications for future vaccine design strategies since efficient presentation of conserved viral epitopes is necessary to promote enhanced anti-viral immune responses.     

MVPA is associated with lower weight gain in 8-10 year old children: a prospective study with 1 year follow-up

Background

Studies relating physical activity (PA) to weight gain in children have produced mixed results, although there is some evidence for stronger associations with more intense physical activities. The present study tested the hypothesis that weight gain over one year in 8–10 year olds would be more strongly predicted by moderate and vigorous physical activity (MVPA) than total physical activity (total PA) or sedentary behaviour.

Methodology

Participants were 280 children taking part in the Physical Exercise and Appetite in Children Study (PEACHES). Weight status was assessed using body mass index (BMI), fat mass index (FMI), and waist circumference (WC) in school Year 4 (baseline; age 8.7 yrs) and Year 5 (follow-up; age 9.7 yrs). Physical activity was measured at baseline using the Actigraph GT1M accelerometer to assess total PA (mean accelerometers counts per minute), MVPA; ≥4000 counts per minute) and sedentary time (<100 counts per minute).

Principal Findings

After adjustment for baseline BMI, SES, sex and ethnicity, MVPA was significantly associated with follow–up BMI (adjusted β = −0.07; p = 0.002). This association was independent of total PA or sedentary time. Similar results were observed for FMI; again MVPA was significantly associated with follow up FMI (β = −0.16; p = 0.001) independent of total PA or sedentary time. The pattern was similar for WC (β = −0.07), but the association between MVPA and WC did not reach significance at p = 0.06.

Conclusion

The results of this study strongly support promotion of MVPA in children.     

The social network: deciphering fungal language

It has been estimated that up to one quarter of the world's biomass is of fungal origin, comprising approximately 1.5 million species. In order to interact with one another and respond to environmental cues, fungi communicate with their own chemical languages using a sophisticated series of extracellular signals and cellular responses. A new appreciation for the linkage between these chemical languages and developmental processes in fungi has renewed interest in these signalling molecules, which can now be studied using post-genomic resources. In this Review, we focus on the molecules that are secreted by the largest phylum of fungi, the Ascomycota, and the quest to understand their biological function.