Natural immunosurveillance against spontaneous, autochthonous breast cancers revealed and enhanced by blockade of IL-13-mediated negative regulation

Introduction We and others previously observed immunosurveillance against transplantable tumors in mice, and enhancement thereof by blockade of negative regulation by T reg cells or the NKT-IL-13-myeloid cell-TGF-β regulatory circuit. However, it was unknown whether natural immunosurveillance inhibits growth of completely spontaneous autochthonous tumors, and whether it can be improved by inhibition of negative regulation. Materials and methods To examine the existence of T cell-mediated immunosurveillance against spontaneous tumors, BALB-neuT mice were treated with anti-CD4 and/or anti-CD8. A role for IL-13 in the suppression of immunosurveillance was investigated by treating mice with IL-13 inhibitor. Results We show that even spontaneous autochthonous breast carcinomas arising in Her-2/neu transgenic mice appear more quickly when the mice are depleted of T cells, evidence for T-cell mediated immunosurveillance slowing tumor growth. This immunosurveillance could be further enhanced by blockade of IL-13 (but not IL-4) which slowed the appearance of these autologous tumors compared to control antibody-treated mice. Conclusion Thus, even completely spontaneous, autochthonous breast cancers can be controlled in part by natural immunosurveillance, and blockade of negative regulation can improve this control. This work was in part supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.     

From PMTCT to a more comprehensive AIDS response for women: a much-needed shift

Half of the 33.2 million people living with HIV today are women. Yet, responses to the epidemic are not adequately meeting the needs of women. This article critically evaluates how prevention of mother-to-child transmission (PMTCT) programs, the principal framework under which women's health is currently addressed in the global response to AIDS, have tended to focus on the prevention of HIV transmission from HIV-positive women to their infants. This paper concludes that more than ten years after their inception, PMTCT programs still do not successfully ensure the adequate treatment, care and support of HIV-infected women. Of particular concern is the continued widespread use of single-dose nevirapine despite World Health Organization recommendations to employ more effective combination therapies that do not potentially jeopardize women's future treatment outcomes. In response, the article calls for a more comprehensive approach that places women's health needs at the centre of AIDS responses. This is critical in settings where the pandemic is generalized and there is a push to greatly expand PMTCT programs, as a more effective and equitable way of meeting the needs of women in the context of HIV. Without such a comprehensive approach, women will continue to be impacted disproportionately by the pandemic, and current strategies for prevention, including PMTCT, and treatment will not be as effective and responsive as they need to be.     

Separation of light-induced linear, cyclic and stroma-sourced electron fluxes to P700+ in cucumber leaf discs after pre-illumination at a chilling temperature

Pre-illumination of cucumber leaf discs at 4 degrees C with low-irradiance white light (i) led to a marked decrease in the extent of photo-oxidation of P700 (the special chlorophyll pair in the PSI reaction center) in actinic light at room temperature and (ii) hastened the post-illumination re-reduction of P700+. Quantifying the linear, cyclic and stroma-sourced electron fluxes to P700+ in two actinic light regimes, we found that there was no increase in cyclic or linear electron fluxes to account for these changes. Rather, we observed a decrease in the maximum extent of P700 photo-oxidation assayed by a strong flash superimposed on continuous, background light of wavelength 723 nm, which we interpret to represent a loss of stable charge separation in PSI due to enhanced charge recombination as a result of the pre-illumination treatment. The funneling of electrons towards fewer non-damaged PSI complexes could explain the hastened post-illumination re-reduction of P700+, aided by a slight increase in a stroma-sourced electron flux after prolonged pre-illumination at 4 degrees C. Quantifying the separate fluxes to P700+ helps to elucidate the effects of chilling of cucumber leaf discs in the light and the reasons for the hastened post-illumination re-reduction of P700+.     

Effect of group racial composition on weight loss in African Americans

Objective: We do not know how racial composition of a group influences behavior change for African Americans (AAs) in group‐based weight loss programs. We tested the hypothesis that AA who participate in all AA weight loss intervention groups will lose more weight than AA who participate in mixed race groups. Methods and Procedures: This observational study was ancillary to Phase 1 of the Weight Loss Maintenance Study, a multi‐center trial of strategies to maintain weight loss after a 20‐week behavior modification program. Three of four centers recruited several all‐AA intervention groups. Remaining groups were combinations of AA and non‐AA participants. All participants received the same weight loss intervention. Change in weight was the primary outcome, comparing participants of all‐AA groups with AA participants of mixed race groups conducted by the same AA interventionists. Secondary outcomes included measures of intervention adherence and behavior change. Results: Participants of all‐AA groups (n = 271) were comparable to other AA participants (n = 106). The mean proportion of AA in mixed race groups was 56%. All‐AA group participants had similar weight loss as those in mixed groups (?4.2 vs. ?4.2 kg, P = 0.97). There were no differences between the groups in mean number of sessions attended or changes in dietary intake. Discussion: Significant weight loss was observed in both groups, with no effect of group composition on adherence or weight loss outcomes. Special logistics to accommodate all‐AA groups may not be necessary. Despite varying instructional environments, AA appeared to respond positively to intervention messages with significant changes in dietary intake, physical activity (PA), and weight.     

Is There a Role for Gastric Accommodation and Satiety in Asymptomatic Obese People?

Objective: The relationships of gastric accommodation and satiety in moderately obese individuals are unclear. We hypothesized that obese people had increased gastric accommodation and reduced postprandial satiety. The objective of this study was to compare gastric accommodation and satiety between obese and non‐obese asymptomatic subjects. Research Methods and Procedures: In 13 obese (body mass index [BMI] ≥ 30 kg/m²; mean BMI, 37.0 ± 4.9 kg/m²) and 19 non‐obese control subjects (BMI < 30 kg/m²; mean BMI, 26.2 ± 2.9 kg/m²), we used single photon emission computed tomography to measure fasting and postprandial gastric volumes and expressed the accommodation response as the ratio of postprandial/fasting volumes. The satiety test measured maximum tolerable volume of ingestion of liquid nutrient meal (Ensure) and symptoms 30 minutes after cessation of ingestion. Results: Total fasting and postprandial gastric volumes and the ratio of postprandial/fasting gastric volume were not different between asymptomatic obese and control subjects. However, the fasting volume of the distal stomach was greater in obese than in control subjects. Maximum tolerable volume of ingested Ensure and aggregate symptom score 30 minutes later were also not different between obese and control subjects. Discussion: Asymptomatic obese individuals (within the BMI range of 32.6 to 48 kg/m²) did not show either increased postprandial gastric accommodation or reduced satiety. These datasuggest that gastric accommodation is unlikely to provide an important contribution to development of moderate obesity.     

Various Shapes of Cultural Biosemiotics

There is a steady and maybe growing impulse in biosemiotics to open itself to the arts and humanities. Recent events and publications indicate a desire expressed by biosemioticians and non-biosemioticians to engage in a dialogue concerning the manner in which living systems are cast, understood and dealt with, a dialogue that will determine the future course of those fields of research. In this article, I react to two recent monographs on the subject, Paul Cobley’s Cultural implications of biosemiotics (2016) and Wendy Wheeler’s Expecting the earth. Life, culture, biosemiotics (2016). After a close reading of these two books, I then briefly present certain issues that shed a different light on cultural biosemiotics: human pressure on other-than-human organisms, domestication and reproductive rights.     

Characterization of the inhibitory effect of PEG-lipid conjugates on the intracellular delivery of plasmid and antisense DNA mediated by cationic lipid liposomes

Poly(ethylene glycol)-lipid (PEG-lipid) conjugates are widely used in the field of liposomal drug delivery to provide a polymer coat that can confer favorable pharmacokinetic characteristics on particles in the circulation. More recently these lipids have been employed as an essential component in the self-assembly of cationic and neutral lipids with polynucleic acids to form small, stable lipid/DNA complexes that exhibit long circulation times in vivo and accumulate at sites of disease. However, the presence of a steric barrier lipid might be expected to inhibit the transfection activity of lipid/DNA complexes by reducing particle-membrane contact. In this study we examine what effect varying the size of the hydrophobic anchor and hydrophilic head group of PEG-lipids has on both gene and antisense delivery into cells in culture. Lipid/DNA complexes were made using unilamellar vesicles composed of 5 mole% PEG-lipids in combination with equimolar dioleoylphosphatidylethanolamine and the cationic lipid dioleyldimethylammonium chloride. Using HeLa and HepG2 cells we show that under the conditions employed PEG-lipids had a minimal effect on the binding and subsequent endocytosis of lipid/DNA complexes but they severely inhibited active gene transfer and the endosomal release of antisense oligodeoxynucleotides into the cytoplasm. Decreasing the size of the hydrophobic anchor or the size of the grafted hydrophilic PEG moiety enhanced DNA transfer by the complexes.     

Two adaptor proteins differentially modulate the phosphorylation and biophysics of Kv1.3 ion channel by SRC kinase.

The Shaker family K(+) channel protein, Kv1.3, is tyrosine phosphorylated by v-Src kinase at Tyr(137) and Tyr(449) to modulate current magnitude and kinetic properties. Despite two proline rich sequences and these phosphotyrosines contained in the carboxyl and amino terminals of the channel, v-Src kinase fails to co-immunoprecipitate with Kv1.3 as expressed in HEK 293 cells, indicating a lack of direct Src homology 3- or Src homology 2-mediated protein-protein interaction between the channel and the kinase. We show that the adaptor proteins, n-Shc and Grb10, are expressed in the olfactory bulb, a region of the brain where Kv1.3 is highly expressed. In HEK 293 cells, co-expression of Kv1.3 plus v-Src with Grb10 causes a decrease in v-Src-induced Kv1.3 tyrosine phosphorylation and a reversal of v-Src-induced Kv1.3 current suppression, increase in inactivation time constant (tau(inact)), and disruption of cumulative inactivation properties. Co-expression of Kv1.3 plus v-Src with n-Shc did not significantly alter v-Src-induced Kv1.3 current suppression but reversed v-Src induced increased tau(inact) and restored the right-shifted voltage at half-activation (V(1/2)) induced by v-Src. The v-Src-induced shift in V(1/2) and increased tau(inact) was retained when Tyr(220), Tyr(221), and Tyr(304) in the CH domain of n-Shc were mutated to Phe (triple Shc mutant) but was reversed back to control values when either wild-type Shc or the family member Sck, which is not a substrate for Src kinase, was substituted for the triple Shc mutant. Thus the portion of the CH domain that includes Tyr(220), Tyr(221), and Tyr(304) may regulate a shift in Kv1.3 voltage dependence and inactivation kinetics produced by n-Shc in the presence of v-Src. Collectively these data indicate that Grb10 and n-Shc adaptor molecules differentially modulate the degree of Kv1.3 tyrosine phosphorylation, the channel's biophysical properties, and the physical complexes associated with Kv1.3 in the presence of Src kinase.     

Effects of agricultural activities and best management practices on water quality of seasonal prairie pothole wetlands

Long-term effects of within-basin tillage can constrain condition andfunction of prairie wetlands even after uplands are restored. Runoff wassignificantly greater to replicate wetlands within tilled basins with orwithoutvegetated buffer strips as compared to Conservation Reserve Program restorationcontrols with revegetated uplands (REST). However, mean water levels for nativeprairie reference sites were higher than for REST controls, becauseinfiltrationrates were lower for native prairie basins, which had no prior history oftillage. Nutrient dynamics changed more in response to changes in water leveland vegetation structure than to increased nutrient inputs in watershed runoff.Dissolved oxygen increased between dry and wet years except in basins or zoneswith dense vegetation. As sediment redox dropped, water-column phosphatedeclined as phosphate likely co-precipitated with iron on the sediment surfacewithin open-water or sparsely vegetated zones. In response, N:P ratios shiftedfrom a region indicating N limitation to P limitation. REST sites, with densevegetation and low DO, also maintained high DOC, which maintains phosphate insolution through chelation of iron and catalysis of photoreduction. Referencesites in native prairie and restored uplands diverged over the course of thewet-dry cycle, emphasizing the importance of considering climatic variation inplanning restoration efforts.