Hypoxia Is a Dominant Remodeler of the Effector T Cell Surface Proteome Relative to Activation and Regulatory T Cell Suppression

Immunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the antitumor immune response. T cell surface receptors and surface proteins that influence interactions and function in the TME are proven targets for cancer immunotherapy. However, how the entire surface proteome remodels in primary human T cells in response to specific suppressive factors in the TME remains to be broadly and systematically characterized. Here, using a reductionist cell culture approach with primary human T cells and stable isotopic labeling with amino acids in cell culture–based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8⁺ surface proteome (surfaceome). Surprisingly, coculturing primary CD8⁺ T cells with Tregs only modestly affected the CD8⁺ surfaceome but did partially reverse activation-induced surfaceomic changes. In contrast, hypoxia drastically altered the CD8⁺ surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4⁺ T cell surfaceome similarly responded to hypoxia, revealing a common hypoxia-induced surface receptor program. Our surfaceomics findings suggest that hypoxic environments create a challenge for T cell activation. These studies provide global insight into how Tregs and hypoxia remodel the T cell surfaceome and we believe represent a valuable resource to inform future therapeutic efforts to enhance T cell function.     

The evolution of human fatness and susceptibility to obesity: an ethological approach

Human susceptibility to obesity is an unusual phenomenon amongst animals. An evolutionary analysis, identifying factors favouring the capacity for fat deposition, may aid in the development of preventive public health strategies. This article considers the proximate causes, ontogeny, fitness value and evolutionary history of human fat deposition. Proximate causes include diet composition, physical activity level, feeding behaviour, endocrine and genetic factors, psychological traits, and exposure to broader environmental factors. Fat deposition peaks during late gestation and early infancy, and again during adolescence in females. As in other species, human fat stores not only buffer malnutrition, but also regulate reproduction and immune function, and are subject to sexual selection. Nevertheless, our characteristic ontogenetic pattern of fat deposition, along with relatively high fatness in adulthood, contrasts with the phenotype of other mammals occupying the tropical savannah environment in which hominids evolved. The increased value of energy stores in our species can be attributed to factors increasing either uncertainty in energy availability, or vulnerability to that uncertainty. Early hominid evolution was characterised by adaptation to a more seasonal environment, when selection would have favoured general thriftiness. The evolution of the large expensive brain in the genus Homo then favoured increased energy stores in the reproducing female, and in the offspring in early life. More recently, the introduction of agriculture has had three significant effects: exposure to regular famine; adaptation to a variety of local niches favouring population-specific adaptations; and the development of social hierarchies which predispose to differential exposure to environmental pressures. Thus, humans have persistently encountered greater energy stress than that experienced by their closest living relatives during recent evolution. The capacity to accumulate fat has therefore been a major adaptive feature of our species, but is now increasingly maladaptive in the modern environment where fluctuations in energy supply have been minimised, and productivity is dependent on mechanisation rather than physical effort. Alterations to the obesogenic environment are predicted to play a key role in reducing the prevalence of obesity.     

Absorption and tissue distribution of cholesterol in Manduca sexta

In Manduca sexta larvae, radioactive free cholesterol is absorbed directly from the midgut into mucosal cells where it is stored both in the free form (87% in males and 93% in females) and esterified form (13% in males and 7% in females). Subsequently, cholesterol is transported to fat body via lipophorin in the hemolymph exclusively in the free form. In fat body, the distribution of cholesterol between the free and esterified form varied significantly between genders and developmental stages. Except for the larval stage, males and females were able to store cholesterol in both free and esterified forms in the fat body and in the adult stage cholesterol ester accounted for more than 75% of the stored cholesterol. Placement of radioactive cholesterol at different locations in the gut-foregut, midgut, and hindgut-demonstrated that the midgut is the site where cholesterol is absorbed and released into the hemolymph. Cholesterol-labeled lipophorin injected into larval hemolymph was cleared from the hemolymph with a half-life of 10.2 h. After 17 h, most of the cleared radioactivity was recovered in the fat body (38%). Arch.     

Embryos of Robertsonian Translocation Carriers Exhibit a Mitotic Interchromosomal Effect That Enhances Genetic Instability during Early Development

Balanced chromosomal rearrangements represent one of the most common forms of genetic abnormality affecting approximately 1 in every 500 (0.2%) individuals. Difficulties processing the abnormal chromosomes during meiosis lead to an elevated risk of chromosomally abnormal gametes, resulting in high rates of miscarriage and/or children with congenital abnormalities. It has also been suggested that the presence of chromosome rearrangements may also cause an increase in aneuploidy affecting structurally normal chromosomes, due to disruption of chromosome alignment on the spindle or disturbance of other factors related to meiotic chromosome segregation. The existence of such a phenomenon (an inter-chromosomal effect—ICE) remains controversial, with different studies presenting contradictory data. The current investigation aimed to demonstrate conclusively whether an ICE truly exists. For this purpose a comprehensive chromosome screening technique, optimized for analysis of minute amounts of tissue, was applied to a unique collection of samples consisting of 283 oocytes and early embryos derived from 44 patients carrying chromosome rearrangements. A further 5,078 oocytes and embryos, derived from chromosomally normal individuals of identical age, provided a robust control group for comparative analysis. A highly significant (P = 0.0002) increase in the rate of malsegregation affecting structurally normal chromosomes was observed in association with Robertsonian translocations. Surprisingly, the ICE was clearly detected in early embryos from female carriers, but not in oocytes, indicating the possibility of mitotic rather than the previously suggested meiotic origin. These findings have implications for our understanding of genetic stability during preimplantation development and are of clinical relevance for patients carrying a Robertsonian translocation. The results are also pertinent to other situations when cellular mechanisms for maintaining genetic fidelity are relaxed and chromosome rearrangements are present (e.g. in tumors displaying chromosomal instability).     

Neglect of biological riches: the economics of nature tourism in Nepal

Nepal's spectacular parks and reserves have attracted dramatically increasing numbers of foreign visitors. It might be expected that these protected areas would be nurtured as valuable and irreplaceable economic assets. However they are becoming seriously degraded and the financial resources provided for their management have been inadequate. This paper explores why — starting with the hypothesis that so little of the economic value of protected area tourism in Nepal is captured through fees and other charges assessed on foreign visitors that the protected areas are perceived as being of inconsequential value. It is conservatively estimated that $27 million of tourists' total expenditure in Nepal were attributable to the protected area network in 1988, when the costs of managing the parks were less than $5 million but direct fees colleeted from tourists visiting the protected areas amounted to less than $1 million. These figures suggest the parks are a good investment. But it could also be argued that the costs of park management were more than five times the revenues collected by the government from park tourists. Policy measures are identified which could help Nepal increase the economic as well as environmental benefits from nature tourism.Case studies of Nepal's most-visited protected areas emphasize that the lack of funds for protected area management is not the only constraint on effective management. Some important economic and institutional interests have yet to be effectively reconciled with conservation in the protected areas. Most problematic are local people's economic aspirations and the operating practices of the principal government agencies involved — the Department of National Parks and Wildlife Conservation and the Ministry of Tourism. Fortunately there have recently been some encouraging signs of change within both of these agencies.     

Sexually Dimorphic Intrasexual Duetting in an Otherwise Monomorphic Green Lacewing (Neuroptera, Chrysopidae, Chrysoperla plorabunda): Sexual Selection or Sex Recognition?

Songs produced during heterosexual duets in a green lacewing, C. plorabunda, are sexually monomorphic. However, individuals of either sex will also engage in intrasexual duets, which can exhibit sexual dimorphism. We confined males and females together in various combinations in a small arena to study the phenotypes, behavioral interactions, and functional roles of duetting in this species. The goal was to test whether sexual selection or sex recognition provided the better explanation of song sexual dimorphism. We determined that the monomorphic form of the intrasexual duet was long and stable, and could take place either between males or between females. Such “standard” intrasexual duetting songs were acoustically indistinguishable from heterosexual songs. However, males could also engage other males in special “fast duets” that sped up and terminated abruptly. Equivalent fast duets were not part of the female repertory. Fast duetting songs between males differed significantly from other types of male or female duetting songs in every measurable characteristic, but their role in the mating system was ambiguous. Contrary to one prediction of the sexual selection hypothesis, fast duetting between males occurred less often in situations where it might be the most useful to males in securing mates, i.e., during male-male-female interactions (trios). In addition, fast songs that started, ended, both started and ended, or neither started nor ended duets were acoustically indistinguishable, making it unlikely that females were choosing males based on such variation. However, songs that “both started and ended” fast duets were associated with a significant mating advantage, indicating a possible role for fast duetting in male-male sexual competition. Because the alternative hypothesis of sex recognition was also supported by some of our results, we conclude that aggressive qualities of male-male fast duets probably mediate intrasexual selection, while their increasing tempo serves as an adaptive response to promote rapid sex recognition by truncating unproductive and potentially dangerous intrasexual duetting.