Putting the K+ in K+aloric Restriction.

Metabolic changes affect T lymphocyte function, and understanding this phenomenon could improve immunotherapy. In a recent paper in Science, Vodnala et al. (2019) report that tumor microenvironmental potassium impairs T cell nutrient uptake and thus causes functional caloric restriction and allows improved anti-tumor immune responses.

Low glycaemic diets alter lipid metabolism to influence tumour growth.

Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth1-5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels6-8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth.

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.

Stopping the Clock with MYC.

In a recent paper in Cell Metabolism, Altman et al. (2015) report that MYC disrupts the molecular clock in cancer cells and describe a link between oncogenesis, circadian rhythms, and metabolism.

Initial compatibility during a "Speed-Dating" test predicts postpairing affiliation in titi monkeys (Plecturocebus cupreus).

Behavioral compatibility plays a critical role in shaping how potential mates interact with and evaluate each other and whether they choose to pursue a relationship. Compatibility is especially important for mate choice and relationship quality in pair-bonding species that form long-term attachments between mates. Although this process has been studied in humans and birds, relatively few studies have investigated it in non-human primates. In this study, we investigated whether pairing titi monkeys (Plecturocebus cupreus) based on initial compatibility increased postpairing affiliation between mates. Subjects were 12 unpaired adult titi monkeys (two cohorts of three males and three females). We determined each subject's initial interest in each opposite-sex potential mate in their cohort across a series of six 30-min interaction periods (i.e., "speed-dates"). To determine initial compatibility, we used the Social Relations Model to calculate relationship effects in initial interest (how much each subject uniquely preferred each potential mate beyond their own affiliative disposition and their partner's popularity). We then paired monkeys in a way that maximized net relationship effects between pairs, and measured longitudinal pair affiliation (Proximity, Contact, Tail Twining, and Combined Affiliation) for 6 months postpairing using daily scan-sample observations and monthly home-cage video recordings. Multilevel models showed that, on average, the six speed-dating pairs exhibited higher levels of Tail Twining (determined from scan-sample observations; ß = 0.31) compared to a group of 13 age-matched colony pairs that were determined quasi-randomly without quantifying compatibility. The degree of initial compatibility within speed-dating pairs also predicted higher levels of Combined Affiliation (determined from video recordings) at earlier post-pairing time points, with the association peaking at 2 months postpairing (ß = 0.57). These findings suggest that initial compatibility facilitates pair bonding in titi monkeys. We conclude by discussing how the speed-dating design can be used for colony management to inform pair-housing decisions.

Room size and offspring presence impact pair-bonded primate affiliation.

Primates live in a variety of social groupings and vary in the expression of species-typical behaviors depending upon social conditions. Coppery titi monkeys (Plecturocebus cupreus) are pair-bonding, territorial primates often used to study neurobiology and social behavior in captivity at the California National Primate Research Center (CNPRC). At the center, titi monkeys are housed in cages of standardized size. However, the number of cages--and thus families--per room varies based upon the room size (small or large). Anecdotal evidence suggests titi monkeys behave differently in the two different room sizes. To empirically test this, we measured rates of pair-bonding related affiliation in 23 pairs of titi monkeys. We predicted that monkeys in small rooms would show higher rates of affiliation compared to large rooms. We used a between- and within- subjects design in which all subjects moved from either small to large or large to small rooms. Affiliative behavior was recorded via bihourly instantaneous scan samples. We found that titi monkey pairs affiliated significantly more in small rooms compared to large rooms (partial R2 = 0.1468, t(33) = -3.729, p-value < .0005). We also confirmed that the presence of offspring negatively impacts pair affiliation rates (partial R2 = 0.2240, t(33) = -0.181, p-value = 0.0011). The results of this study suggest that titi monkey pair behavior is influenced by room size, and thus the number of neighboring groups. Management decisions should consider the implications that housing may have on the results of social behavior research.

Moderate evidence for heritability in the duet contributions of a South American primate.

Acoustic signals are ubiquitous across mammalian taxa. They serve a myriad of functions related to the formation and maintenance of social bonds and can provide conspecifics information about caller condition, motivation and identity. Disentangling the relative importance of evolutionary mechanisms that shape vocal variation is difficult, and little is known about heritability of mammalian vocalizations. Duetting--coordinated vocalizations within male and female pairs--arose independently at least four times across the Primate Order. Primate duets contain individual- or pair-level signatures, but the mechanisms that shape this variation remain unclear. Here, we test for evidence of heritability in two call types (pulses and chirps) from the duets of captive coppery titi monkeys (Plecturocebus cupreus). We extracted four features--note rate, duration, minimum and maximum fundamental frequency--from spectrograms of pulses and chirps, and estimated heritability of the features. We also tested whether features varied with sex or body weight. We found evidence for moderate heritability in one of the features examined (chirp note rate), whereas inter-individual variance was the most important source of variance for the rest of the features. We did not find evidence for sex differences in any of the features, but we did find that body weight and fundamental frequency of chirp elements covaried. Kin recognition has been invoked as a possible explanation for heritability or kin signatures in mammalian vocalizations. Although the function of primate duets remains a topic of debate, the presence of moderate heritability in titi monkey chirp elements indicates duets may serve a kin recognition function.

What is a pair bond?

Pair bonding is a psychological construct that we attempt to operationalize via behavioral and physiological measurements. Yet, pair bonding has been both defined differently in various taxonomic groups as well as used loosely to describe not just a psychological and affective phenomenon, but also a social structure or mating system (either social monogamy or just pair living). In this review, we ask the questions: What has been the historical definition of a pair bond? Has this definition differed across taxonomic groups? What behavioral evidence do we see of pair bonding in these groups? Does this observed evidence alter the definition of pair bonding? Does the observed neurobiology underlying these behaviors affect this definition as well? And finally, what are the upcoming directions in which the study of pair bonding needs to head?

Relationships between cortisol and urinary androgens in female titi monkeys (Plecturocebus cupreus).

Steroid hormones are critical to the regulation of sociosexual behavior. Their role in the formation of pair bonds is complicated by the relative scarcity of this social system in mammals, as well as species and taxonomic differences in endocrine systems. In the present study, we experimentally manipulated the hypothalamic-pituitary-adrenal axis in female titi monkeys (Plecturocebus cupreus), a neotropical monkey studied for its strong, selective pair bonds. We validated an assay for plasma and urinary cortisol in this species, showing a strong suppression of cortisol following dexamethasone injection, and a significant but somewhat blunted response to adrenocorticotrophin hormone (ACTH) stimulation. Urinary androgens did not change in response to dexamethasone or ACTH. Plasma and urinary cortisol were moderately correlated, whereas urinary cortisol and androgens were only correlated when extreme cortisol values were included. In this study, we laid groundwork for studying the role of glucocorticoids and androgens (and eventually, their interactions with peptides) in the behavioral endocrinology of pair bonds in female titi monkeys.

Parenting costs time: Changes in pair bond maintenance across pregnancy and infant rearing in a monogamous primate (Plecturocebus cupreus).

Relationships support social animals' health, but maintaining relationships is challenging. When transitioning to parenthood, new parents balance pair-bond maintenance with infant care. We studied pair-bond maintenance via affiliation in 22 adult titi monkey pairs (Plecturocebus cupreus) for 16 months centered around their first offspring's birth. Pair affiliation peaked during pregnancy, decreased across the postpartum period, and rose after reaching minimum affiliation 32.6 weeks postpartum. Pairs in which fathers carry infants more than average had lower affiliation at the infant's birth and return to an increase in affiliation sooner. Parents of infants who were slow to independence had higher rates of affiliation. Titi monkey infants actively prefer their fathers; mothers may avoid their infant-carrying mate, suggesting infants play an active role in parental affiliative decline. Our data supports previous findings that affiliation between partners declines following an infant's birth, but demonstrates new knowledge about the extent and duration of affiliative decline.

Individuality in the vocalizations of infant and adult coppery titi monkeys (Plecturocebus cupreus).

As social animals, many primates use acoustic communication to maintain relationships. Vocal individuality has been documented in a diverse range of primate species and call types, many of which have presumably different functions. Auditory recognition of one's neighbors may confer a selective advantage if identifying conspecifics decreases the need to participate in costly territorial behaviors. Alternatively, vocal individuality may be nonadaptive and the result of a unique combination of genetics and environment. Pair-bonded primates, in particular, often participate in coordinated vocal duets that can be heard over long distances by neighboring conspecifics. In contrast to adult calls, infant vocalizations are short-range and used for intragroup communication. Here, we provide two separate but complementary analyses of vocal individuality in distinct call types of coppery titi monkeys (Plecturocebus cupreus) to test whether individuality occurs in call types from animals of different age classes with presumably different functions. We analyzed 600 trill vocalizations from 30 infants and 169 pulse-chirp duet vocalizations from 30 adult titi monkeys. We predicted that duet contributions would exhibit a higher degree of individuality than infant trills, given their assumed function for long-distance, intergroup communication. We estimated 7 features from infant trills and 16 features from spectrograms of adult pulse-chirps, then used discriminant function analysis with leave-one-out cross-validation to classify individuals. We correctly classified infants with 48% accuracy and adults with 83% accuracy. To further investigate variance in call features, we used a multivariate variance components model to estimate variance partitioning in features across two levels: within- and between-individuals. Between-individual variance was the most important source of variance for all features in adults, and three of four features in infants. We show that pulse-chirps of adult titi monkey duets are individually distinct, and infant trills are less individually distinct, which may be due to the different functions of the vocalizations.

New approaches to quantify social development in rhesus macaques (Macaca mulatta): Integrating eye tracking with traditional assessments of social behavior.

The nonhuman primate provides a sophisticated animal model system both to explore neurobiological mechanisms underlying complex behaviors and to facilitate preclinical research for neurodevelopmental and neuropsychiatric disease. A better understanding of evolutionarily conserved behaviors and brain processes between humans and nonhuman primates will be needed to successfully apply recently released NIMH guidelines (NOT-MH-19-053) for conducting rigorous nonhuman primate neurobehavioral research. Here, we explore the relationship between two measures of social behavior that can be used in both humans and nonhuman primates-traditional observations of social interactions with conspecifics and eye gaze detection in response to social stimuli. Infant male rhesus macaques (Macaca mulatta) serving as controls (N = 14) for an ongoing study were observed in their social rearing groups and participated in a noninvasive, longitudinal eye-tracking study. We found significant positive relationships between time spent viewing eyes of faces in an eye tracker and number of initiations made for social interactions with peers that is consistent with similar observations in human populations. Although future studies are needed to determine if this relationship represents species-typical social developmental processes, these preliminary results provide a novel framework to explore the relationship between social interactions and social attention in nonhuman primate models for neurobehavioral development.

Increased PHGDH expression promotes aberrant melanin accumulation.

BACKGROUND: Copy number gain of the D-3-phosphoglycerate dehydrogenase (PHGDH) gene, which encodes the first enzyme in serine biosynthesis, is found in some human cancers including a subset of melanomas. METHODS: In order to study the effect of increased PHGDH expression in tissues in vivo, we generated mice harboring a PHGDHtetO allele that allows tissue-specific, doxycycline-inducible PHGDH expression, and we analyzed the phenotype of mice with a ubiquitous increase in PHGDH expression. RESULTS: Tissues and cells derived from PHGDHtetO mice exhibit increased serine biosynthesis. Histological examination of skin tissue from PHGDHtetO mice reveals the presence of melanin granules in early anagen hair follicles, despite the fact that melanin synthesis is closely coupled to the hair follicle cycle and does not normally begin until later in the cycle. This phenotype occurs in the absence of any global change in hair follicle cycle timing. The aberrant presence of melanin early in the hair follicle cycle following PHGDH expression is also accompanied by increased melanocyte abundance in early anagen skin. CONCLUSIONS: These data suggest increased PHGDH expression impacts normal melanocyte biology, but PHGDH expression alone is not sufficient to cause cancer.

Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis.

Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease.

Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosin-related kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxia-inducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma.

Expression of bond-related behaviors affects titi monkey responsiveness to oxytocin and vasopressin treatments.

Social bonds influence physiology and behavior, which can shape how individuals respond to physical and affective challenges. Coppery titi monkey (Plecturocebus cupreus) offspring form selective bonds with their fathers, making them ideal for investigating how father-daughter bonds influence juveniles' responses to oxytocin (OT) and arginine-vasopressin (AVP) manipulations. We quantified the expression of father-daughter bond-related behaviors in females (n = 10) and gave acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or an OT receptor antagonist (OTA) to subjects prior to a parent preference test. While females spent more time in proximity to their parents than strangers, we found a large degree of individual variation. Females with greater expression of bonding behaviors responded to OT treatments in a dose-dependent manner. Subjects also spent less time in proximity to strangers when treated with High OT (p = 0.003) and Low OT (p = 0.007), but more time when treated with High AVP (p = 0.007), Low AVP (p = 0.009), and OTA (p = 0.001). Findings from the present study suggest that variation in the expression of bond-related behaviors may alter responsiveness to OT and AVP, increasing engagement with unfamiliar social others. This enhanced sociality with strangers may promote the formation of pair bonds with partners.

Stem cells and regenerative medicine in lung biology and diseases.

A number of novel approaches for repair and regeneration of injured lung have developed over the past several years. These include a better understanding of endogenous stem and progenitor cells in the lung that can function in reparative capacity as well as extensive exploration of the potential efficacy of administering exogenous stem or progenitor cells to function in lung repair. Recent advances in ex vivo lung engineering have also been increasingly applied to the lung. The current status of these approaches as well as initial clinical trials of cell therapies for lung diseases are reviewed below.

Pairing status and stimulus type predict responses to audio playbacks in female titi monkeys.

Some paired primates use complex, coordinated vocal signals to communicate within and between family groups. The information encoded within those signals is not well understood, nor is the intricacy of individuals' behavioral and physiological responses to these signals. Considering the conspicuous nature of these vocal signals, it is a priority to better understand paired primates' responses to conspecific calls. Pair-bonded titi monkeys (Plecturocebus cupreus) sing duets comprised of the male and female's long call. Here, we use a playback study to assess female titi monkeys' responses to different vocal stimuli based on the subject's pairing status. Six adult female titi monkeys participated in the study at two timepoints--pre-pairing and post-pairing. At each timepoint, subjects underwent three distinct playbacks--control recording, male solo vocalization, and pair duet. Behaviors such as locomotion and vocalizations were scored during and after the playback, and cortisol and androgen values were assessed via a plasma blood sample. Female titi monkeys attended more to social signals compared to the control, regardless of pairing status. However, in the time immediately following any playback type, female titi monkeys trilled more and spent a greater proportion of time locomoting during pre-pairing timepoints (compared to post-pairing). Female titi monkeys' behavioral responses to social audio stimuli, combined with subjects' increases in cortisol and androgens as paired individuals, imply female titi monkeys attend and respond to social signals territorially.

Intranasal oxytocin does not change partner preference in female titi monkeys (Plecturocebus cupreus), but intranasal vasopressin decreases it.

Strong social bonds are critical to human health; however, the mechanisms by which social bonds are formed and maintained are still being elucidated. The neurohormones oxytocin (OT) and vasopressin (AVP) are considered likely candidates. Primate females, both human and nonhuman, remain understudied populations. Here, we conducted a pharmacological study coupled with a behavioral partner preference test (PPT) to better understand the mechanistic basis of attachment in adult female titi monkeys (Plecturocebus cupreus). This pair-bonding species shares a conserved form of oxytocin with humans and is an excellent model organism to study the neural basis of social bonding. We performed intranasal administration of three doses of oxytocin (IN-OT), two doses of vasopressin (IN-AVP), one dose of an oxytocin antagonist (IN-OTA) and one dose of a saline treatment. We found that compared to the saline control, the IN-AVP treatment (lower dose, 40 IU/kg) decreased the time spent in proximity to the partner and increased lip-smacking toward the stranger. We found no effects of IN-OT or IN-OTA manipulation on partner preference. In contrast, low-dose IN-AVP weakened the partner preference in female titi monkeys.

Titi monkey father-daughter bond-related behaviors explain stress response variability.

Social interactions regulate our behavior and physiology, and strong social bonds can buffer us from stress. Coppery titi monkeys (Plecturocebus cupreus) are socially monogamous South American monkeys that display strong social bonds. Infants form selective bonds with their fathers, making them ideal for studying father-daughter bonds. We established a method for quantifying variability in expression of bond-related behaviors in females (n = 12), and the present study is the second to use this method for explaining titi monkey responses to behavioral tests. We also investigated how manipulations of oxytocin (OT) and vasopressin (AVP) influenced juvenile behavior and physiology. Subjects received acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or OT receptor antagonist (OTA) prior to an acute social separation. General linear mixed-effects model results revealed fathers were significant behavioral and physiological stress buffers for their daughters, as evidenced by fewer distress vocalizations (p < 0.001), less locomotion (p < 0.001), and lower plasma cortisol (p < 0.001) in a social separation paradigm. Females vocalized less if they exhibited greater expression of bond-related behaviors with their fathers as infants (p = 0.01), and this stress-buffering effect remained even when the daughter was separated from the father (p = 0.001). While treatments did not alter behaviors, OTA treatment caused the largest rise in plasma cortisol (p < 0.001), suggesting blockade of OT receptors can inhibit fathers' stress-buffering effects. Remarkably, females with greater expression of father-daughter bond-related behaviors exhibited an overall reduced physiological separation distress response (p = 0.04). Findings from the present study advance current knowledge of the neurobiological mechanisms foundational to female bonds and help inform how social disruptions may differently impact individuals based on expression of bond-related behaviors.