The social microbiome: The missing mechanism mediating the sociality-fitness nexus?

In many social mammals, early social life and social integration in adulthood largely predict individual health, lifespan, and reproductive success. So far, research has mainly focused on chronic stress as the physiological mediator between social environment and fitness. Here, we propose an alternative, non-exclusive mechanism relying on microbially mediated effects: social relationships with conspecifics in early life and adulthood might strongly contribute to diversifying host microbiomes and to the transmission of beneficial microbes. In turn, more diverse and valuable microbiomes would promote pathogen resistance and optimal health and translate into lifelong fitness benefits. This mechanism relies on recent findings showing that microbiomes are largely transmitted via social routes and play a pervasive role in host development, physiology and susceptibility to pathogens. We suggest that the social transmission of microbes could explain the sociality-fitness nexus to a similar or higher extent than chronic social stress and deserves empirical studies in social mammals.

Stillbirth of a mandrill (Mandrillus sphinx) in the wild: perinatal behaviors and delivery sequences.

Birth is a fundamental event in the life of animals, including our own species. More reports of wild non-human primate births and stillbirths are thus needed to better understand the evolutionary pressures shaping parturition behaviors in our lineage. In diurnal non-human primates, births generally occur at night, when individuals are resting. Consequently, they are difficult to observe in the wild and most of the current knowledge regarding perinatal behaviors comes from rare daytime births. Information about stillbirths is even rarer and their proximate causes are generally unknown. Here, we present detailed observations of a daytime birth of a stillborn wild mandrill (Mandrillus sphinx). During this event, which lasted an entire day, we recorded the behaviors of the parturient female ad libitum, using video recordings and photos. The 5-year-old female was primiparous and of low dominance rank. The length of her pregnancy was shorter than usual and the partum phase was extremely long compared to other birth reports in non-human primates. The female disappeared shortly after this event and was assumed to have died. We discuss the possible causes of this stillbirth including the infant's presentation at birth and maternal inexperience.

Socially bonded females face more sexual coercion in a female-philopatric primate.

Sexual coercion is a manifestation of sexual conflict increasing male mating success while inflicting costs to females. Although previous work has examined inter-individual variation in male sexually coercive tactics, little is known about female counter-strategies. We investigated whether social bonding mitigates the extent of sexual coercion faced by female mandrills (Mandrillus sphinx), as a putative mechanism linking sociality to fitness. Surprisingly, females faced the most coercion from those males with whom they formed the strongest bonds, while the strength of a female-male bond was also positively correlated with coercion from all other males. Finally, greater social integration in the female network was positively correlated with coercion, through a direct 'public exposure' mechanism and not mediated by female reproductive success or retaliation potential. Altogether, this study shows that neither between- nor within-sex bonds are protective against sexual coercion and identifies, instead, a hidden cost of social bonding.

Social and sexual consequences of facial femininity in a non-human primate.

In humans, femininity shapes women's interactions with both genders, but its influence on animals remains unknown. Using 10 years of data on a wild primate, we developed an artificial intelligence-based method to estimate facial femininity from naturalistic portraits. Our method explains up to 30% of the variance in perceived femininity in humans, competing with classical methods using standardized pictures taken under laboratory conditions. We then showed that femininity estimated on 95 female mandrills significantly correlated with various socio-sexual behaviors. Unexpectedly, less feminine female mandrills were approached and aggressed more frequently by both sexes and received more male copulations, suggesting a positive valuation of masculinity attributes rather than a perception bias. This study contributes to understand the role of femininity on animal's sociality and offers a framework for non-invasive research on visual communication in behavioral ecology.

Mother-to-daughter transmission of hygienic anti-parasite behaviour in mandrills.

Social animals are particularly exposed to infectious diseases. Pathogen-driven selection pressures have thus favoured the evolution of behavioural adaptations to decrease transmission risk such as the avoidance of contagious individuals. Yet, such strategies deprive individuals of valuable social interactions, generating a cost-benefit trade-off between pathogen avoidance and social opportunities. Recent studies revealed that hosts differ in these behavioural defences, but the determinants driving such inter-individual variation remain understudied. Using 6 years of behavioural and parasite data on a large natural population of mandrills (Mandrillus sphinx), we showed that, when parasite prevalence was high in the population, females avoided grooming their conspecifics' peri-anal region (PAR), where contagious gastro-intestinal parasites accumulate. Females varied, however, in their propensity to avoid this risky body region: across years, some females consistently avoided grooming it, while others did not. Interestingly, hygienic females (i.e. those avoiding the PAR) were less parasitized than non-hygienic females. Finally, age, dominance rank and grooming frequency did not influence a female's hygiene, but both mother-daughter and maternal half-sisters exhibited similar hygienic levels, whereas paternal half-sisters and non-kin dyads did not, suggesting a social transmission of this behaviour. Our study emphasizes that the social inheritance of hygiene may structure behavioural resistance to pathogens in host populations with potential consequences on the dynamics of infectious diseases.

The Mandrillus Face Database: A portrait image database for individual and sex recognition, and age prediction in a non-human primate.

The Mandrillus Project is a long-term field research project in ecology and evolutionary biology, monitoring, since 2012, a natural population of mandrills (Mandrillus sphinx; primate) located in Southern Gabon. The Mandrillus Face Database was launched at the beginning of the project and now contains 29,495 photographic portraits collected on 397 individuals from this population, from birth to death for some of them. Portrait images have been obtained by manually processing images taken in the field with DSLR cameras: faces have been cropped to remove the ears and rotated to align the eyes horizontally. The database provides portrait images resized to 224 × 224 pixels associated with several manually annotated labels: individual identity, sex, age, face view, and image quality. Labels are stored within the image metadata and in a table accompanying the image database. This database will allow training and comparing methods on individual and sex recognition, and age prediction in a non-human animal.

Mandrill mothers associate with infants who look like their own offspring using phenotype matching.

Behavioral discrimination of kin is a key process structuring social relationships in animals. In this study, we provide evidence for discrimination towards non-kin by third-parties through a mechanism of phenotype matching. In mandrills, we recently demonstrated increased facial resemblance among paternally related juvenile and adult females indicating adaptive opportunities for paternal kin recognition. Here, we hypothesize that mandrill mothers use offspring's facial resemblance with other infants to guide offspring's social opportunities towards similar-looking ones. Using deep learning for face recognition in 80 wild mandrill infants, we first show that infants sired by the same father resemble each other the most, independently of their age, sex or maternal origin, extending previous results to the youngest age class. Using long-term behavioral observations on association patterns, and controlling for matrilineal origin, maternal relatedness and infant age and sex, we then show, as predicted, that mothers are spatially closer to infants that resemble their own offspring more, and that this maternal behavior leads to similar-looking infants being spatially associated. We then discuss the different scenarios explaining this result, arguing that an adaptive maternal behavior is a likely explanation. In support of this mechanism and using theoretical modeling, we finally describe a plausible evolutionary process whereby mothers gain fitness benefits by promoting nepotism among paternally related infants. This mechanism, that we call 'second-order kin selection', may extend beyond mother-infant interactions and has the potential to explain cooperative behaviors among non-kin in other social species, including humans.

The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: Therapeutic implications.

NSCLC is the leading cause of cancer mortality and represents a major challenge in cancer therapy. Intrinsic and acquired anticancer drug resistance are promoted by hypoxia and HIF-1α. Moreover, chemoresistance is sustained by the activation of key signaling pathways (such as RAS and its well-known downstream targets PI3K/AKT and MAPK) and several mutated oncogenes (including KRAS and EGFR among others). In this review, we highlight how these oncogenic factors are interconnected with cell metabolism (aerobic glycolysis, glutaminolysis and lipid synthesis). Also, we stress the key role of four metabolic enzymes (PFK1, dimeric-PKM2, GLS1 and ACLY), which promote the activation of these oncogenic pathways in a positive feedback loop. These four tenors orchestrating the coordination of metabolism and oncogenic pathways could be key druggable targets for specific inhibition. Since PFK1 appears as the first tenor of this orchestra, its inhibition (and/or that of its main activator PFK2/PFKFB3) could be an efficacious strategy against NSCLC. Citrate is a potent physiologic inhibitor of both PFK1 and PFKFB3, and NSCLC cells seem to maintain a low citrate level to sustain aerobic glycolysis and the PFK1/PI3K/EGFR axis. Awaiting the development of specific non-toxic inhibitors of PFK1 and PFK2/PFKFB3, we propose to test strategies increasing citrate levels in NSCLC tumors to disrupt this interconnection. This could be attempted by evaluating inhibitors of the citrate-consuming enzyme ACLY and/or by direct administration of citrate at high doses. In preclinical models, this "citrate strategy" efficiently inhibits PFK1/PFK2, HIF-1α, and IGFR/PI3K/AKT axes. It also blocks tumor growth in RAS-driven lung cancer models, reversing dedifferentiation, promoting T lymphocytes tumor infiltration, and increasing sensitivity to cytotoxic drugs.

[The support of the paediatric nurse in the paediatric emergency rapid response unit]. / L'accompagnement de l'infirmière puéricultrice en Smur pédiatrique.

When a newborn baby is in need of rapid care outside the hospital where the mother has given birth, the nursery nurses work specifically to support the baby during the separation from its parents. They intervene before, during and after the separation of mother and child, particularly during the transfer of the baby to the mobile paediatric emergency and resuscitation unit.

Long-Term Imaging Follow-Up in DIPNECH: Multicenter Experience.

Diffuse pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pre-invasive disease whose pathophysiology remains unclear. We aimed to assess long-term evolution in imaging of DIPNECH, in order to propose follow-up recommendations. Patients with histologically confirmed DIPNECH from four centers, evaluated between 2001 and 2020, were enrolled if they had at least two available chest computed tomography (CT) exams performed at least 24 months apart. CT exams were analyzed for the presence and the evolution of DIPNECH-related CT findings. Twenty-seven patients, mostly of female gender (n = 25/27; 93%) were included. Longitudinal follow-up over a median 63-month duration (IQR: 31-80 months) demonstrated an increase in the size of lung nodules in 19 patients (19/27, 70%) and the occurrence of metastatic spread in three patients (3/27, 11%). The metastatic spread was limited to mediastinal lymph nodes in one patient, whereas the other two patients had both lymph node and distant metastases. The mean time interval between baseline CT scan and metastatic spread was 70 months (14, 74 and 123 months). Therefore, long-term annual imaging follow-up of DIPNECH might be appropriate to encompass the heterogeneous longitudinal behavior of this disease.

Lung carcinoid tumors with Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) exhibit pejorative pathological features.

INTRODUCTION: Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) is a rare disease often associated with carcinoid tumors. We aimed at evaluating the impact of DIPNECH on characteristics and prognosis of patients who underwent radical treatment of pulmonary carcinoid tumors. MATERIAL AND METHODS: We reviewed all patients operated on for curative-intent resection of carcinoid tumor in our department from 2001 to 2020. Cases exhibiting both pathological and radiological features of DIPNECH, as assessed by respective thoracic expert physicians, were analyzed separately. RESULTS: 172 cases of resected carcinoid tumors were identified, including 25 (14.5 %) harboring pathological criteria of DIPNECH and radiologic features like mosaic attenuation (92.0 %), multiple nodules < 5 mm (76.0 %), and mucoid impactions (32 %). In DIPNECH patients, major pulmonary resections were usually performed (92.0 %) and resected tumors were mostly classified as pT1 (92 %). Mean Ki67 staining was 3.7 ± 5.2 %. The early postoperative period was mostly uneventful (96.0 %) and 5-year survival was 92.9 ± 6.9 %. Compared to non-DIPNECH cases, we found that patients were older (mean 65.6 ± 9.3 versus 54.1 ± 17.9, p = 0.002), more frequently female (84.0 % versus 56.5 %, p = 0.009), and exhibiting diabetes mellitus (45.8 % versus 18.5 %, p < 0.001) or hypertension (45.8 % versus 24.1 %, p = 0.039). The rate of atypical carcinoid tumors was significantly higher in DIPNECH patients (40.0 % versus 19.9 %, p = 0.027), as well as rate of mediastinal lymph-nodes involvement (pN2+) (36.0 % versus 4.1 %, p < 0.001). At multivariate analysis, only DIPNECH pattern and atypical histology were independent factors of pN2 invasion which was the only predictor of poorer prognosis on Log-Rank test. CONCLUSION: Carcinoid tumors with proven DIPNECH are associated with negative pathological features and may deserve a dedicated perioperative management.

Natural infection of free-ranging mandrills (Mandrillus sphinx) by enteroviruses and astroviruses in southern Gabon.

Enteroviruses (Picornaviridae) and astroviruses (Astroviridae) cause various diseases in humans and animals, including in non-human primates (NHPs). Some enteroviruses and astroviruses detected in NHPs are genetically related to those infecting humans, indicating the occurrence of interspecies transmissions. In this study, we screened 200 fecal samples of 56 free-ranging mandrills (Mandrillus sphinx) by nested reverse transcription-PCR with primers targeting the VP1 and RdRp genes, to evaluate the diversity of enterovirus and astrovirus infection, respectively, and the associated zoonotic risk. Overall, ten samples from six mandrills were enterovirus-positive (5%), and three samples from three mandrills were astrovirus-positive (1.5%). This is the first evidence of astrovirus infection in mandrills. Phylogenetic analyses based on the VP1 sequences revealed that all ten enterovirus sequences were part of the species Enterovirus J, suggesting low zoonotic risk. Phylogenetic analysis of the three astrovirus sequences showed that they all belonged to the Mamastrovirus genus. Two astrovirus sequences were highly divergent from all human astrovirus sequences (63.4-73% nucleotide identity), while one sequence (AstV-5) suggested cross-species transmission from humans to mandrills. Additional studies are needed to better characterize the identified astroviruses and to confirm whether mandrills are host of astroviruses than can be transmitted to humans.

Seasonality and interindividual variation in mandrill feeding ecology revealed by stable isotope analyses of hair and blood.

Mandrills are large-bodied terrestrial forest primates living in particularly large social groups of several hundred individuals. Following these groups in the wild to assess differences in diet over time as well as among individuals is demanding. We here use isotope analyses in blood and hair obtained during repeated captures of 43 identified free-ranging mandrills (Mandrillus sphinx) from Southern Gabon, to test how dietary variation relates to the season as well as an individual's age and sex. We measured the stable carbon (δ13 C‰) and nitrogen (δ15 N‰) isotope ratios in 46 blood and 214 hair section samples as well as from a small selection of mandrill foods (n = 24). We found some seasonal isotopic effects, with lower δ13 C values but higher δ15 N values observed during the highly competitive long dry season compared to the fruit-rich long rainy season. Variation in δ13 C was further predicted by individual age, with higher δ13 C values generally found in younger individuals suggesting that they may consume more high canopy fruit than older individuals, or that older individuals consume more low canopy foliage. The best predictor for δ15 N values was the interaction between age and sex, with mature and reproductively active males revealing the highest δ15 N values, despite the observation that males consume substantially less animal food items than females. We interpret high δ15 N values in these mature male mandrill blood and hair sections to be the result of nutritional stress associated with intense male-male competition, particularly during mating season. This is the first study showing isotopic evidence for nutritional stress in a free-ranging primate species and may spark further investigations into male mandrill diet and energy balance.

PD-L1-expression patterns in large-cell neuroendocrine carcinoma of the lung: potential implications for use of immunotherapy in these patients: the GFPC 03-2017 "EPNEC" study.

BACKGROUND: Few data are available on programmed cell-death-protein-1-ligand-1 (PD-L1) expression on large-cell neuroendocrine carcinomas of the lung (LCNECs). We analyzed PD-L1 expression on tumor (TCs) and inflammatory cells (ICs) from LCNEC patients to assess relationships between this expression, clinical characteristics, and disease outcomes. METHODS: PD-L1 expression was determined by immunohistochemistry with monoclonal antibody 22C3 in consecutive LCNEC patients managed in 17 French centers between January 2014 and December 2016. RESULTS: After centralized review, only 68 out of 105 (64%) patients had confirmed LCNEC diagnoses. Median overall survival (OS) (95% CI) was 11 (7-16) months for all patients, 7 (5-10), 21 (10-not reached) and not reached months for metastatic, stage III and localized forms (p = 0.0001). Respectively, 11% and 75% of the tumor samples were TC+ and IC+, and 66% had a TC-/IC+ profile. Comparing IC+ versus IC- metastatic LCNEC, the former had significantly longer progression-free survival [9 (4-13) versus 4 (1-8) months; p = 0.03], with a trend towards better median OS [12 (7-18) versus 9.5 (4-14) months; p = 0.21]. Compared to patients with TC- tumors, those with TC+ LCNECs tended to have non-significantly shorter median OS [4 (1-6.2) versus 11 (8-18) months, respectively]. Median OS was significantly shorter for patients with TC+/IC- metastatic LCNECs than those with TC-IC+ lesions (2 versus 8 months, respectively; p = 0.04). CONCLUSION: TC-/IC+ was the most frequent PD-L1-expression profile for LCNECs, a pattern quite specific compared with non-small-cell lung cancer and small-cell lung cancer. IC PD-L1 expression seems to have a prognostic role.

Ecological, parasitological and individual determinants of plasma neopterin levels in a natural mandrill population.

Investigating how individuals adjust their investment into distinct components of the immune system under natural conditions necessitates to develop immune phenotyping tools that reflect the activation of specific immune components that can be measured directly in the field. Here, we examined individual variation of plasma neopterin, a biomarker of Th1 immunity in wild mandrills (Mandrillus sphinx), who are naturally exposed to a suite of parasites, including simian retroviruses and malaria agents. We analyzed a total of 201 plasma samples from 99 individuals and examined the effect of sex, age, social rank, reproductive state and disease status on neopterin levels. We found higher neopterin concentrations in males than females, but were unable to disentangle this effect from possible confounding effects of retroviral infections, which affect nearly all adult males, but hardly any females. We further detected a non-linear age effect with heightened neopterin levels in early and late life. In addition, adult males that harbored very high parasitaemia for Plasmodium gonderi also showed high neopterin levels. There was no effect of social rank in either male or female mandrills, and no effect of female reproductive state. Taken together, these results indicate that plasma neopterin may prove useful to investigate individual variation in investment into specific immune components, as well as to monitor the dynamics of immune responses to naturally occurring diseases that elicit a Th1 immune response.

Unconditional care from close maternal kin in the face of parasites.

Several species mitigate relationships according to their conspecifics' parasite status. Yet, this defence strategy comes with the costs of depriving individuals from valuable social bonds. Animals therefore face a trade-off between the costs of pathogen exposure and the benefits of social relationships. According to the models of social evolution, social bonds are highly kin-biased. However, whether kinship mitigates social avoidance of contagious individuals has never been tested so far. Here, we build on previous research to demonstrate that mandrills (Mandrillus sphinx) modulate social avoidance of contagious individuals according to kinship: individuals do not avoid grooming their close maternal kin when contagious (parasitized with oro-faecally transmitted protozoa), although they do for more distant or non-kin. While individuals' parasite status has seldom been considered as a trait impacting social relationships in animals, this study goes a step beyond by showing that kinship balances the effect of health status on social behaviour in a non-human primate.

Genes, geology and germs: gut microbiota across a primate hybrid zone are explained by site soil properties, not host species.

Gut microbiota in geographically isolated host populations are often distinct. These differences have been attributed to between-population differences in host behaviours, environments, genetics and geographical distance. However, which factors are most important remains unknown. Here, we fill this gap for baboons by leveraging information on 13 environmental variables from 14 baboon populations spanning a natural hybrid zone. Sampling across a hybrid zone allowed us to additionally test whether phylosymbiosis (codiversification between hosts and their microbiota) is detectable in admixed, closely related primates. We found little evidence of genetic effects: none of host genetic ancestry, host genetic relatedness nor genetic distance between host populations were strong predictors of baboon gut microbiota. Instead, gut microbiota were best explained by the baboons' environments, especially the soil's geologic history and exchangeable sodium. Indeed, soil effects were 15 times stronger than those of host-population FST, perhaps because soil predicts which foods are present, or because baboons are terrestrial and consume soil microbes incidentally with their food. Our results support an emerging picture in which environmental variation is the dominant predictor of host-associated microbiomes. We are the first to show that such effects overshadow host species identity among members of the same primate genus.

Dental microwear textural analysis as an analytical tool to depict individual traits and reconstruct the diet of a primate.

OBJECTIVES: Dental microwear is a promising tool to reconstruct animals' diet because it reflects the interplay between the enamel surface and the food items recently consumed. This study examines the sources of inter-individual variations in dietary habits in a free-ranging population of mandrills (Mandrillus sphinx) using a combination of feeding monitoring and in vivo dental microwear textural analysis (DMTA). METHODS: We investigated the impact of seasonality and individual traits on four DMTA parameters. In parallel, we further studied the influence of the physical properties of the food items consumed on these four parameters, using three proxies (mechanical properties, estimates of phytolith and external grit contents). RESULTS: We found that seasonality, age, and sex all impact DMTA parameters but those results differ depending on the facet analyzed (crushing vs. shearing facets). Three DMTA parameters (anisotropy, complexity, and heterogeneity of complexity) appear sensitive to seasonal variations and anisotropy also differs between the sexes while textural fill volume tends to vary with age. Moreover, the physical properties of the food items consumed vary seasonally and also differ depending on individual sex and age. CONCLUSION: Considering the interplay between the tested variables and both dental microwear and diet, we reaffirm that food physical properties play a major role in microwear variations. These results suggest that DMTA parameters may provide valuable hints for paleoecological reconstruction using fragmentary fossil dental remains.