Robotic Resection in Succinate Dehydrogenase Subunit B (SDHB)-Mutated Hereditary Paraganglioma: A Case Report of Two Patients and A Literature Review.

Autosomal dominant hereditary paraganglioma-pheochromocytoma syndrome (HPPS) is a rare genetic disorder characterized by neuroendocrine tumor development associated with pathogenic variants in succinate dehydrogenase (SDH) enzyme complex genes. Particularly, HPPS linked to SDHB mutation poses a significant clinical challenge due to its association with aggressive tumor features and a high risk of malignancy. Our report underscores the diversity in the presentation of patients with SDHB-mutated paraganglioma and the feasibility of managing it with a minimally invasive surgical approach. In the first case, a 17-year-old female was diagnosed with a metabolically active, poorly differentiated extra-adrenal retroperitoneal paraganglioma that required challenging robotic resection. Cascade genetic testing revealed an SDHB mutation not only in her but also in three family members, pointing to the inherited nature of the syndrome. Conversely, the second case involves a 37-year-old male with an asymptomatic well-differentiated left paraaortic paraganglioma incidentally found during an unrelated medical examination. Robotic converted-to-open resection allowed the successful removal of the mass. Subsequent germline testing confirmed a deleterious SDHB mutation, initiating a process of familial cascade testing. Both patients remained symptom- and recurrence-free at 12 and six months, respectively. Through these cases, and supported by a literature review, we highlight the variable clinical presentations of HPPS, arising from the same genetic alteration. The successful application of minimally invasive surgical techniques, combined with genetic evaluation, emphasizes the necessity for a comprehensive, tailored approach to treatment and surveillance. This strategy not only addresses the immediate clinical needs but also fosters proactive management of at-risk family members, ensuring a multidisciplinary approach to this complex hereditary condition.

Sex-specific competitive social feedback amplifies the role of early life contingency in male mice.

Contingency (or 'luck') in early life plays an important role in shaping individuals' development. When individuals live within larger societies, social experiences may cause the importance of early contingencies to be magnified or dampened. Here we test the hypothesis that competition magnifies the importance of early contingency in a sex-specific manner by comparing the developmental trajectories of genetically identical, free-living mice who either experienced high levels of territorial competition (males) or did not (females). We show that male territoriality results in a competitive feedback loop that magnifies the importance of early contingency and pushes individuals onto divergent, self-reinforcing life trajectories, while the same process appears absent in females. Our results indicate that the strength of sexual selection may be self-limiting, as within-sex competition increases the importance of early life contingency, thereby reducing the ability of selection to lead to evolution. They also demonstrate the potential for contingency to lead to dramatic differences in life outcomes, even in the absence of any underlying differences in ability ('merit').

Neural correlates of individual facial recognition in a social wasp.

Individual recognition is critical for social behavior across species. Whether recognition is mediated by circuits specialized for social information processing has been a matter of debate. Here we examine the neurobiological underpinning of individual visual facial recognition in Polistes fuscatus paper wasps. Front-facing images of conspecific wasps broadly increase activity across many brain regions relative to other stimuli. Notably, we identify a localized subpopulation of neurons in the protocerebrum which show specialized selectivity for front-facing wasp images, which we term wasp cells . These wasp cells encode information regarding the facial patterns, with ensemble activity correlating with facial identity. Wasp cells are strikingly analogous to face cells in primates, indicating that specialized circuits are likely an adaptive feature of neural architecture to support visual recognition. One-Sentence Summary: We identify a localized population of neurons specifically tuned to wasp faces in a social wasp that has independently evolved individual facial recognition analogous to the face cells of primates.

Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models.

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for over a century. However, laboratory mice capture only a subset of the genetic variation found in wild mouse populations, ultimately limiting the potential of classical inbred strains to uncover phenotype-associated variants and pathways. Wild mouse populations are reservoirs of genetic diversity that could facilitate the discovery of new functional and disease-associated alleles, but the scarcity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently developed, sequenced, and phenotyped a set of 11 inbred strains derived from wild-caught Mus musculus domesticus. Each of these "Nachman strains" immortalizes a unique wild haplotype sampled from one of five environmentally distinct locations across North and South America. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the GRCm39 mouse reference, with 42.5% of variants in the Nachman strain genomes absent from current classical inbred mouse strain panels. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels. These novel wild-derived inbred mouse strain resources are set to empower new discoveries in both basic and preclinical research.

Genetically identical mice express alternative reproductive tactics depending on social conditions in the field.

In many species, establishing and maintaining a territory is critical to survival and reproduction, and an animal's ability to do so is strongly influenced by the presence and density of competitors. Here we manipulate social conditions to study the alternative reproductive tactics displayed by genetically identical, age-matched laboratory mice competing for territories under ecologically realistic social environmental conditions. We introduced adult males and females of the laboratory mouse strain C57BL/6J into a large, outdoor field enclosure containing defendable resource zones under one of two social conditions. We first created a low-density social environment, such that the number of available territories exceeded the number of males. After males established stable territories, we introduced a pulse of intruder males and observed the resulting defensive and invasive tactics employed. In response to this change in social environment, males with large territories invested more in patrolling but were less effective at excluding intruder males as compared with males with small territories. Intruding males failed to establish territories and displayed an alternative tactic featuring greater exploration as compared with genetically identical territorial males. Alternative tactics did not lead to equal reproductive success-males that acquired territories experienced greater survival and had greater access to females.

Open-label, single-center, clinical study evaluating the safety, tolerability and clinical effects of pentosan polysulfate sodium in subjects with mucopolysaccharidosis I.

Lysosomal enzyme deficiency in mucopolysaccharidosis (MPS) I results in glycosaminoglycan (GAG) accumulation leading to pain and limited physical function. Disease-modifying treatments for MPS I, enzyme replacement, and hematopoietic stem cell therapy (HSCT), do not completely resolve MPS I symptoms, particularly skeletal manifestations. The GAG reduction, anti-inflammatory, analgesic, and tissue remodeling properties of pentosan polysulfate sodium (PPS) may provide disease-modifying treatment for musculoskeletal symptoms and joint inflammation in MPS I following ERT and/or HSCT. The safety and efficacy of PPS were evaluated in four subjects with MPS I aged 14-19 years, previously treated with ERT and/or HSCT. Subjects received doses of 0.75 mg/kg or 1.5 mg/kg PPS via subcutaneous injections weekly for 12 weeks, then every 2 weeks for up to 72 weeks. PPS was well tolerated at both doses with no serious adverse events. MPS I GAG fragment (UA-HNAc [1S]) levels decreased at 73 weeks. Cartilage degradation biomarkers serum C-telopeptide of crosslinked collagen (CTX) type I (CTX-I) and type II (CTX-II) and urine CTX-II decreased in all subjects through 73 weeks. PROMIS scores for pain interference, pain behavior, and fatigue decreased in all subjects through 73 weeks. Physical function, measured by walking distance and dominant hand function, improved at 49 and 73 weeks. Decreased GAG fragments and cartilage degradation biomarkers, and positive PROMIS outcomes support continued study of PPS as a potential disease-modifying treatment for MPS I with improved pain and function outcomes.

Efficacy of Oral Cinacalcet in Non-PTH Nonmalignant Hypercalcemia from Excess 1,25-Dihydroxyvitamin D.

Elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) is a rare cause of non-parathyroid hormone (PTH)-mediated hypercalcemia seen in granulomatous disease, malignancy (most often lymphoma), or genetic mutations. Therapeutic options are limited. We report the case of a 67-year-old White man with nonmalignant, nongranulomatous, 1,25(OH)2D-mediated hypercalcemia treated successfully with cinacalcet. At presentation, he had hypercalcemia, hypercalciuria with recurrent nephrolithiasis, low PTH, elevated 1,25(OH)2D, and normal 25-hydroxyvitamin D. The 1,25(OH)2D levels were inappropriate in the setting of hypercalcemia with low PTH. Evaluations for sarcoidosis, tuberculosis, and malignancy were negative. Genetic testing showed biallelic variants in the CYP24A1 gene. Cinacalcet was trialed and showed normalization of calcium levels. On cinacalcet, biochemical indices showed a slight increase in 1,25(OH)2D and 24-hour urine calcium and mild decrease in PTH. He briefly experienced symptomatic hypocalcemia that resolved after reducing cinacalcet dose. Due to limited symptomatic benefit, he opted to stop cinacalcet. Additional follow-up showed intermittently elevated serum calcium levels after stopping cinacalcet, most recently 10.3 mg/dL. Cinacalcet may be a therapeutic option in nonmalignant, 1,25(OH)2D-mediated hypercalcemia. Further study is necessary to confirm efficacy, understand risks and benefits, and elucidate mechanism(s) of action.

Time to Move Beyond a Binary Criterion for Gestational Diabetes?

Over the years, several international guidelines have been developed by specialist organizations for the diagnosis of gestational diabetes mellitus (GDM). However, these guidelines vary and lack consensus on what level of glycemia defines GDM and worryingly, there is now evidence of over- or- under-diagnosis of women with GDM by current criteria. Towards this end, the National Priorities Research Program (NPRP) funded a program of research aimed at elucidating the problem with GDM diagnosis. It was determined, on completion of the project, that the solution required diagnosis of graded levels of dysglycemia in pregnancy and not just a diagnosis of presence or absence of GDM. A new diagnostic criterion (called the NPRP criterion) was created based on a single numerical summary of the three readings from the oral glucose tolerance test (GTT) that diagnosed women in pregnancy into four levels: normal, impaired, GDM and high risk GDM. This paper now examines existing GDM criteria vis-à-vis the NPRP criterion. It is noted that no significant change has happened over the years for existing criteria except for a gradual reduction in the threshold values of individual time-points or the number of time points, bringing us towards over-diagnosis of GDM in pregnancy. The new criterion unifies all readings from the GTT into one numerical value and, because it results in four levels of glycemia, represents a new way forwards for GDM diagnosis and can potentially reduce the rates of under diagnosis and over diagnosis of GDM.

Female behavior drives the formation of distinct social structures in C57BL/6J versus wild-derived outbred mice in field enclosures.

BACKGROUND: Social behavior and social organization have major influences on individual health and fitness. Yet, biomedical research focuses on studying a few genotypes under impoverished social conditions. Understanding how lab conditions have modified social organizations of model organisms, such as lab mice, relative to natural populations is a missing link between socioecology and biomedical science. RESULTS: Using a common garden design, we describe the formation of social structure in the well-studied laboratory mouse strain, C57BL/6J, in replicated mixed-sex populations over 10-day trials compared to control trials with wild-derived outbred house mice in outdoor field enclosures. We focus on three key features of mouse social systems: (i) territory establishment in males, (ii) female social relationships, and (iii) the social networks formed by the populations. Male territorial behaviors were similar but muted in C57 compared to wild-derived mice. Female C57 sharply differed from wild-derived females, showing little social bias toward cage mates and exploring substantially more of the enclosures compared to all other groups. Female behavior consistently generated denser social networks in C57 than in wild-derived mice. CONCLUSIONS: C57 and wild-derived mice individually vary in their social and spatial behaviors which scale to shape overall social organization. The repeatable societies formed under field conditions highlights opportunities to experimentally study the interplay between society and individual biology using model organisms.

Major urinary protein (Mup) gene family deletion drives sex-specific alterations in the house-mouse gut microbiota.

The gut microbiota is shaped by host metabolism. In house mice (Mus musculus), major urinary protein (MUP) pheromone production represents a considerable energy investment, particularly in sexually mature males. Deletion of the Mup gene family shifts mouse metabolism toward an anabolic state, marked by lipogenesis, lipid accumulation, and body mass increases. Given the metabolic implications of MUPs, they may also influence the gut microbiota. Here, we investigated the effect of a deletion of the Mup gene family on the gut microbiota of sexually mature mice. Shotgun metagenomics revealed distinct taxonomic and functional profiles between wild-type and knockout males but not females. Deletion of the Mup gene cluster significantly reduced diversity in microbial families and functions in male mice. Additionally, a species of Ruminococcaceae and several microbial functions, such as transporters involved in vitamin B5 acquisition, were significantly depleted in the microbiota of Mup knockout males. Altogether, these results show that MUPs significantly affect the gut microbiota of house mouse in a sex-specific manner.IMPORTANCEThe community of microorganisms that inhabits the gastrointestinal tract can have profound effects on host phenotypes. The gut microbiota is in turn shaped by host genes, including those involved with host metabolism. In adult male house mice, expression of the major urinary protein (Mup) gene cluster represents a substantial energy investment, and deletion of the Mup gene family leads to fat accumulation and weight gain in males. We show that deleting Mup genes also alters the gut microbiota of male, but not female, mice in terms of both taxonomic and functional compositions. Male mice without Mup genes harbored fewer gut bacterial families and reduced abundance of a species of Ruminococcaceae, a family that has been previously shown to reduce obesity risk. Studying the impact of the Mup gene family on the gut microbiota has the potential to reveal the ways in which these genes affect host phenotypes.

Evidence for a selective link between cooperation and individual recognition.

The ability to recognize others is a frequent assumption of models of the evolution of cooperation. At the same time, cooperative behavior has been proposed as a selective agent favoring the evolution of individual recognition abilities. Although theory predicts that recognition and cooperation may co-evolve, data linking recognition abilities and cooperative behavior with evidence of selection are elusive. Here, we provide evidence of a selective link between individual recognition and cooperation in the paper wasp Polistes fuscatus through a combination of clinal, common garden, and population genomics analyses. We identified latitudinal clines in both rates of cooperative nesting and color pattern diversity, consistent with a selective link between recognition and cooperation. In behavioral experiments, we replicated previous results demonstrating individual recognition in cooperative and phenotypically diverse P. fuscatus from New York. In contrast, wasps from a less cooperative and phenotypically uniform Louisiana population showed no evidence of individual recognition. In a common garden experiment, groups of wasps from northern populations formed more stable and individually biased associations, indicating that recognition facilitates group stability. The strength of recent positive selection on cognition-associated loci likely to mediate individual recognition is substantially greater in northern compared with southern P. fuscatus populations. Collectively, these data suggest that individual recognition and cooperative nesting behavior have co-evolved in P. fuscatus because recognition helps stabilize social groups. This work provides evidence of a specific cognitive phenotype under selection because of social interactions, supporting the idea that social behavior can be a key driver of cognitive evolution.

Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models.

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for a century. However, laboratory mice capture a narrow subset of the genetic variation found in wild mouse populations. This consideration inherently restricts the scope of potential discovery in laboratory models and narrows the pool of potentially identified phenotype-associated variants and pathways. Wild mouse populations are reservoirs of predicted functional and disease-associated alleles, but the sparsity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently imported, sequenced, and phenotyped a set of 11 wild-derived inbred strains developed from wild-caught Mus musculus domesticus. Each of these "Nachman strains" immortalizes a unique wild haplotype sampled from five environmentally diverse locations across North and South America: Saratoga Springs, New York, USA; Gainesville, Florida, USA; Manaus, Brazil; Tucson, Arizona, USA; and Edmonton, Alberta, Canada. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the mouse reference assembly, with 42.5% of variants in the Nachman strain genomes absent from classical inbred mouse strains. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels alone. Taken together, our work introduces a novel wild-derived inbred mouse strain resource that will enable new discoveries in basic and preclinical research. These strains are currently available through The Jackson Laboratory Repository under laboratory code NachJ.

Postural analysis reveals persistent changes in paper wasp foundress behavioral state after conspecific challenge.

Vigilant animals detect and respond to threats in the environment, often changing posture and movement patterns. Vigilance is modulated not only by predators but also by conspecific threats. In social animals, precisely how conspecific threats alter vigilance behavior over time is relevant to long-standing hypotheses about social plasticity. We report persistent effects of a simulated conspecific challenge on behavior of wild northern paper wasp foundresses, Polistes fuscatus. During the founding phase of the colony cycle, conspecific wasps can usurp nests from the resident foundress, representing a severe threat. We used automated tracking to monitor the movement and posture of P. fuscatus foundresses in response to simulated intrusions. Wasps displayed increased movement, greater bilateral wing extension, and reduced antennal separation after the threat was removed. These changes were not observed after presentation with a wooden dowel. By rapidly adjusting individual behavior after fending off an intruder, paper wasp foundresses might invest in surveillance of potential threats, even when such threats are no longer immediately present. The prolonged vigilance-like behavioral state observed here is relevant to plasticity of social recognition processes in paper wasps.

Genetically Identical Mice Express Alternative Reproductive Tactics Depending on Social Conditions in the Field.

In many species, establishing and maintaining a territory is critical to survival and reproduction, and an animal's ability to do so is strongly influenced by the presence and density of competitors. Here we manipulate social conditions to study the alternative reproductive tactics displayed by genetically identical, age-matched laboratory mice competing for territories under ecologically realistic social environmental conditions. We introduced adult males and females of the laboratory mouse strain (C57BL/6J) into a large, outdoor field enclosure containing defendable resource zones under one of two social conditions. We first created a low-density social environment, such that the number of available territories exceeded the number of males. After males established stable territories, we introduced a pulse of intruder males and observed the resulting defensive and invasive tactics employed. In response to this change in social environment, males with large territories invested more in patrolling but were less effective at excluding intruder males as compared to males with small territories. Intruding males failed to establish territories and displayed an alternative tactic featuring greater exploration as compared to genetically identical territorial males. Alternative tactics did not lead to equal reproductive success-males that acquired territories experienced greater survival and had greater access to females.

Major urinary protein (Mup) gene family deletion drives sex-specific alterations on the house mouse gut microbiota.

The gut microbiota is shaped by host metabolism. In house mice (Mus musculus), major urinary protein (MUP) pheromone production represents a considerable energy investment, particularly in sexually mature males. Deletion of the Mup gene family shifts mouse metabolism towards an anabolic state, marked by lipogenesis, lipid accumulation, and body mass increases. Given the metabolic implications of MUPs, they may also influence the gut microbiota. Here, we investigated the effect of deletion of the Mup gene family on the gut microbiota of sexually mature mice. Shotgun metagenomics revealed distinct taxonomic and functional profiles between wildtype and knockout males, but not females. Deletion of the Mup gene cluster significantly reduced diversity in microbial families and functions in male mice. Additionally, specific taxa of the Ruminococcaceae family, which is associated with gut health and reduced risk of developing metabolic syndrome, and several microbial functions, such as transporters involved in vitamin B5 acquisition, were significantly depleted in the microbiota of Mup-knockout males. Altogether these results show that major urinary proteins significantly affect the gut microbiota of house mouse in a sex-specific manner.

Sex differences in deleterious genetic variants in a haplodiploid social insect.

Deleterious variants are selected against but can linger in populations at low frequencies for long periods of time, decreasing fitness and contributing to disease burden in humans and other species. Deleterious variants occur at low frequency but distinguishing deleterious variants from low-frequency neutral variation is challenging based on population genomics data alone. As a result, we have little sense of the number and identity of deleterious variants in wild populations. For haplodiploid species, it has been hypothesised that deleterious alleles will be directly exposed to selection in haploid males, but selection can be masked in diploid females when deleterious variants are recessive, resulting in more efficient purging of deleterious mutations in males. Therefore, comparisons of the differences between haploid and diploid genomes from the same population may be a useful method for inferring rare deleterious variants. This study provides the first formal test of this hypothesis. Using wild populations of Northern paper wasps (Polistes fuscatus), we find that males have fewer missense and nonsense variants per generation than females from the same population. Allele frequency differences are especially pronounced for rare missense and nonsense variants and these differences lead to a lower mutational load in males than females. Based on these data we infer that many highly deleterious mutations are segregating in the paper wasp population. Stronger selection against deleterious alleles in haploid males may have implications for adaptation in other haplodiploid insects and provides evidence that wild populations harbour abundant deleterious variants.

Home-site advantage for host species-specific gut microbiota.

Mammalian species harbor compositionally distinct gut microbial communities, but the mechanisms that maintain specificity of symbionts to host species remain unclear. Here, we show that natural selection within house mice (Mus musculus domesticus) drives deterministic assembly of the house-mouse gut microbiota from mixtures of native and non-native microbiotas. Competing microbiotas from wild-derived lines of house mice and other mouse species (Mus and Peromyscus spp.) within germ-free wild-type (WT) and Rag1-knockout (Rag1-/-) house mice revealed widespread fitness advantages for native gut bacteria. Native bacterial lineages significantly outcompeted non-native lineages in both WT and Rag1-/- mice, indicating home-site advantage for native microbiota independent of host adaptive immunity. However, a minority of native Bacteriodetes and Firmicutes favored by selection in WT hosts were not favored or disfavored in Rag1-/- hosts, indicating that Rag1 mediates fitness advantages of these strains. This study demonstrates home-site advantage for native gut bacteria, consistent with local adaptation of gut microbiota to their mammalian species.

Re-wilding model organisms: Opportunities to test causal mechanisms in social determinants of health and aging.

Social experiences are strongly associated with individuals' health, aging, and survival in many mammalian taxa, including humans. Despite their role as models of many other physiological and developmental bases of health and aging, biomedical model organisms (particularly lab mice) remain an underutilized tool in resolving outstanding questions regarding social determinants of health and aging, including causality, context-dependence, reversibility, and effective interventions. This status is largely due to the constraints of standard laboratory conditions on animals' social lives. Even when kept in social housing, lab animals rarely experience social and physical environments that approach the richness, variability, and complexity they have evolved to navigate and benefit from. Here we argue that studying biomedical model organisms outside under complex, semi-natural social environments ("re-wilding") allows researchers to capture the methodological benefits of both field studies of wild animals and laboratory studies of model organisms. We review recent efforts to re-wild mice and highlight discoveries that have only been made possible by researchers studying mice under complex, manipulable social environments.

Dynamic changes to signal allocation rules in response to variable social environments in house mice.

Urine marking is central to mouse social behavior. Males use depletable and costly urine marks in intrasexual competition and mate attraction. We investigate how males alter signaling decisions across variable social landscapes using thermal imaging to capture spatiotemporal marking data. Thermal recording reveals fine-scale adjustments in urinary motor patterns in response to competition and social odors. Males demonstrate striking winner-loser effects in scent mark allocation effort and timing. Competitive experience primes temporal features of marking and modulates responses to scent familiarity. Males adjust signaling effort, mark latency, and marking rhythm, depending on the scent identities in the environment. Notably, recent contest outcome affects how males respond to familiar and unfamiliar urine. Winners increase marking effort toward unfamiliar relative to familiar male scents, whereas losers reduce marking effort to unfamiliar but increase to familiar rival scents. All males adjust their scent mark timing after a contest regardless of fight outcome, and deposit marks in more rapid bursts during marking bouts. In contrast to this dynamism, initial signal investment predicts aspects of scent marking days later, revealing the possibility of alternative marking strategies among competitive males. These data show that mice flexibly update their signaling decisions in response to changing social landscapes.