The gene "degrees of kevin bacon" (dokb) regulates a social network behaviour in Drosophila melanogaster.

Social networks are a mathematical representation of interactions among individuals which are prevalent across various animal species. Studies of human populations have shown the breadth of what can spread throughout a social network: obesity, smoking cessation, happiness, drug use and divorce. 'Betweenness centrality' is a key property of social networks that indicates an individual's importance in facilitating communication and cohesion within the network. Heritability of betweenness centrality has been suggested in several species, however the genetic regulation of this property remains enigmatic. Here, we demonstrate that the gene CG14109, referred to as degrees of kevin bacon (dokb), influences betweenness centrality in Drosophila melanogaster. We identify strain-specific alleles of dokb with distinct amino acid sequences and when the dokb allele is exchanged between strains, flies exhibit the betweenness centrality pattern dictated by the donor allele. By inserting a GAL4 reporter into the dokb locus, we confirm that dokb is expressed in the central nervous system. These findings define a novel genetic entry point to study social network structure and thereby establish gene-to-social structure relationships. While dokb sequence homology is exclusive to Diptera, we anticipate that dokb-associated molecular pathways could unveil convergent neural mechanisms of social behaviour that apply in diverse animal species.

Planetary Protection Knowledge Gap Closure Enabling Crewed Missions to Mars.

As focus for exploration of Mars transitions from current robotic explorers to development of crewed missions, it remains important to protect the integrity of scientific investigations at Mars, as well as protect the Earth's biosphere from any potential harmful effects from returned martian material. This is the discipline of planetary protection, and the Committee on Space Research (COSPAR) maintains the consensus international policy and guidelines on how this is implemented. Based on National Aeronautics and Space Administration (NASA) and European Space Agency (ESA) studies that began in 2001, COSPAR adopted principles and guidelines for human missions to Mars in 2008. At that point, it was clear that to move from those qualitative provisions, a great deal of work and interaction with spacecraft designers would be necessary to generate meaningful quantitative recommendations that could embody the intent of the Outer Space Treaty (Article IX) in the design of such missions. Beginning in 2016, COSPAR then sponsored a multiyear interdisciplinary meeting series to address planetary protection "knowledge gaps" (KGs) with the intent of adapting and extending the current robotic mission-focused Planetary Protection Policy to support the design and implementation of crewed and hybrid exploration missions. This article describes the outcome of the interdisciplinary COSPAR meeting series, to describe and address these KGs, as well as identify potential paths to gap closure. It includes the background scientific basis for each topic area and knowledge updates since the meeting series ended. In particular, credible solutions for KG closure are described for the three topic areas of (1) microbial monitoring of spacecraft and crew health; (2) natural transport (and survival) of terrestrial microbial contamination at Mars, and (3) the technology and operation of spacecraft systems for contamination control. The article includes a KG data table on these topic areas, which is intended to be a point of departure for making future progress in developing an end-to-end planetary protection requirements implementation solution for a crewed mission to Mars. Overall, the workshop series has provided evidence of the feasibility of planetary protection implementation for a crewed Mars mission, given (1) the establishment of needed zoning, emission, transport, and survival parameters for terrestrial biological contamination and (2) the creation of an accepted risk-based compliance approach for adoption by spacefaring actors including national space agencies and commercial/nongovernment organizations.

Characterizing the Protein Isoforms of foraging (for), the PKGI Ortholog in Drosophila melanogaster.

The foraging (for) gene of Drosophila melanogaster encodes a cGMP-dependent protein kinase (PKG), which is a major effector of the cGMP signaling pathway involved in the regulation of behaviour and metabolic traits. Despite being well studied at the transcript level, little is known about the for gene at the protein level. Here, we provide a detailed characterization of the for gene protein (FOR) products and present new tools for their study, including five isoform-specific antibodies and a transgenic strain that carries an HA-labelled for allele (forBAC::HA). Our results showed that multiple FOR isoforms were expressed in the larval and adult stages of D. melanogaster and that the majority of whole-body FOR expression arises from three (P1, P1α, and P3) of eight putative protein isoforms. We found that FOR expression differed between the larval and adult stages and between the dissected larval organs we analyzed, which included the central nervous system (CNS), fat body, carcass, and intestine. Moreover, we showed that the FOR expression differed between two allelic variants of the for gene, namely, fors (sitter) and forR (rover), that are known to differ in many food-related traits. Together, our in vivo identification of FOR isoforms and the existence of temporal, spatial, and genetic differences in their expression lay the groundwork for determining their functional significance.

AAV Vector Mediated Delivery of NG2 Function Neutralizing Antibody and Neurotrophin NT-3 Improves Synaptic Transmission, Locomotion, and Urinary Tract Function after Spinal Cord Contusion Injury in Adult Rats.

NG2 is a structurally unique transmembrane chondroitin sulfate proteoglycan (CSPG). Its role in damaged spinal cord is dual. NG2 is considered one of key inhibitory factors restricting axonal growth following spinal injury. Additionally, we have recently detected its novel function as a blocker of axonal conduction. Some studies, however, indicate the importance of NG2 presence in the formation of synaptic contacts. We hypothesized that the optimal treatment would be neutralization of inhibitory functions of NG2 without its physical removal. Acute intraspinal injections of anti-NG2 monoclonal antibodies reportedly prevented an acute block of axonal conduction by exogenous NG2. For prolonged delivery of NG2 function neutralizing antibody, we have developed a novel gene therapy: adeno-associated vector (AAV) construct expressing recombinant single-chain variable fragment anti-NG2 antibody (AAV-NG2Ab). We examined effects of AAV-NG2Ab alone or in combination with neurotrophin NT-3 in adult female rats with thoracic T10 contusion injuries. A battery of behavioral tests was used to evaluate locomotor function. In vivo single-cell electrophysiology was used to evaluate synaptic transmission. Lower urinary tract function was assessed during the survival period using metabolic chambers. Terminal cystometry, with acquisition of external urethral sphincter activity and bladder pressure, was used to evaluate bladder function. Both the AAV-NG2Ab and AAV-NG2Ab combined with AAV-NT3 treatment groups demonstrated significant improvements in transmission, locomotion, and bladder function compared with the control (AAV-GFP) group. These functional improvements associated with improved remyelination and plasticity of 5-HT fibers. The best results were observed in the group that received combinational AAV-NG2Ab+AAV-NT3 treatment.SIGNIFICANCE STATEMENT We recently demonstrated beneficial, but transient, effects of neutralization of the NG2 proteoglycan using monoclonal antibodies delivered intrathecally via osmotic mini-pumps after spinal cord injury. Currently, we have developed a novel gene therapy tool for prolonged and clinically relevant delivery of a recombinant single-chain variable fragment anti-NG2 antibody: AAV-rh10 serotype expressing scFv-NG2 (AAV-NG2Ab). Here, we examined effects of AAV-NG2Ab combined with transgene delivery of Neurotrophin-3 (AAV-NT3) in adult rats with thoracic contusion injuries. The AAV-NG2Ab and AAV-NG2Ab+AAV-NT3 treatment groups demonstrated significant improvements of locomotor function and lower urinary tract function. Beneficial effects of this novel gene therapy on locomotion and bladder function associated with improved transmission to motoneurons and plasticity of axons in damaged spinal cord.

UBR4/POE facilitates secretory trafficking to maintain circadian clock synchrony.

Ubiquitin ligases control the degradation of core clock proteins to govern the speed and resetting properties of the circadian pacemaker. However, few studies have addressed their potential to regulate other cellular events within clock neurons beyond clock protein turnover. Here, we report that the ubiquitin ligase, UBR4/POE, strengthens the central pacemaker by facilitating neuropeptide trafficking in clock neurons and promoting network synchrony. Ubr4-deficient mice are resistant to jetlag, whereas poe knockdown flies are prone to arrhythmicity, behaviors reflective of the reduced axonal trafficking of circadian neuropeptides. At the cellular level, Ubr4 ablation impairs the export of secreted proteins from the Golgi apparatus by reducing the expression of Coronin 7, which is required for budding of Golgi-derived transport vesicles. In summary, UBR4/POE fulfills a conserved and unexpected role in the vesicular trafficking of neuropeptides, a function that has important implications for circadian clock synchrony and circuit-level signal processing.

Using Flies to Understand Social Networks.

Many animals live in groups and interact with each other, creating an organized collective structure. Social network analysis (SNA) is a statistical tool that aids in revealing and understanding the organized patterns of shared social connections between individuals in groups. Surprisingly, the application of SNA revealed that Drosophila melanogaster, previously considered a solitary organism, displays group dynamics and that the structure of group life is inherited. Although the number of studies investigating Drosophila social networks is currently limited, they address a wide array of questions that have only begun to capture the details of group level behavior in this insect. Here, we aim to review these studies, comparing their respective scopes and the methods used, to draw parallels between them and the broader body of knowledge available. For example, we highlight how despite methodological differences, there are similarities across studies investigating the effects of social isolation on social network dynamics. Finally, this review aims to generate hypotheses and predictions that inspire future research in the emerging field of Drosophila social networks.

The Drosophila melanogaster foraging gene affects social networks.

Drosophila melanogaster displays social behaviors including courtship, mating, aggression, and group foraging. Recent studies employed social network analyses (SNAs) to show that D. melanogaster strains differ in their group behavior, suggesting that genes influence social network phenotypes. Aside from genes associated with sensory function, few studies address the genetic underpinnings of these networks. The foraging gene (for) is a well-established example of a pleiotropic gene that regulates multiple behavioral phenotypes and their plasticity. In D. melanogaster, there are two naturally occurring alleles of for called rover and sitter that differ in their larval and adult food-search behavior as well as other behavioral phenotypes. Here, we hypothesize that for affects behavioral elements required to form social networks and the social networks themselves. These effects are evident when we manipulate gene dosage. We found that flies of the rover and sitter strains exhibit differences in duration, frequency, and reciprocity of pairwise interactions, and they form social networks with differences in assortativity and global efficiency. Consistent with other adult phenotypes influenced by for, rover-sitter heterozygotes show intermediate patterns of dominance in many of these characteristics. Multiple generations of backcrossing a rover allele into a sitter strain showed that many but not all of these rover-sitter differences may be attributed to allelic variation at for. Our findings reveal the significant role that for plays in affecting social network properties and their behavioral elements in Drosophila melanogaster.

The gut microbiome defines social group membership in honey bee colonies.

In the honey bee, genetically related colony members innately develop colony-specific cuticular hydrocarbon profiles, which serve as pheromonal nestmate recognition cues. Yet, despite high intracolony relatedness, the innate development of colony-specific chemical signatures by individual colony members is largely determined by the colony environment, rather than solely relying on genetic variants shared by nestmates. Therefore, it is puzzling how a nongenic factor could drive the innate development of a quantitative trait that is shared by members of the same colony. Here, we provide one solution to this conundrum by showing that nestmate recognition cues in honey bees are defined, at least in part, by shared characteristics of the gut microbiome across individual colony members. These results illustrate the importance of host-microbiome interactions as a source of variation in animal behavioral traits.

Critical period regulation across multiple timescales.

Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.

Drosophila melanogaster behaviour changes in different social environments based on group size and density.

Many organisms, when alone, behave differently from when they are among a crowd. Drosophila similarly display social behaviour and collective behaviour dynamics within groups not seen in individuals. In flies, these emergent behaviours may be in response to the global size of the group or local nearest-neighbour density. Here we investigate i) which aspect of social life flies respond to: group size, density, or both and ii) whether behavioural changes within the group are dependent on olfactory support cells. Behavioural assays demonstrate that flies adjust their interactive behaviour to group size but otherwise compensate for density by achieving a standard rate of movement, suggesting that individuals are aware of the number of others within their group. We show that olfactory support cells are necessary for flies to behave normally in large groups. These findings shed insight into the subtle and complex life of Drosophila within a social setting.

Behavioral and environmental contributions to drosophilid social networks.

Animals interact with each other in species-specific reproducible patterns. These patterns of organization are captured by social network analysis, and social interaction networks (SINs) have been described for a wide variety of species including fish, insects, birds, and mammals. The aim of this study is to understand the evolution of social organization in Drosophila Using a comparative ecological, phylogenetic, and behavioral approach, the different properties of SINs formed by 20 drosophilids were compared. We investigate whether drosophilid network structures arise from common ancestry, a response to the species' past climate, other social behaviors, or a combination of these factors. This study shows that differences in past climate predicted the species' current SIN properties. The drosophilid phylogeny offered no value to predicting species' differences in SINs through phylogenetic signal tests. This suggests that group-level social behaviors in drosophilid species are shaped by divergent climates. However, we find that the social distance at which flies interact correlated with the drosophilid phylogeny, indicating that behavioral elements of SINs have remained largely unchanged in their evolutionary history. We find a significant correlation of leg length to social distance, outlining the interdependence of anatomy and complex social structures. Although SINs display a complex evolutionary relationship across drosophilids, this study suggests that the ecology, and not common ancestry, contributes to diversity in social structure in Drosophila.

Pharmacist intervention in colorectal cancer screening initiative.

OBJECTIVES: To assess the novel approach of using the community pharmacist as the primary health care team member to facilitate colorectal cancer (CRC) risk counseling and screening in socioeconomically disadvantaged populations. SETTING: A collaborative effort between the UConn Health Colon Cancer Prevention Program and UConn School of Pharmacy in conjunction with large independent chain pharmacies (medium to medium-high volume) located in metropolitan areas of Connecticut, including Hartford, Bridgeport, New Haven, and Stamford. Pharmacies located in hospitals, across the street from a large physician practice, or within the community. PRACTICE DESCRIPTION: The study involved 2 phases. The first phase involved education and training for community pharmacists regarding counseling approaches for patients on the topic of CRC. The second phase of the study involved patient recruitment and counseling with subsequent fecal immunohistochemical testing (FIT). PRACTICE INNOVATION: A community pharmacist provided face-to-face counseling on CRC risk factor reduction and provided CRC screening to patients who were without insurance or underinsured. No CRC screening or education program existed beforehand. EVALUATION: A target sample size of 60 participants was needed with a type 1 error rate of 5% and a power of 80%. Exploration of variables using multivariate logistic regression model included any variable with a univariate P < 0.2. Multivariate P values < 0.05 were considered independent predictors. RESULTS: After approaching 312 consumers, 16 of them consented to the study. The majority of participants (88%) were African American or Latino, and 69% were currently unemployed. Eight participants agreed to complete FIT, and 88% of participants completed FIT correctly. Only 1 positive FIT result was observed, but a subsequent colonoscopy was negative. Of the 12 questions that assessed baseline CRC knowledge in the initial survey, 16 participants answered an average of 2.6 (range, 0-6, SD, 1.6) questions incorrectly. Only 4 participants completed the follow-up survey of CRC knowledge and program satisfaction; thus, exploration of variables was not conducted. Patients indicated high satisfaction with the program of education and FIT dispensing. CONCLUSION: This study faced difficulty in recruiting pharmacists to participate, with the main reason being lack of compensation and disruption to workflow. Patient participation in the trial was also low because of a lack of time or interest in participation. Of the patients who did participate, the level of satisfaction in having the pharmacist speak to them about CRC screening was high. This service is an excellent example of how the pharmacist can provide a more accessible, convenient, and responsive approach to patients' needs while improving health equity. Future studies that employ a revenue model to build the infrastructure and capacity necessary to offer this service efficiently and consistently are needed.

Desiccation resistance is an adaptive life-history trait dependent upon cuticular hydrocarbons, and influenced by mating status and temperature in D. melanogaster.

Terrestrial insects are susceptible to desiccation and conserve internal water stores by preventing the loss of water due to transpiration across the cuticle. The epicuticle, a thin waxy layer on the outer surface of the insect cuticle is comprised primarily of a complex blend of cuticular hydrocarbons (CHCs) and is integral to preventing cuticular water loss. How the composition of epicuticular lipids (quantity and quality of the specific hydrocarbons) relates to desiccation resistance, however, has been difficult to determine. Here, we establish a model system to test the capacity of CHCs to protect against desiccation in the vinegar fly, Drosophila melanogaster. Using this system, we demonstrate that the oenocytes and CHCs produced by these cells are critically important for desiccation resistance, as measured by survival under desiccative conditions. Additionally, we show that both mating status and developmental temperature influence desiccation resistance. Prior mating increased desiccation survival through the direct transfer of CHCs between sexual partners, as well as through a female-specific response to a male-derived factor transferred during copulation. Together, our results demonstrate that desiccation resistance is an adaptive life-history trait dependent upon CHCs and influenced by prior social interactions and environmental conditions.

Network analyses reveal structure in insect social groups.

Animals, from flies to humans, interact with each other, forming complex relationships and structured social interaction networks. These networks describe patterns of interactions that occur within a group. Social network analysis (SNA) is the statistical analysis of nodes, which represent individuals within a network who are connected by social ties, often called edges, that represent interactions between individuals. Here, we review recent studies on social interaction networks in insects with an emphasis on flies. In flies and other insects, SNA has revealed the contribution of group structure to disease transmission, feeding strategy, fighting, mating, and oviposition. The literature shows that SNAs are useful to understand mechanisms underlying group behavior as well as the evolution of social structure.

A Symphony of Signals: Intercellular and Intracellular Signaling Mechanisms Underlying Circadian Timekeeping in Mice and Flies.

The central pacemakers of circadian timekeeping systems are highly robust yet adaptable, providing the temporal coordination of rhythms in behavior and physiological processes in accordance with the demands imposed by environmental cycles. These features of the central pacemaker are achieved by a multi-oscillator network in which individual cellular oscillators are tightly coupled to the environmental day-night cycle, and to one another via intercellular coupling. In this review, we will summarize the roles of various neurotransmitters and neuropeptides in the regulation of circadian entrainment and synchrony within the mammalian and Drosophila central pacemakers. We will also describe the diverse functions of protein kinases in the relay of input signals to the core oscillator or the direct regulation of the molecular clock machinery.

Update in Surveillance Recommendations in Individuals With Conventional Adenomas.

PURPOSE OF REVIEW: Conventional adenomas, which are precursors to almost 70% of colorectal carcinomas, are found in more than one-third of screening colonoscopies. Surveillance recommendations, based on adenoma size, histology, and number, have evolved over the years and are currently reflective of index adenoma categorization as either low-risk (LRA) or high-risk (HRA). In this review, recent guideline recommendations as well as primary data that have helped to shape these recommendations are presented. RECENT FINDINGS: Recent data have demonstrated that individuals with HRA on index exams may be at increased risk for CRC while those with LRA may have a minimal long-term risk for CRC, similar to those adults with normal index exams. Furthermore, the quality of the index exams is important for minimizing CRC risk. While individuals with HRA may require close surveillance intervals of 3 years, those with LRA or normal exams may need longer such as 10-year follow-up.

The cuticular hydrocarbon profiles of honey bee workers develop via a socially-modulated innate process.

Large social insect colonies exhibit a remarkable ability for recognizing group members via colony-specific cuticular pheromonal signatures. Previous work suggested that in some ant species, colony-specific pheromonal profiles are generated through a mechanism involving the transfer and homogenization of cuticular hydrocarbons (CHCs) across members of the colony. However, how colony-specific chemical profiles are generated in other social insect clades remains mostly unknown. Here we show that in the honey bee (Apis mellifera), the colony-specific CHC profile completes its maturation in foragers via a sequence of stereotypic age-dependent quantitative and qualitative chemical transitions, which are driven by environmentally-sensitive intrinsic biosynthetic pathways. Therefore, the CHC profiles of individual honey bees are not likely produced through homogenization and transfer mechanisms, but instead mature in association with age-dependent division of labor. Furthermore, non-nestmate rejection behaviors seem to be contextually restricted to behavioral interactions between entering foragers and guards at the hive entrance.

Tissue-Specific cis-Regulatory Divergence Implicates eloF in Inhibiting Interspecies Mating in Drosophila.

Reproductive isolation is a key component of speciation. In many insects, a major driver of this isolation is cuticular hydrocarbon pheromones, which help to identify potential intraspecific mates [1-3]. When the distributions of related species overlap, there may be strong selection on mate choice for intraspecific partners [4-9] because interspecific hybridization carries significant fitness costs [10]. Drosophila has been a key model for the investigation of reproductive isolation; although both male and female mate choices have been extensively investigated [6, 11-16], the genes underlying species recognition remain largely unknown. To explore the molecular mechanisms underlying Drosophila speciation, we measured tissue-specific cis-regulatory divergence using RNA sequencing (RNA-seq) in D. simulans × D. sechellia hybrids. By focusing on cis-regulatory changes specific to female oenocytes, the tissue that produces cuticular hydrocarbons, we rapidly identified a small number of candidate genes. We found that one of these, the fatty acid elongase eloF, broadly affects the hydrocarbons present on D. sechellia and D. melanogaster females, as well as the propensity of D. simulans males to mate with them. Therefore, cis-regulatory changes in eloF may be a major driver in the sexual isolation of D. simulans from multiple other species. Our RNA-seq approach proved to be far more efficient than quantitative trait locus (QTL) mapping in identifying candidate genes; the same framework can be used to pinpoint candidate drivers of cis-regulatory divergence in traits differing between any interfertile species.