Behavioral traits that define social dominance are the same that reduce social influence in a consensus task.

Dominant individuals are often most influential in their social groups, affecting movement, opinion, and performance across species and contexts. Yet, behavioral traits like aggression, intimidation, and coercion, which are associated with and in many cases define dominance, can be socially aversive. The traits that make dominant individuals influential in one context may therefore reduce their influence in other contexts. Here, we examine this association between dominance and influence using the cichlid fish Astatotilapia burtoni, comparing the influence of dominant and subordinate males during normal social interactions and in a more complex group consensus association task. We find that phenotypically dominant males are aggressive, socially central, and that these males have a strong influence over normal group movement, whereas subordinate males are passive, socially peripheral, and have little influence over normal movement. However, subordinate males have the greatest influence in generating group consensus during the association task. Dominant males are spatially distant and have lower signal-to-noise ratios of informative behavior in the association task, potentially interfering with their ability to generate group consensus. In contrast, subordinate males are physically close to other group members, have a high signal-to-noise ratio of informative behavior, and equivalent visual connectedness to their group as dominant males. The behavioral traits that define effective social influence are thus highly context specific and can be dissociated with social dominance. Thus, processes of hierarchical ascension in which the most aggressive, competitive, or coercive individuals rise to positions of dominance may be counterproductive in contexts where group performance is prioritized.

Paternal care regulates the timing, synchrony and success of hatching in a coral reef fish.

In oviparous species, the timing of hatching is a crucial decision, but for developing embryos, assessing cues that indicate the optimal time to hatch is challenging. In species with pre-hatching parental care, parents can assess environmental conditions and induce their offspring to hatch. We provide the first documentation of parental hatching regulation in a coral reef fish, demonstrating that male neon gobies (Elacatinus colini) directly regulate hatching by removing embryos from the clutch and spitting hatchlings into the water column. All male gobies synchronized hatching within 2 h of sunrise, regardless of when eggs were laid. Paternally incubated embryos hatched later in development, more synchronously, and had higher hatching success than artificially incubated embryos that were shaken to provide a vibrational stimulus or not stimulated. Artificially incubated embryos displayed substantial plasticity in hatching times (range: 80-224 h post-fertilization), suggesting that males could respond to environmental heterogeneity by modifying the hatching time of their offspring. Finally, paternally incubated embryos hatched with smaller yolk sacs and larger propulsive areas than artificially incubated embryos, suggesting that paternal effects on hatchling phenotypes may influence larval dispersal and fitness. These findings highlight the complexity of fish parental care behaviour and may have important, and currently unstudied, consequences for fish population dynamics.

Nitric oxide (NO) elicits aminoglycoside tolerance in Escherichia coli but antibiotic resistance gene carriage and NO sensitivity have not co-evolved.

The spread of multidrug-resistance in Gram-negative bacterial pathogens presents a major clinical challenge, and new approaches are required to combat these organisms. Nitric oxide (NO) is a well-known antimicrobial that is produced by the immune system in response to infection, and numerous studies have demonstrated that NO is a respiratory inhibitor with both bacteriostatic and bactericidal properties. However, given that loss of aerobic respiratory complexes is known to diminish antibiotic efficacy, it was hypothesised that the potent respiratory inhibitor NO would elicit similar effects. Indeed, the current work demonstrates that pre-exposure to NO-releasers elicits a > tenfold increase in IC50 for gentamicin against pathogenic E. coli (i.e. a huge decrease in lethality). It was therefore hypothesised that hyper-sensitivity to NO may have arisen in bacterial pathogens and that this trait could promote the acquisition of antibiotic-resistance mechanisms through enabling cells to persist in the presence of toxic levels of antibiotic. To test this hypothesis, genomics and microbiological approaches were used to screen a collection of E. coli clinical isolates for antibiotic susceptibility and NO tolerance, although the data did not support a correlation between increased carriage of antibiotic resistance genes and NO tolerance. However, the current work has important implications for how antibiotic susceptibility might be measured in future (i.e. ± NO) and underlines the evolutionary advantage for bacterial pathogens to maintain tolerance to toxic levels of NO.

Bioprocess development for scalable production of cultivated meat.

Traditional farm-based products based on livestock are one of the main contributors to greenhouse gas emissions. Cultivated meat is an alternative that mimics animal meat, being produced in a bioreactor under controlled conditions rather than through the slaughtering of animals. The first step in the production of cultivated meat is the generation of sufficient reserves of starting cells. In this study, bovine adipose-derived stem cells (bASCs) were used as starting cells due to their ability to differentiate towards both fat and muscle, two cell types found in meat. A bioprocess for the expansion of these cells on microcarriers in spinner flasks was developed. Different cell seeding densities (1,500, 3,000, and 6,000 cells/cm2 ) and feeding strategies (80%, 65%, 50%, and combined 80%/50% medium exchanges) were investigated. Cell characterization was assessed pre- and postbioprocessing to ensure that bioprocessing did not negatively affect bASC quality. The best growth was obtained with the lowest cell seeding density (1,500 cells/cm2 ) with an 80% medium exchange performed (p < .0001) which yielded a 28-fold expansion. The ability to differentiate towards adipogenic, osteogenic, and chondrogenic lineages was retained postbioprocessing and no significant difference (p > .5) was found in clonogenicity pre- or postbioprocessing in any of the feeding regimes tested.

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer.

Cells establish and sustain structural and functional integrity of the genome to support cellular identity and prevent malignant transformation. In this review, we present a strategic overview of epigenetic regulatory mechanisms including histone modifications and higher order chromatin organization (HCO) that are perturbed in breast cancer onset and progression. Implications for dysfunctions that occur in hormone regulation, cell cycle control, and mitotic bookmarking in breast cancer are considered, with an emphasis on epithelial-to-mesenchymal transition and cancer stem cell activities. The architectural organization of regulatory machinery is addressed within the contexts of translating cancer-compromised genomic organization to advances in breast cancer risk assessment, diagnosis, prognosis, and identification of novel therapeutic targets with high specificity and minimal off target effects.

Innate Immune Response Following AAV Administration.

Recombinant adeno-associated virus (rAAV) is a widely used tool for gene delivery due to its high efficiency to transduce postmitotic cells. However, host immune reactions targeting AAV can limit its therapeutic benefit in clinical applications. While most studies focused on adaptive immunity, initial innate immune responses are the first line of defense against viral vectors and help modulate subsequent adaptive immune responses. The understanding of innate immune responses to AAV can potentially improve safety and therapeutic efficiency of AAV. This article provides an overview of innate immune responses to AAV vectors.

Clinical Trial of the Potassium Channel Activator Diazoxide for Major Depressive Disorder Halted Due to Intolerability.

BACKGROUND: Some glutamatergic modulators have demonstrated rapid and relatively sustained antidepressant properties in patients with major depressive disorder. Because the potassium channel activator diazoxide increases glutamate uptake via potassium channel activation, we hypothesized that it might exert antidepressant effects by increasing the removal of glutamate from the synaptic cleft, thereby reducing excessive glutamate transmission. METHODS: This randomized, double-blind, placebo-controlled, crossover, single-site inpatient clinical study was conducted at the National Institute of Mental Health to assess the efficacy and safety of a 3-week course of diazoxide (200-400 mg daily, twice a day) versus a 3-week course of placebo in 6 participants with treatment-refractory major depressive disorder. The primary clinical outcome measure was change in Montgomery-Asberg Depression Rating Scale score from baseline to posttreatment. Quantitative insulin sensitivity check index, as well as concomitant imaging measures (electroencephalography, proton magnetic resonance spectroscopy, magnetoencephalography), were used as potential surrogate markers of target (KATP channel) engagement. RESULTS: The study was halted due to severe adverse effects. Given the small sample size, statistical evaluation of the effect of diazoxide on Montgomery-Asberg Depression Rating Scale scores or the imaging measures was not pursued. Visual inspection of the quantitative insulin sensitivity check index test revealed no evidence of target engagement. CONCLUSIONS: Although the results are negative, they are an important addition to the literature in this rapidly changing field.

CO2 sensing in fungi: at the heart of metabolic signaling.

Adaptation to the changing environmental CO2 levels is essential for all living cells. In particular, microorganisms colonizing and infecting the human body are exposed to highly variable concentrations, ranging from atmospheric 0.04 to 5% and more in blood and specific host niches. Carbonic anhydrases are highly conserved metalloenzymes that enable fixation of CO2 by its conversion into bicarbonate. This process is not only crucial to ensure the supply of adequate carbon amounts for cellular metabolism, but also contributes to several signaling processes in fungi, including morphology and communication. The fungal specific carbonic anhydrase gene NCE103 is transcribed in response to CO2 availability. As recently shown, this regulation relies on the ATF/CREB transcription factor Cst6 and the AGC family protein kinase Sch9. Here, we review the regulatory mechanisms which control NCE103 expression in the model organism Saccharomyces cerevisiae and the pathogenic yeasts Candida albicans and Candida glabrata and discuss which additional factors might contribute in this novel CO2 sensing cascade.

A mitochondrial CO2-adenylyl cyclase-cAMP signalosome controls yeast normoxic cytochrome c oxidase activity.

Mitochondria, the major source of cellular energy in the form of ATP, respond to changes in substrate availability and bioenergetic demands by employing rapid, short-term, metabolic adaptation mechanisms, such as phosphorylation-dependent protein regulation. In mammalian cells, an intramitochondrial CO2-adenylyl cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway regulates aerobic energy production. One target of this pathway involves phosphorylation of cytochrome c oxidase (COX) subunit 4-isoform 1 (COX4i1), which modulates COX allosteric regulation by ATP. However, the role of the CO2-sAC-cAMP-PKA signalosome in regulating COX activity and mitochondrial metabolism and its evolutionary conservation remain to be fully established. We show that in Saccharomyces cerevisiae, normoxic COX activity measured in the presence of ATP is 55% lower than in the presence of ADP. Moreover, the adenylyl cyclase Cyr1 activity is present in mitochondria, and it contributes to the ATP-mediated regulation of COX through the normoxic subunit Cox5a, homologue of human COX4i1, in a bicarbonate-sensitive manner. Furthermore, we have identified 2 phosphorylation targets in Cox5a (T65 and S43) that modulate its allosteric regulation by ATP. These residues are not conserved in the Cox5b-containing hypoxic enzyme, which is not regulated by ATP. We conclude that across evolution, a CO2-sAC-cAMP-PKA axis regulates normoxic COX activity.

Synaptic abnormalities in the infralimbic cortex of a model of congenital depression.

Multiple lines of evidence suggest that disturbances in excitatory transmission contribute to depression. Whether these defects involve the number, size, or composition of glutamatergic contacts is unclear. This study used recently introduced procedures for fluorescence deconvolution tomography in a well-studied rat model of congenital depression to characterize excitatory synapses in layer I of infralimbic cortex, a region involved in mood disorders, and of primary somatosensory cortex. Three groups were studied: (1) rats bred for learned helplessness (cLH); (2) rats resistant to learned helplessness (cNLH); and (3) control Sprague Dawley rats. In fields within infralimbic cortex, cLH rats had the same numerical density of synapses, immunolabeled for either the postsynaptic density (PSD) marker PSD95 or the presynaptic protein synaptophysin, as controls. However, PSD95 immunolabeling intensities were substantially lower in cLH rats, as were numerical densities of synapse-sized clusters of the AMPA receptor subunit GluA1. Similar but less pronounced differences (comparable numerical densities but reduced immunolabeling intensity for PSD95) were found in the somatosensory cortex. In contrast, non-helpless rats had 25% more PSDs than either cLH or control rats without any increase in synaptophysin-labeled terminal frequency. Compared with controls, both cLH and cNLH rats had fewer GABAergic contacts. These results indicate that congenital tendencies that increase or decrease depression-like behavior differentially affect excitatory synapses.

Simultaneous assessment of rodent behavior and neurochemistry using a miniature positron emission tomograph.

Positron emission tomography (PET) neuroimaging and behavioral assays in rodents are widely used in neuroscience. PET gives insights into the molecular processes of neuronal communication, and behavioral methods analyze the actions that are associated with such processes. These methods have not been directly integrated, because PET studies in animals have until now required general anesthesia to immobilize the subject, which precludes behavioral studies. We present a method for imaging awake, behaving rats with PET that allows the simultaneous study of behavior. Key components include the 'rat conscious animal PET' or RatCAP, a miniature portable PET scanner that is mounted on the rat's head, a mobility system that allows considerable freedom of movement, radiotracer administration techniques and methods for quantifying behavior and correlating the two data sets. The simultaneity of the PET and behavioral data provides a multidimensional tool for studying the functions of different brain regions and their molecular constituents.

The bZIP transcription factor Rca1p is a central regulator of a novel CO2 sensing pathway in yeast.

Like many organisms the fungal pathogen Candida albicans senses changes in the environmental CO(2) concentration. This response involves two major proteins: adenylyl cyclase and carbonic anhydrase (CA). Here, we demonstrate that CA expression is tightly controlled by the availability of CO(2) and identify the bZIP transcription factor Rca1p as the first CO(2) regulator of CA expression in yeast. We show that Rca1p upregulates CA expression during contact with mammalian phagocytes and demonstrate that serine 124 is critical for Rca1p signaling, which occurs independently of adenylyl cyclase. ChIP-chip analysis and the identification of Rca1p orthologs in the model yeast Saccharomyces cerevisiae (Cst6p) point to the broad significance of this novel pathway in fungi. By using advanced microscopy we visualize for the first time the impact of CO(2) build-up on gene expression in entire fungal populations with an exceptional level of detail. Our results present the bZIP protein Rca1p as the first fungal regulator of carbonic anhydrase, and reveal the existence of an adenylyl cyclase independent CO(2) sensing pathway in yeast. Rca1p appears to regulate cellular metabolism in response to CO(2) availability in environments as diverse as the phagosome, yeast communities or liquid culture.

Lost gallstones during laparoscopic cholecystectomy as a common but underestimated complication-case report and review of the literature.

Introduction: Laparoscopic cholecystectomy (LC) represents one of the most commonly performed routine abdominal surgeries. Nevertheless, besides bile duct injury, problems caused by lost gallstones represent a heavily underestimated and underreported possible late complication after LC. Methods: Case report of a Clavien-Dindo IVb complication after supposedly straightforward LC and review of all published case reports on complications from lost gallstones from 2000-2022. Case Report: An 86-year-old patient developed a perihepatic abscess due to lost gallstones 6 months after LC. The patient had to undergo open surgery to successfully drain the abscess. Reactive pleural effusion needed additional drainage. Postoperative ICU stay was 13 days. The patient was finally discharged after 33 days on a geriatric remobilization ward and died 12 months later due to acute cardiac decompensation. Conclusion: Intraabdominal abscess formation due to spilled gallstones may present years after LC as a late complication. Surgical management in order to completely evacuate the abscess and remove all spilled gallstones may be required, which could be associated with high morbidity and mortality, especially in elderly patients. Regarding the overt underreporting of gallstone spillage in case of postoperative gallstone-related complications, focus need be put on precise reporting of even apparently innocuous complications during LC.

Timing decisions as the next frontier for collective intelligence.

The past decade has witnessed a growing interest in collective decision making, particularly the idea that groups can make more accurate decisions compared with individuals. However, nearly all research to date has focused on spatial decisions (e.g., food patches). Here, we highlight the equally important, but severely understudied, realm of temporal collective decision making (i.e., decisions about when to perform an action). We illustrate differences between temporal and spatial decisions, including the irreversibility of time, cost asymmetries, the speed-accuracy tradeoff, and game theoretic dynamics. Given these fundamental differences, temporal collective decision making likely requires different mechanisms to generate collective intelligence. Research focused on temporal decisions should lead to an expanded understanding of the adaptiveness and constraints of living in groups.

Multidimensional social influence drives leadership and composition-dependent success in octopus-fish hunting groups.

Collective behaviour, social interactions and leadership in animal groups are often driven by individual differences. However, most studies focus on same-species groups, in which individual variation is relatively low. Multispecies groups, however, entail interactions among highly divergent phenotypes, ranging from simple exploitative actions to complex coordinated networks. Here we studied hunting groups of otherwise-solitary Octopus cyanea and multiple fish species, to unravel hidden mechanisms of leadership and associated dynamics in functional nature and complexity, when divergence is maximized. Using three-dimensional field-based tracking and field experiments, we found that these groups exhibit complex functional dynamics and composition-dependent properties. Social influence is hierarchically distributed over multiscale dimensions representing role specializations: fish (particularly goatfish) drive environmental exploration, deciding where, while the octopus decides if, and when, the group moves. Thus, 'classical leadership' can be insufficient to describe complex heterogeneous systems, in which leadership instead can be driven by both stimulating and inhibiting movement. Furthermore, group composition altered individual investment and collective action, triggering partner control mechanisms (that is, punching) and benefits for the de facto leader, the octopus. This seemingly non-social invertebrate flexibly adapts to heterospecific actions, showing hallmarks of social competence and cognition. These findings expand our current understanding of what leadership is and what sociality is.

Selective breeding for helplessness in rats alters the metabolic profile of the hippocampus and frontal cortex: a 1H-MRS study at 9.4 T.

In humans metabolic changes, particularly in frontal areas of the brain, accompany depressive disorders, but few studies were conducted in animal models of depression. We used hydrogen-1 magnetic resonance spectroscopy at 9.4 T to measure the metabolic profiles of the hippocampus and frontal cortex in congenital learned helpless (cLH) and wild-type (WT) rats. The learned helplessness model of depression exposes animals to uncontrollable stress to induce changes in emotion, cognition and behaviour, but cLH rats were selectively bred to show changes in behaviour even without exposure to uncontrollable stress. Experimentally naive male 8- to 10-wk-old cLH (n = 10) and WT rats (n = 22) underwent spectroscopy and were exposed to uncontrollable stress 1 wk after the scan. We found that cLH compared to WT rats had lower levels of glutamate in the hippocampus and lower levels of choline-containing compounds in the hippocampus and frontal cortex, but higher levels of taurine and phosphocreatine in these regions, pointing to compensatory efforts of the brain to reduce excitotoxic potential and to increase neuroprotection and energy, possibly as a result of cellular stress and damage. The reduction in choline-containing phospholipids might represent a source or correlate of such stress. Overall, the results indicate that metabolic abnormalities are present in animals with a predisposition to helplessness even without exposure to explicit stress and may help identify non-invasive biomarkers in individuals who are prone to depression.

Carbonic anhydrase inhibitors: inhibition of the ß-class enzyme from the pathogenic yeast Candida glabrata with sulfonamides, sulfamates and sulfamides.

The fungal pathogen Candida glabrata encodes for a ß-carbonic anhydrase (CA, EC 4.2.1.1), CgNce103, recently discovered. Only anions have been investigated as CgNce103 inhibitors up until now. Here we report the first sulfonamides inhibition study of this enzyme. Simple sulfonamides showed weak or moderate CgNce103 inhibitory properties, whereas acetazolamide, and a series of 4-substituted ureido-benzene-sulfonamides, sulfamates and sulfamides showed effective CgNce103 inhibitory properties, with KIs in the range of 4.1-115 nM, being also ineffective as human CA II inhibitors. As there is significant resistance of C. glabrata clinical isolates to many classical antifungal agents, inhibition of the ß-CA from this organism may allow an interesting means of controlling the pathogen growth, eventually leading to antifungals with a novel mechanism of action.

Carbonic anhydrase regulation and CO(2) sensing in the fungal pathogen Candida glabrata involves a novel Rca1p ortholog.

Carbon dioxide (CO2) is a ubiquitous gas present at 0.0391% in atmospheric air and 5.5% in human blood. It forms part of numerous carboxylation and decarboxylation reactions carried out in every cell. Carbonic anhydrases (CA) enhance the hydration of CO2 to generate bicarbonate, which is subsequently used in cellular metabolism. In microorganisms, including the yeasts Candida albicans and Saccharomyces cerevisiae, inactivation of CA leads to a growth defect in air, which is complemented in an atmosphere enriched with CO2. In this study we characterize the CA from the fungal pathogen of humans Candida glabrata, CgNce103p, and report a comparable phenotype following its inactivation. Furthermore, we show that expression of the C. glabrata CA is strongly regulated by environmental CO2 at both the protein and transcript level. Similar to what we have previously reported for C. albicans and S. cerevisiae, C. glabrata CA regulation by CO2 is independent from the cAMP-PKA pathway and requires the novel bZIP transcription factor CgRca1p. We show that CgRca1p is an ortholog of the transcription factors Rca1p from C. albicans and Cst6p from S. cerevisiae and prove that CA induction in low CO2 involves the conserved DNA-binding motif TGACGTCA located on this C. glabrata promoter. However, in contrast to what is found in C. albicans CgRca1p expression itself is not affected by CO2. Although our results suggest a high level of similarity between the CO2 sensing pathways from C. glabrata, S. cerevisiae and C. albicans, they also point out significant intrinsic differences.

Vertebrate genome evolution and the zebrafish gene map.

In chordate phylogeny, changes in the nervous system, jaws, and appendages transformed meek filter feeders into fearsome predators. Gene duplication is thought to promote such innovation. Vertebrate ancestors probably had single copies of genes now found in multiple copies in vertebrates and gene maps suggest that this occurred by polyploidization. It has been suggested that one genome duplication event occurred before, and one after the divergence of ray-finned and lobe-finned fishes. Holland et al., however, have argued that because various vertebrates have several HOX clusters, two rounds of duplication occurred before the origin of jawed fishes. Such gene-number data, however, do not distinguish between tandem duplications and polyploidization events, nor whether independent duplications occurred in different lineages. To investigate these matters, we mapped 144 zebrafish genes and compared the resulting map with mammalian maps. Comparison revealed large conserved chromosome segments. Because duplicated chromosome segments in zebrafish often correspond with specific chromosome segments in mammals, it is likely that two polyploidization events occurred prior to the divergence of fish and mammal lineages. This zebrafish gene map will facilitate molecular identification of mutated zebrafish genes, which can suggest functions for human genes known only by sequence.

[Treatment of facial paralysis with temporalis lengthening myoplasty and dysarthria improvement]. / Myoplastie d'allongement du temporal et amélioration de la dysarthrie des patients paralysés faciaux.

INTRODUCTION: The dysfunctions engendered by the peripheral facial paralysis (PFP) induce modifications of the verbal and para-verbal functions. The purpose of our study was to observe if the temporalis lengthening myoplasty (TLM) allowed to decrease dysarthria observed on the operated patients. MATERIALS AND METHODS: We followed-up seven patients affected by a peripheral facial paralysis with various etiologies. Due to specifics needs of this study, we created an evaluation grid of the articulation, which allowed us to measure evolutions after the operation by a tri-phase evaluation: before surgery, at 3 and 6months after it. RESULTS: Results show a definite improvement of dysarthria in the whole test group. CONCLUSION: TLM operation, in addition to be very efficient for the recovering of the paralyzed side, can also treat dysarthria on these patients.