Stress-sensitive neural circuits change the gut microbiome via duodenal glands.

Negative psychological states impact immunity by altering the gut microbiome. However, the relationship between brain states and microbiome composition remains unclear. We show that Brunner's glands in the duodenum couple stress-sensitive brain circuits to bacterial homeostasis. Brunner's glands mediated the enrichment of gut Lactobacillus species in response to vagus nerve stimulation. Cell-specific ablation of the glands markedly suppressed Lactobacilli counts and heightened vulnerability to infection. In the forebrain, we mapped a vagally mediated, polysynaptic circuit connecting the central nucleus of the amygdala to Brunner's glands. Chronic stress suppressed central amygdala activity and phenocopied the effects of gland lesions. Conversely, excitation of either the central amygdala or parasympathetic vagal neurons activated Brunner's glands and reversed the effects of stress on the gut microbiome and immunity. The findings revealed a tractable brain-body mechanism linking psychological states to host defense.

A case of Winkia neuii (Actinomyces neuii) vertebral osteomyelitis and review of the literature.

This case report presents an unusual occurrence of Winkia (Actinomyces) neuii vertebral osteomyelitis in a 55-year-old male patient with diabetes mellitus. W. neuii is a distinct species formerly placed within the Actinomyces genus, exhibiting unique morphological and clinical characteristics. Vertebral osteomyelitis caused by Actinomyces species is rare, with only one prior case reported in the literature. The patient was successfully managed with a combination of intravenous ceftriaxone during hospitalization and an oral antibiotic regimen for an extended period. This case report contributes to the limited body of knowledge surrounding W. neuii, as well as actinomycotic vertebral osteomyelitis.

An Amygdalar-Vagal-Glandular Circuit Controls the Intestinal Microbiome.

Psychological states can regulate intestinal mucosal immunity by altering the gut microbiome. However, the link between the brain and microbiome composition remains elusive. We show that Brunner's glands in the duodenal submucosa couple brain activity to intestinal bacterial homeostasis. Brunner's glands mediated the enrichment of gut probiotic species in response to stimulation of abdominal vagal fibers. Cell-specific ablation of the glands triggered transmissible dysbiosis associated with an immunodeficiency syndrome that led to mortality upon gut infection with pathogens. The syndrome could be largely prevented by oral or intra-intestinal administration of probiotics. In the forebrain, we identified a vagally-mediated, polysynaptic circuit connecting the glands of Brunner to the central nucleus of the amygdala. Intra-vital imaging revealed that excitation of central amygdala neurons activated Brunner's glands and promoted the growth of probiotic populations. Our findings unveil a vagal-glandular neuroimmune circuitry that may be targeted for the modulation of the gut microbiome. The glands of Brunner may be the critical cells that regulate the levels of Lactobacilli species in the intestine.

Advances in transposable elements: from mechanisms to applications in mammalian genomics.

It has been 70 years since Barbara McClintock discovered transposable elements (TE), and the mechanistic studies and functional applications of transposable elements have been at the forefront of life science research. As an essential part of the genome, TEs have been discovered in most species of prokaryotes and eukaryotes, and the relative proportion of the total genetic sequence they comprise gradually increases with the expansion of the genome. In humans, TEs account for about 40% of the genome and are deeply involved in gene regulation, chromosome structure maintenance, inflammatory response, and the etiology of genetic and non-genetic diseases. In-depth functional studies of TEs in mammalian cells and the human body have led to a greater understanding of these fundamental biological processes. At the same time, as a potent mutagen and efficient genome editing tool, TEs have been transformed into biological tools critical for developing new techniques. By controlling the random insertion of TEs into the genome to change the phenotype in cells and model organisms, critical proteins of many diseases have been systematically identified. Exploiting the TE's highly efficient in vitro insertion activity has driven the development of cutting-edge sequencing technologies. Recently, a new technology combining CRISPR with TEs was reported, which provides a novel targeted insertion system to both academia and industry. We suggest that interrogating biological processes that generally depend on the actions of TEs with TEs-derived genetic tools is a very efficient strategy. For example, excessive activation of TEs is an essential factor in the occurrence of cancer in humans. As potent mutagens, TEs have also been used to unravel the key regulatory elements and mechanisms of carcinogenesis. Through this review, we aim to effectively combine the traditional views of TEs with recent research progress, systematically link the mechanistic discoveries of TEs with the technological developments of TE-based tools, and provide a comprehensive approach and understanding for researchers in different fields.

Spatiotemporal Trends Spanning Three Decades Show Toxic Levels of Chemical Contaminants in Marine Mammals.

Despite their ban and restriction under the 2001 Stockholm Convention, persistent organic pollutants (POPs) are still widespread and pervasive in the environment. Releases of these toxic and bioaccumulative chemicals are ongoing, and their contribution to population declines of marine mammals is of global concern. To safeguard their survival, it is of paramount importance to understand the effectiveness of mitigation measures. Using one of the world's largest marine mammals strandings data sets, we combine published and unpublished data to examine pollutant concentrations in 11 species that stranded along the coast of Great Britain to quantify spatiotemporal trends over three decades and identify species and regions where pollutants pose the greatest threat. We find that although levels of pollutants have decreased overall, there is significant spatial and taxonomic heterogeneity such that pollutants remain a threat to biodiversity in several species and regions. Of individuals sampled within the most recent five years (2014-2018), 48% of individuals exhibited a concentration known to exceed toxic thresholds. Notably, pollutant concentrations are highest in long-lived, apex odontocetes (e.g., killer whales (Orcinus orca), bottlenose dolphins (Tursiops truncatus), and white-beaked dolphins (Lagenorhynchus albirostris)) and were significantly higher in animals that stranded on more industrialized coastlines. At the present concentrations, POPs are likely to be significantly impacting marine mammal health. We conclude that more effective international elimination and mitigation strategies are urgently needed to address this critical issue for the global ocean health.

Centralized red muscle in Odontaspis ferox and the prevalence of regional endothermy in sharks.

The order Lamniformes contains charismatic species such as the white shark Carcharodon carcharias and extinct megatooth shark Otodus megalodon, and is of particular interest given their influence on marine ecosystems, and because some members exhibit regional endothermy. However, there remains significant debate surrounding the prevalence and evolutionary origin of regional endothermy in the order, and therefore the development of phenomena such as gigantism and filter-feeding in sharks generally. Here we show a basal lamniform shark, the smalltooth sand tiger shark Odontaspis ferox, has centralized skeletal red muscle and a thick compact-walled ventricle; anatomical features generally consistent with regionally endothermy. This result, together with the recent discovery of probable red muscle endothermy in filter feeding basking sharks Cetorhinus maximus, suggests that this thermophysiology is more prevalent in the Lamniformes than previously thought, which in turn has implications for understanding the evolution of regional endothermy, gigantism, and extinction risk of warm-bodied shark species both past and present.

Variable task switching in the feeding network of Aplysia is a function of differential command input.

Command systems integrate sensory information and then activate the interneurons and motor neurons that mediate behavior. Much research has established that the higher-order projection neurons that constitute these systems can play a key role in specifying the nature of the motor activity induced, or determining its parametric features. To a large extent, these insights have been obtained by contrasting activity induced by stimulating one neuron (or set of neurons) to activity induced by stimulating a different neuron (or set of neurons). The focus of our work differs. We study one type of motor program, ingestive feeding in the mollusc Aplysia californica, which can either be triggered when a single projection neuron (CBI-2) is repeatedly stimulated or can be triggered by projection neuron coactivation (e.g., activation of CBI-2 and CBI-3). We ask why this might be an advantageous arrangement. The cellular/molecular mechanisms that configure motor activity are different in the two situations because the released neurotransmitters differ. We focus on an important consequence of this arrangement, the fact that a persistent state can be induced with repeated CBI-2 stimulation that is not necessarily induced by CBI-2/3 coactivation. We show that this difference can have consequences for the ability of the system to switch from one type of activity to another.NEW & NOTEWORTHY We study a type of motor program that can be induced either by stimulating a higher-order projection neuron that induces a persistent state, or by coactivating projection neurons that configure activity but do not produce a state change. We show that when an activity is configured without a state change, it is possible to immediately return to an intermediate state that subsequently can be converted to any type of motor program.

Northerly range expansion and first confirmed records of the smalltooth sand tiger shark, Odontaspis ferox, in the United Kingdom and Ireland.

Three Odontaspis ferox (confirmed by mtDNA barcoding) were found in the English Channel and Celtic Sea in 2023 at Lepe, UK (50.7846, -1.3508), Kilmore Quay, Ireland (52.1714, -6.5937), and Lyme Bay, UK (50.6448, -2.9302). These are the first records of O. ferox in either country, and extend the species' range by over three degrees of latitude, to >52° N. They were ~275 (female), 433 (female), and 293 cm (male) total length, respectively. These continue a series of new records, possibly indicative of a climate change-induced shift in the species' range.

Persistent modulatory actions and task switching in the feeding network of Aplysia.

The activity of multifunctional networks is configured by neuromodulators that exert persistent effects. This raises a question, does this impact the ability of a network to switch from one type of activity to another? We review studies that have addressed this question in the Aplysia feeding circuit. Task switching in this system occurs "asymmetrically." When there is a switch from egestion to ingestion neuromodulation impedes switching (creates a "negative bias"). When there is a switch from ingestion to egestion the biasing is "positive." Ingestion promotes subsequent egestion. We contrast mechanisms responsible for the two types of biasing and show that the observed asymmetry is a consequence of the fact that there is more than one set of egestive circuit parameters.

Tissue-Specific Vulnerability to Apoptosis in Machado-Joseph Disease.

Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD and to evaluate if expression alterations of specific apoptosis genes/proteins can be used as transcriptional biomarkers of disease, the expression levels of BCL2, BAX and TP53 and the BCL2/BAX ratio (an indicator of susceptibility to apoptosis) were assessed in blood and post-mortem brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood BCL2 transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood BAX transcripts and decreased BCL2/BAX ratio are associated with earlier onset of disease, indicating a possible association with MJD pathogenesis. Post-mortem MJD brains show increased BCL2/BAX transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood BCL2 and TP53 transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood BCL2, BAX, and TP53 transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue-dependent behavior is partially replicated in a MJD mouse model.

Sensory deficit screen identifies nsf mutation that differentially affects SNARE recycling and quality control.

The AAA+ NSF complex is responsible for SNARE complex disassembly both before and after membrane fusion. Loss of NSF function results in pronounced developmental and degenerative defects. In a genetic screen for sensory deficits in zebrafish, we identified a mutation in nsf, I209N, that impairs hearing and balance in a dosage-dependent manner without accompanying defects in motility, myelination, and innervation. In vitro experiments demonstrate that while the I209N NSF protein recognizes SNARE complexes, the effects on disassembly are dependent upon the type of SNARE complex and I209N concentration. Higher levels of I209N protein produce a modest decrease in binary (syntaxin-SNAP-25) SNARE complex disassembly and residual ternary (syntaxin-1A-SNAP-25-synaptobrevin-2) disassembly, whereas at lower concentrations binary disassembly activity is strongly reduced and ternary disassembly activity is absent. Our study suggests that the differential effect on disassembly of SNARE complexes leads to selective effects on NSF-mediated membrane trafficking and auditory/vestibular function.

Impact of exposure to urban air pollution on grey squirrel (Sciurus carolinensis) lung health.

The increased rate of global urbanisation has recently exacerbated the significant public health problem of traffic related air pollution. Despite the known significant impact on human health, little is known about the effects of air pollution on wildlife health. The lung is the primary target organ for the effects of exposure to air pollution, leading to lung inflammation, altering the lung epigenome, culminating in respiratory disease. In this study, we aimed to assess lung health and DNA methylation profiles in Eastern grey squirrel (Sciurus carolinensis) populations living across an urban-rural air pollution gradient. Squirrel lung health was assessed in four populations situated across the most polluted inner-city boroughs to the less polluted edges of Greater London. We also assessed lung DNA methylation across three London sites and a further two rural sites in Sussex and North Wales. Lung and tracheal diseases were present in 28% and 13% of the squirrels respectively. Specifically, focal inflammation (13%), focal macrophages with vacuolated cytoplasm (3%) and endogenous lipid pneumonia (3%). There was no significant difference in prevalence of lung, tracheal diseases, anthracosis (carbon presence) or lung DNA methylation levels between urban sites and urban and rural sites respectively or NO2 levels. BALT (Bronchus-Associated Lymphoid Tissue) was significantly smaller in the site with highest NO2 and contained the highest carbon loading compared to sites with lower NO2, however differences in carbon loading in between sites were not significant. High pollution site individuals also had significantly higher numbers of alveolar macrophages which suggests that grey squirrels are exposed to and respond to traffic-related air pollution and further research is needed to understand the impact of traffic-related air pollutants on wildlife health.

An investigation into the effects of climate change on baleen whale distribution in the British Isles.

Climate change is predicted to impact the distribution of many marine species. In the North-East Atlantic and elsewhere in the world, studies indicate that climate change is leading to poleward shifts in cetacean distribution. Here, strandings data collected in the British Isles from 1990 to 2020 were used to assess whether there is evidence of a shift in baleen whale distribution. Linear regression models were used to compare the number of strandings over time between six regions of the British Isles and, whilst the results indicate no significant change in the number of strandings in the most southerly region of the British Isles, there have been significant increases in more northern regions. Data related to stranded minke whales is the primary driver of these increases, with a number of potential variables affecting this trend, including observer effort. These variables are discussed and further research to explore this potential association is suggested.

Evaluation of a marine mammal status and trends contaminants indicator for European waters.

Marine mammals are vulnerable to the bioaccumulation, biomagnification and lactational transfer of specific types of pollutants, such as industrial polychlorinated biphenyls (PCBs), due to their long-life spans, feeding at a high trophic level and unique fat stores that can serve as depots for these lipophilic contaminants. Currently, European countries are developing indicators for monitoring pollutants in the marine environment and assessing the state of biodiversity, requirements under both Regional Seas Conventions and European legislation. As sentinel species for marine ecosystem and human health, marine mammals can be employed to assess bioaccumulated contaminants otherwise below current analytical detection limits in water and lower trophic level marine biota. To aid the development of Regional Seas marine mammal contaminants indicators, as well as Member States obligations under descriptor 8 of the EU Marine Strategy Framework Directive, the current study aims to further develop appropriate methodological standards using data collected by the established UK marine mammal pollutant monitoring programme (1990 to 2017) to assess the trends and status of PCBs in harbour porpoises. Within this case study, temporal trends of PCB blubber concentration in juvenile harbour porpoises were analysed using multiple linear regression models and toxicity thresholds for the onset of physiological (reproductive and immunological) endpoints were applied to all sex-maturity groups. Mean PCB blubber concentrations were observed to decline in all harbour porpoise Assessment Units and OSPAR Assessment Areas in UK waters. However, a high proportion of animals were exposed to concentrations deemed to be a toxicological threat, though the relative proportion declined in most Assessment Units/Areas over the last 10 years of the assessment. Recommendations were made for improving the quality of the assessment going forward, including detailing monitoring requirements for the successful implementation of such an indicator.

Frozen in time: Rangewide genomic diversity, structure, and demographic history of relict American chestnut populations.

American chestnut (Castanea dentata) was once the most economically and ecologically important hardwood species in the eastern United States. In the first half of the 20th century, an exotic fungal pathogen-Cryphonectria parasitica-decimated the species, killing billions of chestnut trees. Two approaches to developing blight-resistant American chestnut populations show promise, but both will require introduction of adaptive genomic diversity from wild germplasm to produce diverse, locally adapted restoration populations. Here we characterize population structure, demographic history, and genomic diversity in a range-wide sample of 384 wild American chestnuts to inform conservation and breeding with blight-resistant varieties. Population structure analyses suggest that the chestnut range can be roughly divided into northeast, central, and southwest populations. Within-population genomic diversity estimates revealed a clinal pattern with the highest diversity in the southwest, which likely reflects bottleneck events associated with Quaternary glaciation. Finally, we identified genomic regions under positive selection within each population, which suggests that defence against fungal pathogens is a common target of selection across all populations. Taken together, these results show that American chestnut underwent a postglacial expansion from the southern portion of its range leading to three extant genetic populations. These populations will serve as management units for breeding adaptive genetic variation into the blight-resistant tree populations for targeted reintroduction efforts.

An inter-organ neural circuit for appetite suppression.

Glucagon-like peptide-1 (GLP-1) is a signal peptide released from enteroendocrine cells of the lower intestine. GLP-1 exerts anorectic and antimotility actions that protect the body against nutrient malabsorption. However, little is known about how intestinal GLP-1 affects distant organs despite rapid enzymatic inactivation. We show that intestinal GLP-1 inhibits gastric emptying and eating via intestinofugal neurons, a subclass of myenteric neurons that project to abdominal sympathetic ganglia. Remarkably, cell-specific ablation of intestinofugal neurons eliminated intestinal GLP-1 effects, and their chemical activation functioned as a GLP-1 mimetic. GLP-1 sensing by intestinofugal neurons then engaged a sympatho-gastro-spinal-reticular-hypothalamic pathway that links abnormal stomach distension to craniofacial programs for food rejection. Within this pathway, cell-specific activation of discrete neuronal populations caused systemic GLP-1-like effects. These molecularly identified, delimited enteric circuits may be targeted to ameliorate the abdominal bloating and loss of appetite typical of gastric motility disorders.

Severe skin and soft tissue pythiosis acquired in a hot spring in the southwestern United States, a case report and review of North American cases.

BACKGROUND: Human pythiosis, caused primarily by the aquatic oomycete, Pythium insidiosum, is an emerging but uncommon infection in North America. The infection is frequently life-threatening and is often initially unrecognized due to its rarity and similar presentation to certain fungal infections. METHODS: We report a case of skin and soft tissue pythiosis in a patient without significant underlying comorbidities acquired in a New Mexico hot spring and review its successful treatment. We also review all reported pythiosis cases in North America. RESULTS: Eleven confirmed cases of human pythiosis acquired in North America were identified. The majority of cases occurred in children (64%), ten of eleven cases were acquired in the southern U.S., Mexico, Central America or the Caribbean and four of the eleven individuals succumbed to the infection. CONCLUSIONS: With recognition and aggressive surgical and medical treatment good clinical outcomes can be achieved when treating human pythiosis.

Somatic mutation rates scale with lifespan across mammals.

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1-7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans8, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.

GABAA α subunit control of hyperactive behavior in developing zebrafish.

GABAA receptors mediate rapid responses to the neurotransmitter gamma-aminobutyric acid and are robust regulators of the brain and spinal cord neural networks that control locomotor behaviors, such as walking and swimming. In developing zebrafish, gross pharmacological blockade of these receptors causes hyperactive swimming, which is also a feature of many zebrafish epilepsy models. Although GABAA receptors are important to control locomotor behavior, the large number of subunits and homeostatic compensatory mechanisms have challenged efforts to determine subunit-selective roles. To address this issue, we mutated each of the 8 zebrafish GABAA α subunit genes individually and in pairs using a CRISPR-Cas9 somatic inactivation approach and, then, we examined the swimming behavior of the mutants at 2 developmental stages, 48 and 96 h postfertilization. We found that disrupting the expression of specific pairs of subunits resulted in different abnormalities in swimming behavior at 48 h postfertilization. Mutation of α4 and α5 selectively resulted in longer duration swimming episodes, mutations in α3 and α4 selectively caused excess, large-amplitude body flexions (C-bends), and mutation of α3 and α5 resulted in increases in both of these measures of hyperactivity. At 96 h postfertilization, hyperactive phenotypes were nearly absent, suggesting that homeostatic compensation was able to overcome the disruption of even multiple subunits. Taken together, our results identify subunit-selective roles for GABAA α3, α4, and α5 in regulating locomotion. Given that these subunits exhibit spatially restricted expression patterns, these results provide a foundation to identify neurons and GABAergic networks that control discrete aspects of locomotor behavior.

Systemic Erysipelothrix rhusiopathiae in seven free-ranging delphinids stranded in England and Wales.

Microbiology records for 1127 cetaceans stranded on English and Welsh beaches and examined at the Institute of Zoology between 1990 and 2019 were reviewed to identify cases of Erysipelothrix rhusiopathiae, an uncommon but potentially fatal zoonotic pathogen. Once cases were identified, prevalence was calculated, corresponding postmortem reports were reviewed, common gross and histopathological findings were identified, and antibiotic susceptibilities were determined. Overall prevalence for E. rhusiopathiae was 0.62% (7/1127; 95% CI: 0.30-1.28%). It was isolated from 3 bottlenose dolphins Tursiops truncatus, 3 harbor porpoises Phocoena phocoena, and 1 short-beaked common dolphin Delphinus delphis, with a prevalence of 21.4% (3/14; 95% CI: 7.6-47.9%), 0.39% (3/779; 95% CI: 0.13-1.13%), and 0.47% (1/212; 95% CI: 0.08-2.62%) for each species, respectively. E. rhusiopathiae resulted in septicemia in all cases from which it was isolated. Gross necropsy findings included pulmonary edema (5/7), hemorrhage (5/7) and/or congestion of various organs (4/7), and serosanguineous effusion (3/7; pericardial: 3/7, pleural: 2/6, abdominal: 2/6). Congestion (5/5), bacterial emboli (4/5), and hemorrhage (4/5) were commonly observed on histopathology, and acute renal tubular injury (2/5) and pulmonary edema (2/5) were occasionally observed. Routine bacterial cultures were vital in identifying E. rhusiopathiae, since gross lesions were often subtle and nonspecific. The liver, kidney, and brain were key organs from which E. rhusiopathiae was consistently isolated. Antibiotic resistance was uncommon and was only observed for amikacin and trimethoprim sulfonamide. Penicillins were consistently effective, along with fluoroquinolones, macrolides, clindamycin, cephalexin, and oxytetracycline.