Amphioxus functional genomics and the origins of vertebrate gene regulation.

Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that-in vertebrates-over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations.

Alternative Splicing Changes Promoted by NOVA2 Upregulation in Endothelial Cells and Relevance for Gastric Cancer.

Angiogenesis is crucial for cancer progression. While several anti-angiogenic drugs are in use for cancer treatment, their clinical benefits are unsatisfactory. Thus, a deeper understanding of the mechanisms sustaining cancer vessel growth is fundamental to identify novel biomarkers and therapeutic targets. Alternative splicing (AS) is an essential modifier of human proteome diversity. Nevertheless, AS contribution to tumor vasculature development is poorly known. The Neuro-Oncological Ventral Antigen 2 (NOVA2) is a critical AS regulator of angiogenesis and vascular development. NOVA2 is upregulated in tumor endothelial cells (ECs) of different cancers, thus representing a potential driver of tumor blood vessel aberrancies. Here, we identified novel AS transcripts generated upon NOVA2 upregulation in ECs, suggesting a pervasive role of NOVA2 in vascular biology. In addition, we report that NOVA2 is also upregulated in ECs of gastric cancer (GC), and its expression correlates with poor overall survival of GC patients. Finally, we found that the AS of the Rap Guanine Nucleotide Exchange Factor 6 (RapGEF6), a newly identified NOVA2 target, is altered in GC patients and associated with NOVA2 expression, tumor angiogenesis, and poor patient outcome. Our findings provide a better understanding of GC biology and suggest that AS might be exploited to identify novel biomarkers and therapeutics for anti-angiogenic GC treatments.

Uncomplicated Distal Radius Fractures: An Opportunity to Reduce Emergency Medicine Opioid Prescribing?

OBJECTIVES: To assess emergency physician prescribing for simple extremity fractures-specifically, distal radius fractures-and describe the opportunity for reducing opioid prescribing. METHODS: An electronic survey was distributed to 1238 emergency physicians employed by a nationwide practice serving 220 sites in 20 states. The survey presented two plain film views of a simple Colles fracture and asked: "For the last patient you discharged . . . with the above injury, which pain medications did you prescribe or recommend?" Responses were collected using a clickable checklist of common opioid and nonopioid pain medications. Respondents also specified the number of days covered by any prescription. We assessed associations between physician characteristics and opioid prescribing using the χ2 test, the Wilcoxon rank-sum test, and multivariable regression models. RESULTS: Responses were received from 447 (36%) physicians working in 18 states; 93% were trained in emergency medicine, 33% worked at academic sites, 68% had site volumes between 25,000 and 75,000, and the median experience was 10 (interquartile range 5-19) years. Overall, 92% (95% confidence interval 89%-95%) had prescribed an opioid for a median of 3 (interquartile range 3-4) days. The most commonly prescribed opioids were hydrocodone/acetaminophen (55%) and oxycodone/acetaminophen (20%). Physicians at academic sites prescribed opioids less frequently than those at nonacademic sites (88% vs 94%), but in multivariable regression there were no significant associations between physician characteristics and opioid prescribing. CONCLUSIONS: Emergency physicians commonly prescribe opioids for simple distal radius fractures. This represents a potential opportunity to reduce opioid prescribing.

High indirect fitness benefits for helpers across the nesting cycle in the tropical paper wasp Polistes canadensis.

Explaining the evolution of helping behaviour in the eusocial insects where nonreproductive ("worker") individuals help raise the offspring of other individuals ("queens") remains one of the most perplexing phenomena in the natural world. Polistes paper wasps are popular study models, as workers retain the ability to reproduce: such totipotency is likely representative of the early stages of social evolution. Polistes is thought to have originated in the tropics, where seasonal constraints on reproductive options are weak and social groups are effectively perennial. Yet, most Polistes research has focused on nontropical species, where seasonality causes family groups to disperse; cofoundresses forming new nests the following spring are often unrelated, leading to the suggestion that direct fitness through nest inheritance is key in the evolution of helping behaviour. Here, we present the first comprehensive genetic study of social structure across the perennial nesting cycle of a tropical Polistes-Polistes canadensis. Using both microsatellites and newly developed single nucleotide polymorphism markers, we show that adult cofoundresses are highly related and that brood production is monopolized by a single female across the nesting cycle. Nonreproductive cofoundresses in tropical Polistes therefore have the potential to gain high indirect fitness benefits as helpers from the outset of group formation, and these benefits persist through the nesting cycle. Direct fitness may have been less important in the origin of Polistes sociality than previously suggested. These findings stress the importance of studying a range of species with diverse life history and ecologies when considering the evolution of reproductive strategies.

Acute oxygen sensing by the carotid body: a rattlebag of molecular mechanisms.

The molecular underpinnings of the oxygen sensitivity of the carotid body Type I cells are becoming better defined as research begins to identify potential interactions between previously separate theories. Nevertheless, the field of oxygen chemoreception still presents the general observer with a bewildering array of potential signalling pathways by which a fall in oxygen levels might initiate Type I cell activation. The purpose of this brief review is to address five of the current oxygen sensing hypotheses: the lactate-Olfr 78 hypothesis of oxygen chemotransduction; the role mitochondrial ATP and metabolism may have in chemotransduction; the AMP-activated protein kinase hypothesis and its current role in oxygen sensing by the carotid body; reactive oxygen species as key transducers in the oxygen sensing cascade; and the mechanisms by which H2 S, reactive oxygen species and haem oxygenase may integrate to provide a rapid oxygen sensing transduction system. Over the previous 15 years several lines of research into acute hypoxic chemotransduction mechanisms have focused on the integration of mitochondrial and membrane signalling. This review places an emphasis on the subplasmalemmal-mitochondrial microenvironment in Type I cells and how theories of acute oxygen sensing are increasingly dependent on functional interaction within this microenvironment.

High Fat Feeding in Rats Alters Respiratory Parameters by a Mechanism That Is Unlikely to Be Mediated by Carotid Body Type I Cells.

The carotid bodies (CB) respond to changes in blood gases with neurotransmitter release, thereby increasing carotid sinus nerve firing frequency and ultimately correcting the pattern of breathing. It has previously been demonstrated that acute application of the adipokine leptin augments the hypoxic sensory response of the intact in-vitro CB (Pye RL, Roy A, Wilson RJ, Wyatt CN. FASEB J 30(1 Supplement):983.1, 2016) and isolated CB type I cell (Pye RL, Dunn EJ, Ricker EM, Jurcsisn JG, Barr BL, Wyatt CN. Arterial chemoreceptors in physiology and pathophysiology. Advances in experimental medicine and biology. Springer, Cham, 2015). This study's aim was to examine, in-vivo, if elevated leptin modulated CB function and breathing.Rats were fed high fat or control chow for 16-weeks. High fat fed (HFF) animals gained significantly more weight compared to control fed (CF) animals and had significantly higher serum leptin levels compared to CF. Utilizing whole-body plethysmography, HFF animals demonstrated significantly depressed breathing compared to CF at rest and during hypoxia. However, amplitudes in the change in breathing from rest to hypoxia were not significantly different between groups. CB type I cells were isolated and intracellular calcium levels recorded. Averaged and peak cellular hypoxic responses were not significantly different.Despite a small but significant rise in leptin, differences in breathing caused by high fat feeding are unlikely caused by an effect of leptin on CB type I cells. However, the possibility remains that leptin may have in-vivo postsynaptic effects on the carotid sinus nerve; this remains to be investigated.

Adrenaline release evokes hyperpnoea and an increase in ventilatory CO2 sensitivity during hypoglycaemia: a role for the carotid body.

KEY POINTS: Hypoglycaemia is counteracted by release of hormones and an increase in ventilation and CO2 sensitivity to restore blood glucose levels and prevent a fall in blood pH. The full counter-regulatory response and an appropriate increase in ventilation is dependent on carotid body stimulation. We show that the hypoglycaemia-induced increase in ventilation and CO2 sensitivity is abolished by preventing adrenaline release or blocking its receptors. Physiological levels of adrenaline mimicked the effect of hypoglycaemia on ventilation and CO2 sensitivity. These results suggest that adrenaline, rather than low glucose, is an adequate stimulus for the carotid body-mediated changes in ventilation and CO2 sensitivity during hypoglycaemia to prevent a serious acidosis in poorly controlled diabetes. ABSTRACT: Hypoglycaemia in vivo induces a counter-regulatory response that involves the release of hormones to restore blood glucose levels. Concomitantly, hypoglycaemia evokes a carotid body-mediated hyperpnoea that maintains arterial CO2 levels and prevents respiratory acidosis in the face of increased metabolism. It is unclear whether the carotid body is directly stimulated by low glucose or by a counter-regulatory hormone such as adrenaline. Minute ventilation was recorded during infusion of insulin-induced hypoglycaemia (8-17 mIU kg(-1)  min(-1) ) in Alfaxan-anaesthetised male Wistar rats. Hypoglycaemia significantly augmented minute ventilation (123 ± 4 to 143 ± 7 ml min(-1) ) and CO2 sensitivity (3.3 ± 0.3 to 4.4 ± 0.4 ml min(-1)  mmHg(-1) ). These effects were abolished by either ß-adrenoreceptor blockade with propranolol or adrenalectomy. In this hypermetabolic, hypoglycaemic state, propranolol stimulated a rise in P aC O2, suggestive of a ventilation-metabolism mismatch. Infusion of adrenaline (1 µg kg(-1)  min(-1) ) increased minute ventilation (145 ± 4 to 173 ± 5 ml min(-1) ) without altering P aC O2 or pH and enhanced ventilatory CO2 sensitivity (3.4 ± 0.4 to 5.1 ± 0.8 ml min(-1)  mmHg(-1) ). These effects were attenuated by either resection of the carotid sinus nerve or propranolol. Physiological concentrations of adrenaline increased the CO2 sensitivity of freshly dissociated carotid body type I cells in vitro. These findings suggest that adrenaline release can account for the ventilatory hyperpnoea observed during hypoglycaemia by an augmented carotid body and whole body ventilatory CO2 sensitivity.

The bladed Bangiales (Rhodophyta) of the South Eastern Pacific: Molecular species delimitation reveals extensive diversity.

A molecular taxonomic study of the bladed Bangiales of the South Eastern Pacific (coast of Chile) was undertaken based on sequence data of the mitochondrial COI and chloroplast rbcL for 193 specimens collected from Arica (18°S) in the north to South Patagonia (53°S) in the south. The results revealed for the first time that four genera, Porphyra, Pyropia, Fuscifolium and Wildemania were present in the region. Species delimitation was determined based on a combination of a General Mixed Yule Coalescence model (GMYC) and Automatic Barcode Gap Discovery (ABGD) coupled with detection of monophyly in tree reconstruction. The overall incongruence between the species delimitation methods within each gene was 29%. The GMYC method led to over-splitting groups, whereas the ABGD method had a tendency to lump groups. Taking a conservative approach to the number of putative species, at least 18 were recognized and, with the exception of the recently described Pyropia orbicularis, all were new to the Chilean flora. Porphyra and Pyropia were the most diverse genera with eight 'species' each, whereas only a 'single' species each was found for Fuscifolium and Wildemania. There was also evidence of recently diverging groups: Wildemania sp. was distinct but very closely related to W. amplissima from the Northern Hemisphere and raises questions in relation to such disjunct distributions. Pyropia orbicularis was very closely related to two other species, making species delimitation very difficult but provides evidence of an incipient speciation. The difference between the 'species' discovered and those previously reported for the region is discussed in relation to the difficulty of distinguishing species based on morphological identification.

NAADP mobilizes calcium from acidic organelles through two-pore channels.

Ca(2+) mobilization from intracellular stores represents an important cell signalling process that is regulated, in mammalian cells, by inositol-1,4,5-trisphosphate (InsP(3)), cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP(3) and cyclic ADP ribose cause the release of Ca(2+) from sarcoplasmic/endoplasmic reticulum stores by the activation of InsP(3) and ryanodine receptors (InsP(3)Rs and RyRs). In contrast, the nature of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors remain controversial, although evidence indicates that NAADP mobilizes Ca(2+) from lysosome-related acidic compartments. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 (also known as TPCN1) and chicken TPC3 (TPCN3) being expressed on endosomal membranes, and human TPC2 (TPCN2) on lysosomal membranes when expressed in HEK293 cells. Membranes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca(2+) release from lysosome-related stores that is subsequently amplified by Ca(2+)-induced Ca(2+) release by InsP(3)Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but were only attenuated by depleting endoplasmic reticulum Ca(2+) stores or by blocking InsP(3)Rs. Thus, TPCs form NAADP receptors that release Ca(2+) from acidic organelles, which can trigger further Ca(2+) signals via sarcoplasmic/endoplasmic reticulum. TPCs therefore provide new insights into the regulation and organization of Ca(2+) signals in animal cells, and will advance our understanding of the physiological role of NAADP.

Selective mu and kappa Opioid Agonists Inhibit Voltage-Gated Ca2+ Entry in Isolated Neonatal Rat Carotid Body Type I Cells.

It is known that opioids inhibit the hypoxic ventilatory response in part via an action at the carotid body, but little is known about the cellular mechanisms that underpin this. This study's objectives were to examine which opioid receptors are located on the oxygen-sensing carotid body type I cells from the rat and determine the mechanism by which opioids might inhibit cellular excitability.Immunocytochemistry revealed the presence of µ and κ opioid receptors on type I cells. The µ-selective agonist DAMGO (10 µM) and the κ-selective agonist U50-488 (10 µM) inhibited high K(+) induced rises in intracellular Ca(2+) compared with controls. After 3 h incubation (37 °C) with pertussis toxin (150 ng ml(-1)), DAMGO (10 µM) and U50-488 (10 µM) had no significant effect on the Ca(2+) response to high K(+).These results indicate that opioids acting at µ and κ receptors inhibit voltage-gated Ca(2+) influx in rat carotid body type I cells via G(i)-coupled mechanisms. This mechanism may contribute to opioid's inhibitory actions in the carotid body.

The CamKKß Inhibitor STO609 Causes Artefacts in Calcium Imaging and Selectively Inhibits BKCa in Mouse Carotid Body Type I Cells.

It has previously been reported that AMP-activated protein kinase (AMPK) may be critical for hypoxic chemotransduction in carotid body type I cells. This study sought to determine the importance of the regulatory upstream kinase of AMPK, CamKKß, in the acute response to hypoxia in isolated mouse type I cells.Initial data indicated several previously unreported artefacts associated with using the CamKKß inhibitor STO609 and Ca(2+) imaging techniques. Most importantly Fura-2 and X-Rhod1 imaging revealed that STO609 quenched emission fluorescence even in the absence of intracellular Ca(2+) ([Ca(2+)](I)). Furthermore, STO609 (100 µM) rapidly inhibited outward macroscopic currents and this inhibition was abolished in the presence of the selective BK(Ca) inhibitor paxilline.Taken together these data suggest that ST0609 should be used with caution during Ca(2+) imaging studies as it can directly interact with Ca(2+) binding dyes. The rapid inhibitory effect of STO609 on BK(Ca) was unexpected as the majority of studies using this compound required an incubation of approximately 10 min to inhibit the kinase. Furthermore, as AMPK activation inhibits BK(Ca), inhibiting AMPK's upstream kinases would, if anything, be predicted to have the opposite effect on BK(Ca). Future work will determine if the inhibition of BK(Ca) is via CamKKß or via an off target action of STO609 on the channel itself.

Acutely Administered Leptin Increases [Ca2+] i and BK Ca Currents But Does Not Alter Chemosensory Behavior in Rat Carotid Body Type I Cells.

Obesity related pathologies are the health care crisis of our generation. The fat cell derived adipokine leptin has been shown to be a central stimulant of respiration. Very high levels of leptin, however, are associated with the depressed ventilatory phenotype observed in obesity hypoventilation syndrome. Leptin receptors have been identified on carotid body type I cells but how their activation might influence the physiology of these cells is not known.The acute application of leptin evoked calcium signaling responses in isolated type I cells. Cells increased their Fura 2 ratio by 0.074 ± 0.010 ratio units (n = 39, P < 0.001). Leptin also increased the peak membrane currents in 6 of 9 cells increasing the peak macroscopic currents at +10 mV by 61 ± 14 % (p < 0.02). Leptin administered in the presence of the selective BK(Ca) channel inhibitor Paxilline (0.5 µM) failed to increase membrane currents (n = 5). Interestingly, leptin did not significantly alter the resting membrane potential of isolated type I cells (n = 9) and anoxic/acidic depolarizations were unaffected by leptin (n = 7, n = 6).These data suggest that leptin receptors are functional in type I cells but that their acute activation does not alter chemosensory properties. Future studies will use chronic models of leptin dysregulation.

Training on Corrections and Health Within U.S. Academic Health Professions Education: A Scoping Review.

Despite the scale, inequity, and consequences of mass incarceration, health care provider knowledge and awareness on correctional health remain limited. Understanding the educational experiences of health professions learners and the studies used to evaluate them can provide useful information about current gaps to guide future curricular improvement. To address this need, we conducted a scoping review of peer-reviewed studies examining United States-based academic health professions educational programs on correctional health. Studies were coded based on study characteristics, learner outcomes, and degree to which they contained elements described in relevant position statements by two professional medical associations. Overall, 27 articles (1975-2021) were included. Learner outcomes were primarily documented at the "reactions" (93%) and "learning" (52%) levels of the Kirkpatrick model (1979), relative to "behaviors" (11%) and "long-term outcomes" (0%). Comparison of curricula to select position statements revealed multiple content gaps in the realms of prevalent conditions requiring expertise (e.g., violence and self-harm); ethical and medical-legal considerations (e.g., privatization of correctional health care); and correctional health care systems, structures, and administration. Taken together, findings highlight gaps in, and opportunities for, correctional health educational programs. Addressing health care workforce training needs is a necessary yet insufficient step to achieving health equity for populations affected by incarceration.

Social complexity, life-history and lineage influence the molecular basis of castes in vespid wasps.

A key mechanistic hypothesis for the evolution of division of labour in social insects is that a shared set of genes co-opted from a common solitary ancestral ground plan (a genetic toolkit for sociality) regulates caste differentiation across levels of social complexity. Using brain transcriptome data from nine species of vespid wasps, we test for overlap in differentially expressed caste genes and use machine learning models to predict castes using different gene sets. We find evidence of a shared genetic toolkit across species representing different levels of social complexity. We also find evidence of additional fine-scale differences in predictive gene sets, functional enrichment and rates of gene evolution that are related to level of social complexity, lineage and of colony founding. These results suggest that the concept of a shared genetic toolkit for sociality may be too simplistic to fully describe the process of the major transition to sociality.

Co-expression Gene Networks and Machine-learning Algorithms Unveil a Core Genetic Toolkit for Reproductive Division of Labour in Rudimentary Insect Societies.

The evolution of eusociality requires that individuals forgo some or all their own reproduction to assist the reproduction of others in their group, such as a primary egg-laying queen. A major open question is how genes and genetic pathways sculpt the evolution of eusociality, especially in rudimentary forms of sociality-those with smaller cooperative nests when compared with species such as honeybees that possess large societies. We lack comprehensive comparative studies examining shared patterns and processes across multiple social lineages. Here we examine the mechanisms of molecular convergence across two lineages of bees and wasps exhibiting such rudimentary societies. These societies consist of few individuals and their life histories range from facultative to obligately social. Using six species across four independent origins of sociality, we conduct a comparative meta-analysis of publicly available transcriptomes. Standard methods detected little similarity in patterns of differential gene expression in brain transcriptomes among reproductive and non-reproductive individuals across species. By contrast, both supervised machine learning and consensus co-expression network approaches uncovered sets of genes with conserved expression patterns among reproductive and non-reproductive phenotypes across species. These sets overlap substantially, and may comprise a shared genetic "toolkit" for sociality across the distantly related taxa of bees and wasps and independently evolved lineages of sociality. We also found many lineage-specific genes and co-expression modules associated with social phenotypes and possible signatures of shared life-history traits. These results reveal how taxon-specific molecular mechanisms complement a core toolkit of molecular processes in sculpting traits related to the evolution of eusociality.

Putting hornets on the genomic map.

Hornets are the largest of the social wasps, and are important regulators of insect populations in their native ranges. Hornets are also very successful as invasive species, with often devastating economic, ecological and societal effects. Understanding why these wasps are such successful invaders is critical to managing future introductions and minimising impact on native biodiversity. Critical to the management toolkit is a comprehensive genomic resource for these insects. Here we provide the annotated genomes for two hornets, Vespa crabro and Vespa velutina. We compare their genomes with those of other social Hymenoptera, including the northern giant hornet Vespa mandarinia. The three hornet genomes show evidence of selection pressure on genes associated with reproduction, which might facilitate the transition into invasive ranges. Vespa crabro has experienced positive selection on the highest number of genes, including those putatively associated with molecular binding and olfactory systems. Caste-specific brain transcriptomic analysis also revealed 133 differentially expressed genes, some of which are associated with olfactory functions. This report provides a spring-board for advancing our understanding of the evolution and ecology of hornets, and opens up opportunities for using molecular methods in the future management of both native and invasive populations of these over-looked insects.

Selective expression in carotid body type I cells of a single splice variant of the large conductance calcium- and voltage-activated potassium channel confers regulation by AMP-activated protein kinase.

Inhibition of large conductance calcium-activated potassium (BKCa) channels mediates, in part, oxygen sensing by carotid body type I cells. However, BKCa channels remain active in cells that do not serve to monitor oxygen supply. Using a novel, bacterially derived AMP-activated protein kinase (AMPK), we show that AMPK phosphorylates and inhibits BKCa channels in a splice variant-specific manner. Inclusion of the stress-regulated exon within BKCa channel α subunits increased the stoichiometry of phosphorylation by AMPK when compared with channels lacking this exon. Surprisingly, however, the increased phosphorylation conferred by the stress-regulated exon abolished BKCa channel inhibition by AMPK. Point mutation of a single serine (Ser-657) within this exon reduced channel phosphorylation and restored channel inhibition by AMPK. Significantly, RT-PCR showed that rat carotid body type I cells express only the variant of BKCa that lacks the stress-regulated exon, and intracellular dialysis of bacterially expressed AMPK markedly attenuated BKCa currents in these cells. Conditional regulation of BKCa channel splice variants by AMPK may therefore determine the response of carotid body type I cells to hypoxia.

Ion channel regulation by the LKB1-AMPK signalling pathway: the key to carotid body activation by hypoxia and metabolic homeostasis at the whole body level.

Our recent investigations provide further support for the proposal that, consequent to inhibition of mitochondrial oxidative phosphorylation, activation of AMP-activated protein kinase (AMPK) mediates carotid body excitation by hypoxia. Consistent with the effects of hypoxia, intracellular dialysis from a patch pipette of an active (thiophosphorylated) recombinant AMPK heterotrimer (α2ß2γ1) or application of the AMPK activators AICAR and A769662: (1) Inhibited BK(Ca) currents and TASK K(+) currents in rat carotid body type I cells; (2) Inhibited whole-cell currents carried by KCa1.1 and TASK3, but not TASK1 channels expressed in HEK293 cells; (3) Triggered carotid body activation. Furthermore, preliminary studies using mice with conditional knockout in type I cells of the primary upstream kinase that activates AMPK in response to metabolic stresses, LKB1, appear to confirm our working hypothesis. Studies on mice with knockout of the catalytic α1 subunit and α2 subunits of AMPK, respectively, have proved equally consistent. Accumulating evidence therefore suggests that the LKB1-AMPK signalling pathway is necessary for hypoxia-response coupling by the carotid body, and serves to regulate oxygen and therefore energy supply at the whole body level.

The prevalence of dental caries in Missouri and its relation to systemic disease: opportunities for Missouri to improve the health of its citizens.

Recently, it has been recognized that poor oral health conditions, especially periodontitis, have been a contributing factor to several systemic diseases. Evidence shows that Missouri should be concerned about the current state of caries and its prevention. The prevalence of caries and lack of preventative care in Missouri warrants an examination of the current efforts in place to reduce caries and the creation of novel approaches that bridge the gap between oral and medical care. This paper discusses this problem in depth.