PHYLOGENETIC SYSTEMATICS OF THE BOROPHAGINAE (CARNIVORA: CANIDAE)

The subfamily Borophaginae (Canidae, Carnivora, Mammalia) was erected by G. G. Simpson in 1945 to include seven genera of large, bonecrushing ‘‘dogs’’ in the late Tertiary of the northern continents. As a monophyletic group of canids, the Borophaginae is now known to be much more diverse than was originally envisioned but is confined within the middle to late Tertiary of North America. Fossil records of the borophagines are well represented and members of this prolific clade are often the most common predators in the late Tertiary deposits. Largely due to the Childs Frick Collection at the American Museum of Natural History, borophagines are represented by some of the best materials among fossil carnivorans in anatomical representation, sample size, and stratigraphic density. As a result of this explosive growth of new information, borophagine systematics is now in need of a complete rethinking at a level that could not have been attempted by previous studies. A detailed study of borophagine phylogenetic systematics is presented here, publishing for the first time the entire Frick Collection. A total of 66 species of borophagines, including 18 new species, ranging from Orellan through Blancan ages, are presently recognized. A phylogenetic analysis of these species is performed using cladistic methods, with Hesperocyoninae, an archaic group of canids, as an outgroup. At its base, the Borophaginae has a sister relationship with the subfamily Caninae, which includes all living canids and their most recent fossil relatives. The Borophaginae– Caninae clade is in turn derived from the subfamily Hesperocyoninae. Apart from some transitional forms, most of the Borophaginae can be organized in four major clades (all erected as new tribes or subtribes): Phlaocyonini, Cynarctina, Aelurodontina, and Borophagina. The Borophaginae begins with a group of small fox-sized genera, such as Archaeocyon, Oxetocyon, Otarocyon, and Rhizocyon, in the Orellan through early Arikareean. Relationships among these genera are difficult to resolve due to their primitiveness. Slightly more derived, but still near the base of the Borophaginae, is the Phlaocyonini, a hypocarnivorous clade of the Arikareean and Hemingfordian that includes Cynarctoides and Phlaocyon. These two genera represent divergent approaches toward hypocarnivory. Species of Cynarctoides trend toward selenodonty and remain small in size, whereas species of Phlaocyon specialize toward bunodont dentitions but of increasing size, with an unusual trend toward hypercarnivory by two terminal species in the clade. Four transitional taxa (species of Cormocyon and Desmocyon) occupy intermediate positions between the Phlaocyonini and Cynarctina, and represent a gradual size increase toward mediumsize individuals. The subtribe Cynarctina, the second hypocarnivorous clade, includes Paracynarctus and Cynarctus in the Hemingfordian through Clarendonian, and represents a larger size group than the Phlaocyonini, although there is a tendency toward size reduction among advanced species of Cynarctus. The cynarctines feature the most bunodont dentition known among canids. The next series of transitional taxa (Metatomarctus, Euoplocyon, Psalidocyon, Microtomarctus, Protomarctus, and Tephrocyon) are of medium size and occupy a pectinated sequence that contains a rather diverse set of dental morphology. These include the most hypercarnivorous borophagine Euoplocyon, the peculiarly trenchant Psalidocyon, and the dwarf lineage Microtomarctus. The next clade, Aelurodontina, is the first major hypercarnivorous group and is represented by Tomarctus and Aelurodon in the Barstovian and Clarendonian. The aelurodontines evolve around a more consistent theme of increasingly more hypercarnivorous dentitions with strong premolars, forming a rather linear series from Tomarctus to various species of Aelurodon. The terminal clade Borophagina, sister to the Aelurodontina, begins with the mostly mesocarnivorous Paratomarctus and Carpocyon in the late Barstovian through late Hemphillian. The terminal species of Carpocyon, C. limosus, shows some hypocarnivorous adaptations. Protepicyon in the Barstovian initiates the hypercarnivorous trend in the terminal clade. Epicyon, the largest known canid, is the dominant predator in the Clarendonian and Hemphillian. Finally, an enlarged concept of Borophagus consists of a series of pectinated species terminated by B. diversidens in the late Blancan. Epicyon and Borophagusare the most highly evolved in their capacity to crush bones. Phylogenetic reconstruction was greatly aided by the high quality of fossil records and the large number of transitional forms. The latter ensures a morphological continuity that facilitates the identification of homoplasies that otherwise could easily be mistaken as synapomorphies. Confidence in the phylogeny is further enhanced by a high congruence between the cladistic rank and the stratigraphic sequence. The temporal and morphological continuity in many borophagine lineages also permits further postulation about their evolutionary processes, such as cladogenetic and anagenetic events. Our considerably enlarged concept of the Borophaginae indicates a much broader trophic diversity than has previously been envisioned. In addition to the commonly recognized hyenalike forms, members of the Borophaginae acquired a wider spectrum of morphologies that surpassed either the hesperocyonine or canine canids. The Borophaginae played broad ecological roles that are performed by at least three living carnivoran families, Canidae, Hyaenidae, and Procyonidae

LIGHTSITE II Randomized Multicenter Trial: Evaluation of Multiwavelength Photobiomodulation in Non-exudative Age-Related Macular Degeneration.

INTRODUCTION Photobiomodulation (PBM) represents a potential treatment for non-exudative age-related macular degeneration (AMD). PBM uses wavelengths of light to target components of the mitochondrial respiratory chain to improve cellular bioenergetic outputs. The aim of this study was to further investigate the effects of PBM on clinical, quality of life (QoL) and anatomical outcomes in subjects with intermediate stage non-exudative AMD. METHODS The multicenter LIGHTSITE II study was a randomized clinical trial evaluating safety and efficacy of PBM in intermediate non-exudative AMD. The LumiThera Valeda® Light Delivery System delivered multiwavelength PBM (590, 660 and 850 nm) or sham treatment 3 × per week over 3-4 weeks (9 treatments per series) with repeated treatments at baseline (BL), 4 and 8 months. Subjects were enrolled with 20/32 to 20/100 best-corrected visual acuity (BCVA) and no central geographic atrophy (GA) within the central fovea (500 μm). RESULTS LIGHTSITE II enrolled 44 non-exudative AMD subjects (53 eyes). PBM-treated eyes showed statistically significant improvement in BCVA at 9 months (n = 32 eyes, p = 0.02) with a 4-letter gain in the PBM-treated group versus a 0.5-letter gain in the sham-treated group (ns, p < 0.1) for patients that received all 27 PBM treatments (n = 29 eyes). Approximately 35.3% of PBM-treated eyes showed ≥ 5-letter improvement at 9 months. Macular drusen volume was not increased over time in the PBM-treated group but did show increases in the sham-treated group. While PBM and sham groups both showed GA lesion growth in the trial period, there was 20% less growth in the PBM group over 10 months, suggesting potential disease-modifying effects. No safety concerns or signs of phototoxicity were observed. CONCLUSION These results confirm previous clinical testing of multiwavelength PBM and support treatment with Valeda as a novel therapy with a unique mechanism of action as a potential treatment for non-exudative AMD. TRIAL REGISTRATION Clinicaltrial.Gov Registration Identifier: NCT03878420

Scanning mutagenesis of the I-II loop of the Cav2.2 calcium channel identifies residues Arginine 376 and Valine 416 as molecular determinants of voltage dependent G protein inhibition

Direct interaction with the β subunit of the heterotrimeric G protein complex causes voltage-dependent inhibition of N-type calcium channels. To further characterize the molecular determinants of this interaction, we performed scanning mutagenesis of residues 372-387 and 410-428 of the N-type channel α1 subunit, in which individual residues were replaced by either alanine or cysteine. We coexpressed wild type Gβ1γ2 subunits with either wild type or point mutant N-type calcium channels, and voltage-dependent, G protein-mediated inhibition of the channels (VDI) was assessed using patch clamp recordings. The resulting data indicate that Arg376 and Val416 of the α1 subunit, residues which are surface-exposed in the presence of the calcium channel β subunit, contribute significantly to the functional inhibition by Gβ1. To further characterize the roles of Arg376 and Val416 in this interaction, we performed secondary mutagenesis of these residues, coexpressing the resulting mutants with wild type Gβ1γ2 subunits and with several isoforms of the auxiliary β subunit of the N-type channel, again assessing VDI using patch clamp recordings. The results confirm the importance of Arg376 for G protein-mediated inhibition and show that a single amino acid substitution to phenylalanine drastically alters the abilities of auxiliary calcium channel subunits to regulate G protein inhibition of the channel

Systematics of Borophaginae

391 p. : ill. ; 26 cm.Includes bibliographical references (p. 344-356)."The subfamily Borophaginae (Canidae, Carnivora, Mammalia) was erected by G.G. Simpson in 1945 to include seven genera of large, bone-crushing "dogs" in the late Tertiary of the northern continents. As a monophyletic group of canids, the Borophaginae is now known to be much more diverse than was originally envisioned but is confined within the middle to late Tertiary of North America. Fossil records of the borophagines are well represented and members of this prolific clade are often the most common predators in the late Tertiary deposits. Largely due to the Childs Frick Collection at the American Museum of Natural History, borophagines are represented by some of the best materials among fossil carnivorans in anatomical representation, sample size, and stratigraphic density. As a result of this explosive growth of new information, borophagine systematics is now in need of a complete rethinking at a level that could not have been attempted by previous studies. A detailed study of borophagine phylogenetic systematics is presented here, publishing for the first time the entire Frick Collection. A total of 66 species of borophagines, including 18 new species, ranging from Orellan through Blancan ages, are presently recognized. A phylogenetic analysis of these species is performed using cladistic methods, with Hesperocyoninae, an archaic group of canids, as an outgroup. At its base, the Borophaginae has a sister relationship with the subfamily Caninae, which includes all living canids and their most recent fossil relatives. The Borophaginae-Caninae clade is in turn derived from the subfamily Hesperocyoninae. Apart from some transitional forms, most of the Borophaginae can be organized in four major clades (all erected as new tribes or subtribes): Phlaocyonini, Cynarctina, Aelurodontina, and Borophagina. The Borophaginae begins with a group of small fox-sized genera, such as Archaeocyon, Oxetocyon, Otarocyon, and Rhizocyon, in the Orellan through early Arikareean. Relationships among these genera are difficult to resolve due to their primitiveness. Slightly more derived, but still near the base of the Borophaginae, is the Phlaocyonini, a hypocarnivorous clade of the Arikareean and Hemingfordian that includes Cynarctoides and Phlaocyon. These two genera represent divergent approaches toward hypocarnivory. Species of Cynarctoides trend toward selenodonty and remain small in size, whereas species of Phlaocyon specialize toward bunodont dentitions but of increasing size, with an unusual trend toward hypercarnivory by two terminal species in the clade. Four transitional taxa (species of Cormocyon and Desmocyon) occupy intermediate positions between the Phlaocyonini and Cynarctina, and represent a gradual size increase toward medium-size individuals. The subtribe Cynarctina, the second hypocarnivorous clade, includes Paracynarctus and Cynarctus in the Hemingfordian through Clarendonian, and represents a larger size group than the Phlaocyonini, although there is a tendency toward size reduction among advanced species of Cynarctus. The cynarctines feature the most bunodont dentition known among canids. The next series of transitional taxa (Metatomarctus, Euoplocyon, Psalidocyon, Microtomarctus, Protomarctus, and Tephrocyon) are of medium size and occupy a pectinated sequence that contains a rather diverse set of dental morphology. These include the most hypercarnivorous borophagine Euoplocyon, the peculiarly trenchant Psalidocyon, and the dwarf lineage Microtomarctus. The next clade, Aelurodontina, is the first major hypercarnivorous group and is represented by Tomarctus and Aelurodon in the Barstovian and Clarendonian. The aelurodontines evolve around a more consistent theme of increasingly more hypercarnivorous dentitions with strong premolars, forming a rather linear series from Tomarctus to various species of Aelurodon. The terminal clade Borophagina, sister to the Aelurodontina, begins with the mostly mesocarnivorous Paratomarctus and Carpocyon in the late Barstovian through late Hemphillian. The terminal species of Carpocyon, C. limosus, shows some hypocarnivorous adaptations. Protepicyon in the Barstovian initiates the hypercarnivorous trend in the terminal clade. Epicyon, the largest known canid, is the dominant predator in the Clarendonian and Hemphillian. Finally, an enlarged concept of Borophagus consists of a series of pectinated species terminated by B. diversidens in the late Blancan. Epicyon and Borophagus are the most highly evolved in their capacity to crush bones. Phylogenetic reconstruction was greatly aided by the high quality of fossil records and the large number of transitional forms. The latter ensures a morphological continuity that facilitates the identification of homoplasies that otherwise could easily be mistaken as synapomorphies. Confidence in the phylogeny is further enhanced by a high congruence between the cladistic rank and the stratigraphic sequence. The temporal and morphological continuity in many borophagine lineages also permits further postulation about their evolutionary processes, such as cladogenetic and anagenetic events. Our considerably enlarged concept of the Borophaginae indicates a much broader trophic diversity than has previously been envisioned. In addition to the commonly recognized hyenalike forms, members of the Borophaginae acquired a wider spectrum of morphologies that surpassed either the hesperocyonine or canine canids. The Borophaginae played broad ecological roles that are performed by at least three living carnivoran families, Canidae, Hyaenidae, and Procyonidae"--P. 9-10

LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the LumiThera Valeda Light Delivery System.

PURPOSE The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) AMD using the LumiThera Valeda® Light Delivery System. METHODS LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were treated with multiwavelength PBM (590, 660 and 850 nm) or Sham treatment delivered 9 treatments over 3-5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report. RESULTS A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy BCVA endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 - -0.1, p = 0.02)(PBM alone: 5.4 letters (SE 0.96), CI: 3.5 - 7.3, p < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7 - 5.2, p < 0.0001). The PBM group showed a significant decrease in new onset GA (p = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed. CONCLUSIONS LIGHTSITE III provides a prospective, randomized controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM

North American fossil Caninae.

218 p. : ill. ; 26 cm. "Issued September 3, 2009." Includes bibliographical references (p. 184-193).The canid subfamily Caninae includes all the living canids and their most recent fossil relatives. Their sister taxon is the Borophaginae with which they share an important modification of the lower carnassial, namely the presence of a bicuspid talonid, which gives this tooth an additional function in mastication. Contributing to this function is the enlargement of the posterolingual cingulum of M1 and development of a hypocone. The Caninae diverged from the Borophaginae in the narrowing and elongation of the premolars separated by diastemata and placed in a shallow ramus and narrow muzzle. These latter features allow the Caninae to be recognized in the fossil record as early as the beginning of the Oligocene ‪(‬34 Ma‪)‬ and constitute evidence that they represent a monophyletic group. In striking contrast to the history of the Borophaginae, the Caninae remain confined to a closely similar group of fox-sized species ‪(‬Leptocyon spp.‪)‬ throughout the Oligocene and showing very limited cladogenesis into the end of the medial Miocene ‪(‬12 Ma‪)‬, a span that saw marked adaptive divergence in the Borophaginae and the origin of all its major clades. By 12 Ma ‪(‬beginning of the Clarendonian Land Mammal age‪)‬ few fox-sized borophagines remained and most of those held hypocarnivorus adaptations. At that point the Vulpini appear both as mesocarnivores ‪(‬Vulpes spp.‪)‬ and hypocarnivores ‪(‬Metalopex spp.‪)‬ reproducing, on a much smaller scale, the range of adaptations shown in the initial radiation of the Borophaginae. By the end of the Clarendonian ‪(‬9 Ma‪)‬ the first members of the tribe Canini appear. Initially this group was represented by the genus Eucyon, largely by a single widespread North American species E. davisi. Our cladistic analysis predicts that the roots of the South American clade subtribe Cerdocyonina, sister taxon to E. davisi and Canis species ‪(‬together, subtribe Canina‪)‬, must also have been present, but taxa representing this group do not appear in the North America record until the earliest Pliocene ‪(‬latest Hemphillian, 5 Ma‪)‬. Species of three genera ‪(‬Cerdocyon, Chrysocyon, and possibly Theriodictis‪)‬, now confined to South America, appear in the fossil record of the southern United States and northern Mexico prior to and just after the opening of the Panamanian Isthmus ‪(‬ca. 3 Ma‪)‬, indicating that important cladogenesis within the South American clade took place in North America. Species of Eucyon make their appearance in the Old World in the late Miocene, and E. davisi has a Pliocene record in Asia. Species of this genus undergo a modest adaptive radiation in Eurasia during the Pliocene. In the late Miocene and early Pliocene two species of Canis appear in North America ‪(‬C. ferox and C. lepophagus‪)‬, representing the initial cladogenesis within the genus. These animals are all coyote-sized and represent a broadening of body size range within a mesocarnivorous dental adaptation. Toward the end of the Pliocene and into the Pleistocene in North America a curious and rare group of jackal-like species ‪(‬C. tho¨oides, C. feneus, and C. cedazoensis‪)‬ seem to form an endemic clade arising near C. lepophagus. These taxa are dentally similar to jackals, especially C. aureus, but share no synapomorphies with them. The early cladogenesis of Canis in the Pliocene of North America produced a somewhat larger form, C. edwardii, that appears in the late Blancan at ca. 3 Ma. It also seems to have a sister relationship with C. lepophagus and with the coyote C. latrans, which appears much later in the record ‪(‬late Irvingtonian‪)‬ and quickly becomes distributed across the United States. The golden jackal ‪(‬C. aureus‪)‬ shares synapomorphies with the coyote and C. edwardii but does not appear in the fossil record until the early Pleistocene of North Africa. Canis edwardii is extinct by the end of the Irvingtonian. Large wolflike species of Canis seem to be the products of evolution in Eurasia. They appear early in the North American record as immigrants of the crown group of Canis that augment the essentially stem group native species of the New World. The first of these is Canis armbrusteri, which appears early in the Irvingtonian, initially in the Southwest but later in the eastern United States where it survived into the early Rancholabrean of Florida. This is a large wolf, a sister taxon of C. lupus, whose appearance early in the Pleistocene predates the earliest midcontinent occurrence of C. lupus by nearly 1 m.y. In the New World C. armbrusteri gave rise to the native dire-wolf ‪(‬C. dirus‪)‬, as evidenced by intergrading morphologies of late Irvingtonian examples that show the transformation to the more hypercarnivorous giant form. The earliest evidence of C. dirus is in the midcontinent and it appears to have displaced C. armbrusteri into the eastern part of the continent while it expanded westward and particularly southward into South America during the late Pleistocene. Canis lupus itself does not appear in midlatitude North America until the late Rancholabrean ‪(‬0.1 Ma, last glacial cycle‪)‬, although it was a resident of Arctic North America since the mid-Pleistocene ‪(‬ca. 0.8 Ma‪)‬. North America has a limited record of canine diversity during the Pleistocene. Most clades of vulpines and canines that reached the Old World during that span underwent significant cladogenesis so that the canid fauna of Eurasia was always more diverse than that of the New World. From time to time waifs from the Old World centers of origin wandered south into midcontinent North America to briefly enrich the fossil record: Xenocyon spp. in the late Irvingtonian; Cuon alpinus and Canis lupus in the late Rancholabrean, along with the living fox species Vulpes vulpes ‪(‬late Rancholabrean‪)‬ and perhaps the swift-fox earlier in the Pleistocene. The center of evolution of the Caninae thus shifted to Eurasia and to South America when avenues of dispersal to those continents were available at the end of the Cenozoic. Because of the diversity of Old World forms that became resident in North America, our analysis of the New World fauna has been expanded to include relevant Old World taxa and to present a broader phylogenetic reconstruction than could be offered only on the basis of strictly New World evidence. This expanded view brings in a greater diversity of morphology, which allows us to better separate homoplasy from true homology. We have considered only Old World taxa that are represented by the most complete material so that missing data are kept to a minimum in our analysis. This still affords sufficient taxa so that the major structure of the phylogeny of Canis can be discerned. Our cladistic analysis found two robustly recognized crown clades within Canis: the mesocarnivorous lupus clade, and the hypercarnivorous Xenocyon clade. The first contains the wolf, C. lupus, and its sister taxon C. armbrusteri + C. dirus, with the latter showing some dental features related to hypercarnivory as an autapomorphy. The Chinese late Pliocene wolf C. chihliensis appears to be a stem group in the Lupus clade and may be closely allied to C. armbrusteri. The Xenocyon clade is also Eurasian in origin and is marked by character reversals to states primitive within Canis. Its earliest record is in the medial Pliocene of eastern Asia ‪(‬Xenocyon dubius‪)‬, after which it dispersed to western Eurasia in the early Pleistocene ‪(‬X. lycaonoides‪)‬. In the Pleistocene Xenocyon achieved a Holarctic distribution including midlatitide North America ‪(‬X. texanus and X. lycaonoides‪)‬. During this episode of expansion the sister taxa Cuon and Lycaon arose in Eurasia and Africa, respectively, most likely from isolated Xenocyon populations. In the latest Pleistocene Cuon alpinus expanded its range into the middle latitudes of the New World. A number of Pliocene and Pleistocene wolf and coyote-sized Eurasian Canis species ‪(‬C. arnensis, C. etruscus, C. palmidens, C. mosbachensis, and C. variabilis‪)‬ were included in our cladistic analysis, but the relationships of those forms were difficult to resolve beyond their paraphyletic relationship to the crown clade

The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease

The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non‐alcoholic fatty liver disease (NAFLD). Eighteen adults were randomised to receive 20g/day of an inulin‐propionate ester (IPE), designed to deliver propionate to the colon, or an inulin‐control for 42‐days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between groups (P=0.082), however IHCL significantly increased within the inulin‐control group (20.9±2.9 to 26.8±3.9%; P=0.012; n=9), which was not observed within the IPE group (22.6±6.9 to 23.5±6.8%; P=0.635; n=9). The predominant SCFA from colonic fermentation of inulin is acetate, which in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate‐mediated increase in IHCL

ATDB: a uni-database platform for animal toxins

Venomous animals possess an arsenal of toxins for predation and defense. These toxins have great diversity in function and structure as well as evolution and therefore are of value in both basic and applied research. Recently, toxinomics researches using cDNA library sequencing and proteomics profiling have revealed a large number of new toxins. Although several previous groups have attempted to manage these data, most of them are restricted to certain taxonomic groups and/or lack effective systems for data query and access. In addition, the description of the function and the classification of toxins is rather inconsistent resulting in a barrier against exchanging and comparing the data. Here, we report the ATDB database and website which contains more than 3235 animal toxins from UniProtKB/Swiss-Prot and TrEMBL and related toxin databases as well as published literature. A new ontology (Toxin Ontology) was constructed to standardize the toxin annotations, which includes 745 distinct terms within four term spaces. Furthermore, more than 8423 TO terms have been manually assigned to 2132 toxins by trained biologists. Queries to the database can be conducted via a user-friendly web interface at http://protchem.hunnu.edu.cn/toxin

Downregulation of the central noradrenergic system by Toxoplasma gondii infection

Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically-infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro. The mechanism responsible for the NE suppression was found to be down-regulation of dopamine β-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine with down-regulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The down-regulation was sex-specific with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection as human cytomegalovirus (CMV) did not down-regulate DBH expression. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically-infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in noradrenergic neurons can elevate dopamine levels which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioural effects of infection and associations with mental illness