FSH, bone, belly and brain.

The pituitary gland orchestrates multiple endocrine organs by secreting tropic hormones, and therefore plays a significant role in a myriad of physiological processes, including skeletal modeling and remodeling, fat and glucose metabolism, and cognition. Expression of receptors for each pituitary hormone and the hormone itself in the skeleton, fat, immune cells, and the brain suggest that their role is much broader than the traditionally attributed functions. FSH, believed solely to regulate gonadal function is also involved in fat and bone metabolism, as well as in cognition. Our emerging understanding of nonreproductive functions of FSH, thus, opens potential therapeutic opportunities to address detrimental health consequences during and after menopause, namely, osteoporosis, obesity, and dementia. In this review, we outline current understanding of the cross-talk between the pituitary, bone, adipose tissue, and brain through FSH. Preclinical evidence from genetic and pharmacologic interventions in rodent models, and human data from population-based observations, genetic studies, and a small number of interventional studies provide compelling evidence for independent functions of FSH in bone loss, fat gain, and congnitive impairment.

Gene-Dose-Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer's Mice.

Alzheimer's disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampal Fshr to drive AD-like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/- and 3xTg;Fshr-/- mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham-operated 3xTg;Fshr-/- mice were implanted with 17ß-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects of Fshr depletion. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice- -thus documenting a clear gene-dose-dependent prevention of hippocampal-dependent spatial memory impairment. At 5 and 10 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the acquasition and/or retrieval phases, suggesting that Fshr deletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10-month-old 3xTg;Fshr-/- mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized 3xTg;Fshr-/- mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene-dose-dependent reduction mainly in the amyloid ß40 isoform in whole brain extracts. Finally, serum FSH levels < 8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of cognitive decline in postmenopausal women.

Absent LH signaling rescues the anxiety phenotype in aging female mice.

Clinical studies and experimental data together support a role for pituitary gonadotropins, including luteinizing hormone (LH), otherwise considered solely as fertility hormones, in age-related cognitive decline. Furthermore, rising levels of LH in post-menopausal women have been implicated in the high prevalence of mood disorders. This study was designed to examine the effect of deficient LH signaling on both cognitive and emotional behavior in 12-month-old Lhcgr-/- mice. For this, we established and validated a battery of five tests, including Dark-Light Box (DLB), Y-Maze Spontaneous Alternation, Novel Object Recognition (NOR), and contextual and cued Fear Conditioning (FCT) tests. We found that 12-month-old female wild type mice display a prominent anxiety phenotype on DLB and FCT. This phenotype was not seen in 12-month-old female Lhcgr-/- mice, indicating full phenotypic rescue. Furthermore, there was no effect of LHCGR depletion on recognition memory or working spatial memory on NOR and Y-maze testing, respectively, in 12-month-old mice, notwithstanding the absence of a basal phenotype in wild type littermates. The latter data do not exclude an effect of LH on cognition documented in previous studies. Finally, 12-month-old male mice and 3-month-old male and female mice did not consistently display deficits on any test. The data collectively document, for the first time, that loss of LH signaling reverses age-related emotional disturbances, a prelude to future targeted therapies that block LH action.

Emerging roles of brain tanycytes in regulating blood-hypothalamus barrier plasticity and energy homeostasis.

Seasonal changes in food intake and adiposity in many animal species are triggered by changes in the photoperiod. These latter changes are faithfully transduced into a biochemical signal by melatonin secreted by the pineal gland. Seasonal variations, encoded by melatonin, are integrated by third ventricular tanycytes of the mediobasal hypothalamus through the detection of the thyroid-stimulating hormone (TSH) released from the pars tuberalis. The mediobasal hypothalamus is a critical brain region that maintains energy homeostasis by acting as an interface between the neural networks of the central nervous system and the periphery to control metabolic functions, including ingestive behavior, energy homeostasis, and reproduction. Among the cells involved in the regulation of energy balance and the blood-hypothalamus barrier (BHB) plasticity are tanycytes. Increasing evidence suggests that anterior pituitary hormones, specifically TSH, traditionally considered to have unitary functions in targeting single endocrine sites, display actions on multiple somatic tissues and central neurons. Notably, modulation of tanycytic TSH receptors seems critical for BHB plasticity in relation to energy homeostasis, but this needs to be proven.

The gut microbiota composition affects dietary polyphenols-mediated cognitive resilience in mice by modulating the bioavailability of phenolic acids.

Dietary polyphenols promote memory in models of sleep deprivation (SD), stress, and neurodegeneration. The biological properties of dietary polyphenols greatly depend upon the bioavailability of their phenolic metabolites derivatives, which are modulated by gut microbiota. We recently demonstrated that supplementation with grape-derived bioactive dietary polyphenol preparation (BDPP) improves SD-induced cognitive impairment. This study examined the role of the gut microbiota in the ability of BDPP to prevent memory impairment in response to SD. C57BL6/J mice, treated with antibiotics mix (ABX) or BDPP or both, were sleep-deprived at the end of a fear conditioning training session and fear memory was assessed the next day. Gut microbiota composition was analyzed in fecal samples and BDPP-driven phenolic acid metabolites extraction was measured in plasma. We report that the beneficial effect of BDPP on memory in SD is attenuated by ABX-induced dysbiosis. We identified specific communities of fecal microbiota that are associated with the bioavailability of BDPP-derived phenolic acids, which in turn, are associated with memory promotion. These results suggest the gut microbiota composition significantly affects the bioavailability of phenolic acids that drive the dietary polyphenols' cognitive resilience property. Our findings provide a preclinical model with which to test the causal association of gut microbiota-polyphenols, with the ultimate goal of potential developing dietary polyphenols for the prevention/treatment of cognitive impairment.

Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity.

The intestinal microbiota actively converts dietary flavanols into phenolic acids, some of which are bioavailable in vivo and may promote resilience to select neurological disorders by interfering with key pathologic mechanisms. Since every person harbors a unique set of gut bacteria, we investigated the influence of the gut microbiota's interpersonal heterogeneity on the production and bioavailability of flavonoid metabolites that may interfere with the misfolding of alpha (α)-synuclein, a process that plays a central role in Parkinson's disease and other α-synucleinopathies. We generated two experimental groups of humanized gnotobiotic mice with compositionally diverse gut bacteria and orally treated the mice with a flavanol-rich preparation (FRP). The two gnotobiotic mouse groups exhibited distinct differences in the generation and bioavailability of FRP-derived microbial phenolic acid metabolites that have bioactivity towards interfering with α-synuclein misfolding or inflammation. We also demonstrated that these bioactive phenolic acids are effective in modulating the development and progression of motor dysfunction in a Drosophila model of α-synucleinopathy. Lastly, through in vitro bacterial fermentation studies, we identified select bacteria that are capable of supporting the generation of these bioavailable and bioactive phenolic acids. Outcomes from our studies provide a better understanding of how interpersonal heterogeneity in the gut microbiota differentially modulates the efficacy of dietary flavanols to protect against select pathologic mechanisms. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies and other neurological disorders involving protein misfolding and/or inflammation.

Dietary polyphenols enhance optogenetic recall of fear memory in hippocampal dentate gyrus granule neuron subpopulations.

Grape-derived polyphenols have been investigated for their role in promoting memory in model systems of stress, but little is known about select subpopulations of neurons that are influenced by polyphenols to improve memory performance. Granule neurons in the hippocampal dentate gyrus are vulnerable to stressors that impair contextual memory function and can be influenced by dietary polyphenols. We utilized a c-fos-tTA/TRE-ChR2 optogenetics model in which neurons activated during fear learning are labeled with ChR2-mCherry and can be optically reactivated in a different context to recapitulate the behavioral output of a related memory. Treatment with dietary polyphenols increased fear memory recall and ChR2-mCherry expression in dentate gyrus neurons, suggesting that dietary polyphenols promote recruitment of neurons to a fear memory engram. We show that dietary polyphenols promote memory function and offer a general method to map cellular subpopulations influenced by dietary polyphenols, in part through the mechanism of c-Fos expression enhancement.

Climatically driven changes in primary production propagate through trophic levels.

Climate and land-use change are the major drivers of global biodiversity loss. Their effects are particularly acute for wide-ranging consumers, but little is known about how these factors interact to affect the abundance of large carnivores and their herbivore prey. We analyzed population densities of a primary and secondary consumer (mule deer, Odocoileus hemionus, and mountain lion, Puma concolor) across a climatic gradient in western North America by combining satellite-based maps of plant productivity with estimates of animal abundance and foraging area derived from Global Positioning Systems telemetry data (GPS). Mule deer density exhibited a positive, linear relationship with plant productivity (r2  = 0.58), varying by a factor of 18 across the climate-vegetation gradient (range: 38-697 individuals/100 km2 ). Mountain lion home range size decreased in response to increasing primary productivity and consequent changes in the abundance of their herbivore prey (range: 20-450 km2 ). This pattern resulted in a strong, positive association between plant productivity and mountain lion density (r2  = 0.67). Despite varying densities, the ratio of prey to predator remained constant across the climatic gradient (mean ± SE = 363 ± 29 mule deer/mountain lion), suggesting that the determinacy of the effect of primary productivity on consumer density was conserved across trophic levels. As droughts and longer term climate changes reduce the suitability of marginal habitats, consumer home ranges will expand in order for individuals to meet basic nutritional requirements. These changes portend decreases in the abundance of large-bodied, wide-ranging wildlife through climatically driven reductions in carrying capacity, as well as increased human-wildlife interactions stemming from anthropogenic land use and habitat fragmentation.

Epigenetic modifications by polyphenolic compounds alter gene expression in the hippocampus.

In this study, we developed an experimental protocol leveraging enhanced reduced representation bisulphite sequencing to investigate methylation and gene expression patterns in the hippocampus in response to polyphenolic compounds. We report that the administration of a standardized bioavailable polyphenolic preparation (BDPP) differentially influences methylated cytosine patterns in introns, UTR and exons in hippocampal genes. We subsequently established that dietary BDPP-mediated changes in methylation influenced the transcriptional pattern of select genes that are involved in synaptic plasticity. In addition, we showed dietary BDPP mediated changes in the transcriptional pattern of genes associated with epigenetic modifications, including members of the DNA methyl transferase family (DNMTs) and the Ten-eleven translocation methylcytosine dioxygenases family (TETs). We then identified the specific brain bioavailable polyphenols effective in regulating the transcription of DNMTs, TETs and a subset of differentially methylated synaptic plasticity-associated genes. The study implicates the regulation of gene expression in the hippocampus by epigenetic mechanisms as a novel therapeutic target for dietary polyphenols.

Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation.

Previous evidence has suggested that dietary supplementation with a bioactive dietary polyphenol preparation (BDPP) rescues impairment of hippocampus-dependent memory in a mouse model of sleep deprivation (SD). In the current study, we extend our previous evidence and demonstrate that a mechanism by which dietary BDPP protects against SD-mediated cognitive impairment is via mechanisms that involve phosphorylation of the mammalian target of rapamycin complex 1 and its direct downstream targets, including the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase ß-1 (p70S6K). In additional mechanistic studies in vitro, we identified the brain bioavailable phenolic metabolites derived from the metabolism of dietary BDPP that are responsible for the attenuation of SD-mediated memory impairments. On the basis of high-throughput bioavailability studies of brain bioavailable metabolites after dietary BDPP treatment, we found that select polyphenol metabolites [ e.g., cyanidin-3'- O-glucoside and 3-(3'-hydroxyphenyl) propionic acid] were able to rescue mTOR and p70S6K phosphorylation in primary cortico-hippocampal neuronal cultures, as well as rescue 4E-BP1 phosphorylation in response to treatment with 4EGI-1, a specific inhibitor of eIF4E-eIF4G interaction. Our findings reveal a previously unknown role for dietary polyphenols in the rescue of SD-mediated memory impairments via mechanisms involving the promotion of protein translation.-Frolinger, T., Smith, C., Cobo, C. F., Sims, S., Brathwaite, J., de Boer, S., Huang, J., Pasinetti, G. M. Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation.

Speyeria (Lepidoptera: Nymphalidae) Conservation.

Speyeria (Nymphalidae) are a conspicuous component of the North American butterfly fauna. There are approximately 16 species and >100 associated subspecies (or geographical variants). Speyeria are univoltine, occupy a wide range of habitats, overwinter as first instar larvae, and feed only on native violets. Speyeria species have become a model group for studies of evolution, speciation, and conservation. Several species and subspecies are threatened or endangered. The reasons for this vary with the taxa involved, but always involve the degradation or loss of quality habitat for larvae and adults. The impacts of climate change must be considered among the causes for habitat degradation and in the establishment of conservation measures. In addition to increasing the available habitat, conservation efforts should consider maintaining habitat in a seral "disturbed" successional stage that selectively favors the growth of violets and preferred adult nectar sources. A major future challenge will be determining the most effective allocation of conservation resources to those species and subspecies that have the greatest potential to respond favorably to these efforts.

Topical and vapor toxicity of saturated fatty acids to the German cockroach (Dictyoptera: Blattellidae).

Topical and fumigant toxicity of saturated aliphatic fatty acids with chain lengths of C1 through C14 were determined against the German cockroach, Blattella germanica (L.). In the C1 to C11 series, topical toxicity (LD50 in milligram per adult male) ranged from 0.145 (C1) to 0.322 mg (C2). Toxicity declined dramatically with C12 and C14 acids whose LD50 values could not be calculated. The relative fumigation toxicity (LC50 in microliter per liter) of C1 through C5 acids was positively correlated with topical toxicity with values ranging from 6.159 (C3) to 12.302 microl/liter (C2). Fumigant toxicity decreased sharply with C6 (LC50 = 37.691 microl/liter) and there was no mortality of cockroaches exposed to vapors from C7 to C14 acids. The low fumigant toxicity of the C6 to C11 acids was correlated with their relatively low vapor pressure, but differences in diffusion of the vapors into the spiracles and subsequent passage to the target sites may have also been involved.

Efficacy of commercial baits and new active ingredients against firebrats and silverfish (Zygentoma: Lepismatidae).

Commercial baits containing boric acid, hydramethynon, and indoxacarb were tested against the firebrat, Thermobia domestica (Packard), and silverfish, Lepisma saccharina L. (both Zygentoma: Lepismatidae), under laboratory conditions. Three boric acid baits were consumed in significantly smaller amounts than untreated control food and did not effectively control either species. Baits containing hydramethylnon and indoxacarb were consumed in greater amounts than boric acid baits, but were relatively ineffective, with LT50 values >9 d. Presence or absence of competitive untreated food did not consistently affect bait efficacy. A ground oat matrix was used to evaluate the potential effectiveness of abamectin, chlorfenapyr, dinotefuran, fipronil, hydramethylnon, metaflumizone, and novaluron baits. The most effective compound was chlorfenapyr. At 0.05 and 0.20% (wt:wt) rates, chlorfenapyr baits produced LT50 values, for both species, ranging from 2 to 4 d. All other compounds had LT50 values >7 d.

OTA highlight paper predicting future displacement of nonoperatively managed lateral compression sacral fractures: can it be done?

PURPOSE: This study was designed to assess the rate of displacement in nondisplaced sacral fractures and to determine if certain fracture patterns are more prone to future displacement. DESIGN: Retrospective. SETTING: Two Level I trauma centers. PATIENTS: Patients consisted of those sustaining a lateral compression pelvic fracture whose age was 17 years or older, had less than 5 mm of initial sacral displacement, were the result of a high-energy mechanism, and had radiographs documenting bony union. INTERVENTION: By protocol, patients meeting these criteria were mobilized and maintenance of alignment was documented by serial radiographs. RESULTS: All fractures were classified according to the Orthopaedic Trauma Association classification system, the Young and Burgess mechanistic classification system, and to the location of the sacral fracture as described by Denis. In addition, sacral fractures were classified as complete or incomplete. Additionally, the number and location of rami fractures were recorded. Of the initial 117 fractures, 23 were determined to displace and largely consisted of a single fracture pattern. Fractures consisting of a complete sacral fracture combined with bilateral rami fractures displaced at a rate of 68% (15 of 22). In contrast, incomplete sacral fractures with an ipsilateral rami injury had no displaced unions. CONCLUSION: Incomplete lateral compression sacral fractures that are associated with ipsilateral rami fractures can be treated nonoperatively and are unlikely to displace. In contrast, those with a complete sacral fracture and bilateral rami fractures displace at a significantly greater rate.

Topical toxicity of essential oils to the German cockroach (Dictyoptera: Blattellidae).

The toxicity of 12 essential oil components [carvacrol, 1,8-cineole, trans-cinnamaldehyde, citronellic acid, eugenol, geraniol, S-(-)-limonene, (-)-linalool, (-)-menthone, (+)-alpha-pinene, (-)-beta-pinene, and thymol] to adult male; adult female; gravid female; and large, medium, and small nymphs of the German cockroach, Blattella germanica (L.) (Dictyoptera: Blattellidae), was determined. Thymol was the most toxic essential oil component to adult males, gravid females, and medium nymphs, with LD50 values of 0.07, 0.12, and 0.06 mg per cockroach, respectively, trans-Cinnamaldehyde was the most toxic essential oil component to adult females, large nymphs, and small nymphs, with LD50 values of 0.19, 0.12, and 0.04 mg per cockroach, respectively. (+)-alpha-Pinene was the least toxic essential oil component to all stages of the German cockroach. The most frequently occurring susceptibility ranking for the stages was small nymphs > medium nymphs > adult males > large nymphs > gravid females > adult females. Adult females were the least susceptible to the essential oils, so they will be the determining factor when considering a rate for field application. Toxicity was positively correlated with essential oil component density and boiling point; however, there was no significant correlation between toxicity and lipophilicity. The effect of essential oil components on ootheca hatch was also investigated. S-(-)-limonene had the least effect on ootheca hatch, with 35.21 (mean) nymphs hatching per ootheca. (-)-menthone had the greatest effect on ootheca hatch with 20.89 nymphs hatching per ootheca The numbers of nymphs hatching from each ootheca generally declined as dose increased. No essential oil component completely prevented ootheca hatch suggesting that multiple treatments might be required in the field to prevent reinfestation.

Comparative toxicity and repellency of microencapsulated and other liquid insecticide formulations to the German cockroach (Dictyoptera: Blattellidae).

Responses of German cockroaches, Blattella germanica (L.) (Dictyoptera: Blattellidae), to microencapsulated (ME) formulations of six insecticides (bifenthrin, chlorpyrifos, cyfluthrin, deltamethrin, lambda-cyhalothrin, and permethrin) were compared with emulsifiable concentrates (EC) (chlorpyrifos, cyfluthrin, deltamethrin, and permethrin) or ready-to-use (RTU) formulations (bifenthin and lambda-cyhalothrin). Two rates were tested per comparison. Baseline toxicity (LT50 value) was determined by continuous exposure to residual deposits. Repellency, toxicity (LT50), and performance index (PI) values were determined using Ebeling choice boxes. Baseline toxicity of the permethrin formulations was similar, but all other active ingredients had significant toxicity differences at one or both formulation x dose comparisons. Baseline toxicity and repellency were negatively correlated. Choice box LT50 and the time to reach 50% of the maximum PI were positively correlated. The maximum PI was positively correlated (P < 0.06) with baseline LT50 and negatively correlated (P < 0.07) with repellency. Chlorpyrifos had the lowest repellency except for the EC at 0.25%. Bifenthrin ME and lambda-cyhalothrin ME had greater PI values than comparative RTU formulations. Cyfluthrin EC at 0.03% and deltamethrin ME at 0.01% had significantly lower PI values than comparison treatments. Permethrin PI value for the EC at 0.03% exceeded that for the ME, but at 0.05% the ME had a significantly greater PI. These data demonstrate the difficulty in making generalizations about the relative performance of ME compared with EC or RTU formulations. Variable results observed within, and between, formulations may be influenced by application rate, formulation type, other formulation components, and the toxicity-repellency of the active ingredient.

Linear alcohol ethoxylates: insecticidal and synergistic effects on German cockroaches (Blattodea: Blattellidae) and other insects.

Sixteen linear ethoxylated alcohol surfactants (AEOs) were studied to determine their contact insecticidal activity to adult German cockroaches, Blattella germanica (L.) (Blattodea: Blattellidae). Within groups of AEOs of equal carbon chain length, insecticidal activity, measured as LT50 values (in minutes) and 24-h mortality after treatment, was inversely related to the amount of ethoxylation. There was a highly significant negative relationship between the hydrophile-lipophile balance (HLB) value of the AEO and contact toxicity. The AEO with the lowest HLB value, Tomadol 23-1 (HLB = 3.7), produced the greatest 24-h cockroach mortality. The contact activity of Tomadol 23-1 was evaluated against a wide range of other insect species. Most species were killed within 24 h by direct exposure (1-4 microl of a 50% ethanol solution) to Tomadol 23-1 or by spray exposure to an aqueous solution. Tomadol 23-1, at a sublethal concentration, was tested in combination with representative members of the carbamate, nicotinoid, organophosphate, pyrethrum, pyrethroid, and pyrrole insecticide classes. Significant synergism was demonstrated in combinations of Tomadol 23-1 and chlorfenapyr, clothianidin, imidacloprid, thiamethoxam, and pyrethrum. Tomadol 23-1 significantly reduced the insecticidal activity of propoxur, suggesting antagonism. The insecticidal activity of Tomadol 23-1 was synergized by coapplication with a sublethal amount of piperonyl butoxide, indicating the involvement of cytochrome P450 microsomal monooxygenases in insect metabolism of AEO surfactants.