High-fat diet-induced obesity ablates gastric vagal afferent circadian rhythms

Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesityStephen J. Kentish, Andrew D. Vincent, David J. Kennaway, Gary A. Wittert, and Amanda J. Pag

Randomized controlled trial of intravenous antivenom versus placebo for latrodectism: the second redback antivenom evaluation (RAVE- II) study.

Objective: Latrodectism is the most important spider envenomation syndrome worldwide. There remains considerable controversy over antivenom treatment. We aimed to investigate whether antivenom resulted in resolution of pain and systemic effects in patients with latrodectism given standardized analgesia. Methods: In a multicentre randomized placebo-controlled trial of redback spider antivenom for latrodectism, 224 patients (>7yr) with a redback spider-bite and severe pain with or without systemic effects were randomized to receive normal saline (placebo) or antivenom, after receiving standardized analgesia. The primary outcome was a clinically significant reduction in pain 2 hours after trial medication compared to baseline. A second primary outcome for the subgroup with systemic features of envenomation was resolution of systemic features at 2 hours. Secondary outcomes were improved pain at 4 and 24 hours, resolution of systemic features at 4 hours, administration of opioid analgesics or unblinded antivenom after 2 hours and adverse reactions. Results: Two hours after treatment, 26/112 patients (23%) from the placebo arm had a clinically significant improvement in pain versus 38/112 (34%) from the antivenom arm (difference in favor of antivenom 10.7%;95%CI:−1.1% to +22.6%;p=0.10). Systemic 2 effects resolved after two hours in 9/41 patients (22%) in the placebo arm and 9/35 (26%) in the antivenom arm (difference 3.8%;95%CI:−15% to +23%;p=0.79). There was no significant difference in any secondary outcome between antivenom and placebo. Acute systemic hypersensitivity reactions occurred in 4/112 (3.6%) patients given antivenom. Conclusions: The addition of antivenom to standardized analgesia in patients with latrodectism, did not significantly improve pain or systemic effects.NHMRC 54522

Time-restricted feeding prevents ablation of diurnal rhythms in gastric vagal afferent mechanosensitivity observed in high-fat diet-induced obese mice

Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food related stimuli allowing time of day specific satiety signalling. This diurnal rhythmicity is ablated in high fat diet (HFD)-induced obesity. Time restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF.Eight-week old male C57BL/6 mice (N=256) were fed a standard laboratory diet (SLD) or HFD for 12wks. After 4wks diet acclimatisation the mice were fed either ad libitum or only during the light (zeitgeber (ZT)0-12) or dark phase (ZT12-24) for 8wks. A subgroup of mice from all conditions (N=8/condition) were placed in metabolic cages. After 12wks, ex vivo GVA recordings were taken at 3h intervals starting at ZT0.HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice but decreased weight gain in the HFD mice irrespective of the TRF period. In SLD mice diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity was dampened. Loss of diurnal rhythmicity in HFD-mice was abrogated by TRF.In conclusion, diurnal rhythmicity in GVA responses to food related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity.SIGNIFICANCE STATEMENTDiurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behaviour, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high fat diet-induced (HFD) obese mice and more importantly prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity.Stephen J. Kentish, George Hatzinikolas, Hui Li, Claudine L. Frisby, Gary A. Wittert and Amanda J. Pag

Ground-state properties of deformed proton emitters in the relativistic Hartree-Bogoliubov model

The Relativistic Hartree Bogoliubov (RHB) model is applied in the description of ground-state properties of proton-rich odd-Z nuclei in the region $53 \leq Z \leq 69$. The NL3 effective interaction is used in the mean-field Lagrangian, and pairing correlations are described by the pairing part of the finite range Gogny interaction D1S. The model predicts the location of the proton drip-line, the ground-state quadrupole deformations and one-proton separation energies at and beyond the drip-line, the deformed single-particle orbitals occupied by the odd valence proton, and the corresponding spectroscopic factors. The results of fully self-consistent RHB calculations are compared with available experimental data, and with predictions of the macroscopic-microscopic mass model.Comment: 39 pages, Latex, 6 e.p.s figures, Nucl. Phys. A in prin

Effective Functional Form of Regge Trajectories

We present theoretical arguments and strong phenomenological evidence that hadronic Regge trajectories are essentially nonlinear and can be well approximated, for phenomenological purposes, by a specific square-root form.Comment: 29 pages, LaTeX. Published versio

Resolutions of C^n/Z_n Orbifolds, their U(1) Bundles, and Applications to String Model Building

We describe blowups of C^n/Z_n orbifolds as complex line bundles over CP^{n-1}. We construct some gauge bundles on these resolutions. Apart from the standard embedding, we describe U(1) bundles and an SU(n-1) bundle. Both blowups and their gauge bundles are given explicitly. We investigate ten dimensional SO(32) super Yang-Mills theory coupled to supergravity on these backgrounds. The integrated Bianchi identity implies that there are only a finite number of U(1) bundle models. We describe how the orbifold gauge shift vector can be read off from the gauge background. In this way we can assert that in the blow down limit these models correspond to heterotic C^2/Z_2 and C^3/Z_3 orbifold models. (Only the Z_3 model with unbroken gauge group SO(32) cannot be reconstructed in blowup without torsion.) This is confirmed by computing the charged chiral spectra on the resolutions. The construction of these blowup models implies that the mismatch between type-I and heterotic models on T^6/Z_3 does not signal a complication of S-duality, but rather a problem of type-I model building itself: The standard type-I orbifold model building only allows for a single model on this orbifold, while the blowup models give five different models in blow down.Comment: 1+27 pages LaTeX, 2 figures, some typos correcte

Parity Mixed Doublets in A = 36 Nuclei

The $\gamma$-circular polarizations ($P_{\gamma}$) and asymmetries ($A_{\gamma}$) of the parity forbidden M1 + E2 $\gamma$-decays: $^{36}Cl^{\ast} (J^{\pi} = 2^{-}; T = 1; E_{x} = 1.95$ MeV) $\rightarrow$ $^{36}Cl (J^{\pi} = 2^{+}; T = 1; g.s.)$ and $^{36}Ar^{\ast} (J^{\pi} = 2^{-}; T = 0; E_{x} = 4.97$ MeV) $\rightarrow$ $^{36}Ar^{\ast} (J^{\pi} = 2^{+}; T = 0; E_{x} = 1.97$ MeV) are investigated theoretically. We use the recently proposed Warburton-Becker-Brown shell-model interaction. For the weak forces we discuss comparatively different weak interaction models based on different assumptions for evaluating the weak meson-hadron coupling constants. The results determine a range of $P_{\gamma}$ values from which we find the most probable values: $P_{\gamma}$ = $1.1 \cdot 10^{-4}$ for $^{36}Cl$ and $P_{\gamma}$ = $3.5 \cdot 10^{-4}$ for $^{36}Ar$.Comment: RevTeX, 17 pages; to appear in Phys. Rev.

Pseudospin symmetry as a relativistic dynamical symmetry in the nucleus

Pseudospin symmetry in nuclei is investigated by solving the Dirac equation with Woods-Saxon scalar and vector radial potentials, and studying the correlation of the energy splittings of pseudospin partners with the nuclear potential parameters. The pseudospin interaction is related to a pseudospin-orbit term that arises in a Schroedinger-like equation for the lower component of the Dirac spinor. We show that the contribution from this term to the energy splittings of pseudospin partners is large. The near pseudospin degeneracy results from a significant cancelation among the different terms in that equation, manifesting the dynamical character of this symmetry in the nucleus. We analyze the isospin dependence of the pseudospin symmetry and find that its dynamical character is behind the different pseudospin splittings observed in neutron and proton spectra of nuclei.Comment: 13 pages, 9 figures, uses REVTeX4 macro

Deletion of Rptor in preosteoblasts reveals a role for the mammalian target of rapamycin complex 1 (mTORC1) complex in dietary-induced changes to bone mass and glucose homeostasis in female mice

The mammalian target of rapamycin complex 1 (mTORC1) complex is the major nutrient sensor in mammalian cells that responds to amino acids, energy levels, growth factors, and hormones, such as insulin, to control anabolic and catabolic processes. We have recently shown that suppression of the mTORC1 complex in bone-forming osteoblasts (OBs) improved glucose handling in male mice fed a normal or obesogenic diet. Mechanistically, this occurs, at least in part, by increasing OB insulin sensitivity leading to upregula- tion of glucose uptake and glycolysis. Given previously reported sex-dependent differences observed upon antagonism of mTORC1 signaling, we investigated the metabolic and skeletal effects of genetic inactivation of preosteoblastic-mTORC1 in female mice. Eight- week-old control diet (CD)-fed Rptor ob −/− mice had a low bone mass with a significant reduction in trabecular bone volume and trabecular number, reduced cortical bone thickness, and increased marrow adiposity. Despite no changes in body composition, CD-fed Rptor ob −/− mice exhibited significant lower fasting insulin and glucose levels and increased insulin sensitivity. Upon high-fat diet (HFD) feeding, Rptor ob −/− mice were resistant to a diet-induced increase in whole-body and total fat mass and protected from the development of diet-induced insulin resistance. Notably, although 12 weeks of HFD increased marrow adiposity, with minimal changes in both trabecular and cortical bone in the female control mice, marrow adiposity was significantly reduced in HFD-fed Rptor ob −/− compared to both HFD-fed control and CD-fed Rptor ob −/− mice. Collectively, our results demonstrate that mTORC1 func- tion in preosteoblasts is crucial for skeletal development and skeletal regulation of glucose homeostasis in both male and female mice. Importantly, loss of mTORC1 function in OBs results in metabolic and physiological adaptations that mirror a caloric restriction phenotype (under CD) and protects against HFD-induced obesity, associated insulin resistance, and marrow adiposity expansion. These results highlight the critical contribution of the skeleton in the regulation of whole-body energy homeostasisPawanrat Tangseefa, Sally K. Martin, Agnieszka Arthur, Vasilios Panagopoulos, Amanda J. Page, Gary A. Wittert ... et al