Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome.

BACKGROUND: The gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis, and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition. RESULTS: In this study, we integrated and interrogated multi-omics data from different organs with fecal 16S rRNA sequences and systemic metabolic phenotypic data using a Transkingdom Network Analysis. By incorporating cell type information from single-cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reduced levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo. CONCLUSIONS: Our findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes of diet-induced obesity and metabolic syndrome. TXN primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in white adipose tissue. Video Abstract.

Sequential Nature of (p,3p) Two-Proton Knockout from Neutron-Rich Nuclei.

Twenty-one two-proton knockout (p,3p) cross sections were measured from neutron-rich nuclei at ∼250 MeV/nucleon in inverse kinematics. The angular distribution of the three emitted protons was determined for the first time, demonstrating that the (p,3p) kinematics are consistent with two sequential proton-proton collisions within the projectile nucleus. Ratios of (p,3p) over (p,2p) inclusive cross sections follow the trend of other many-nucleon removal reactions, further reinforcing the sequential nature of (p,3p) in neutron-rich nuclei.

Metastable States of

Here we present new information on the shape evolution of the very neutron-rich ^{92,94}Se nuclei from an isomer-decay spectroscopy experiment at the Radioactive Isotope Beam Factory at RIKEN. High-resolution germanium detectors were used to identify delayed γ rays emitted following the decay of their isomers. New transitions are reported extending the previously known level schemes. The isomeric levels are interpreted as originating from high-K quasineutron states with an oblate deformation of ß∼0.25, with the high-K state in ^{94}Se being metastable and K hindered. Following this, ^{94}Se is the lowest-mass neutron-rich nucleus known to date with such a substantial K hindrance. Furthermore, it is the first observation of an oblate K isomer in a deformed nucleus. This opens up the possibility for a new region of K isomers at low Z and at oblate deformation, involving the same neutron orbitals as the prolate orbitals within the classic Z∼72 deformed hafnium region. From an interpretation of the level scheme guided by theoretical calculations, an oblate deformation is also suggested for the ^{94}Se_{60} ground-state band.

Prominence of Pairing in Inclusive (p,2p) and (p,pn) Cross Sections from Neutron-Rich Nuclei.

Fifty-five inclusive single nucleon-removal cross sections from medium mass neutron-rich nuclei impinging on a hydrogen target at ∼250 MeV/nucleon are measured at the RIKEN Radioactive Isotope Beam Factory. Systematically higher cross sections are found for proton removal from nuclei with an even number of protons as compared to odd-proton number projectiles for a given neutron separation energy. Neutron removal cross sections display no even-odd splitting, contrary to nuclear cascade model predictions. Both effects are understood through simple considerations of neutron separation energies and bound state level densities originating in pairing correlations in the daughter nuclei. These conclusions are supported by comparison with semimicroscopic model predictions, highlighting the enhanced role of low-lying level densities in nucleon-removal cross sections from loosely bound nuclei.

94 ß-Decay Half-Lives of Neutron-Rich _{55}Cs to _{67}Ho: Experimental Feedback and Evaluation of the r-Process Rare-Earth Peak Formation.

The ß-decay half-lives of 94 neutron-rich nuclei ^{144-151}Cs, ^{146-154}Ba, ^{148-156}La, ^{150-158}Ce, ^{153-160}Pr, ^{156-162}Nd, ^{159-163}Pm, ^{160-166}Sm, ^{161-168}Eu, ^{165-170}Gd, ^{166-172}Tb, ^{169-173}Dy, ^{172-175}Ho, and two isomeric states ^{174m}Er, ^{172m}Dy were measured at the Radioactive Isotope Beam Factory, providing a new experimental basis to test theoretical models. Strikingly large drops of ß-decay half-lives are observed at neutron-number N=97 for _{58}Ce, _{59}Pr, _{60}Nd, and _{62}Sm, and N=105 for _{63}Eu, _{64}Gd, _{65}Tb, and _{66}Dy. Features in the data mirror the interplay between pairing effects and microscopic structure. r-process network calculations performed for a range of mass models and astrophysical conditions show that the 57 half-lives measured for the first time play an important role in shaping the abundance pattern of rare-earth elements in the solar system.

Are There Signatures of Harmonic Oscillator Shells Far from Stability? First Spectroscopy of

The first measurement of the low-lying states of the neutron-rich ^{110}Zr and ^{112}Mo was performed via in-beam γ-ray spectroscopy after one proton removal on hydrogen at ∼200 MeV/nucleon. The 2_{1}^{+} excitation energies were found at 185(11) keV in ^{110}Zr, and 235(7) keV in ^{112}Mo, while the R_{42}=E(4_{1}^{+})/E(2_{1}^{+}) ratios are 3.1(2), close to the rigid rotor value, and 2.7(1), respectively. These results are compared to modern energy density functional based configuration mixing models using Gogny and Skyrme effective interactions. We conclude that first levels of ^{110}Zr exhibit a rotational behavior, in agreement with previous observations of lighter zirconium isotopes as well as with the most advanced Monte Carlo shell model predictions. The data, therefore, do not support a harmonic oscillator shell stabilization scenario at Z=40 and N=70. The present data also invalidate predictions for a tetrahedral ground state symmetry in ^{110}Zr.

Isospin Symmetry at High Spin Studied via Nucleon Knockout from Isomeric States.

One-neutron knockout reactions have been performed on a beam of radioactive ^{53}Co in a high-spin isomeric state. The analysis is shown to yield a highly selective population of high-spin states in an exotic nucleus with a significant cross section, and hence represents a technique that is applicable to the planned new generation of fragmentation-based radioactive beam facilities. Additionally, the relative cross sections among the excited states can be predicted to a high level of accuracy when reliable shell-model input is available. The work has resulted in a new level scheme, up to the 11^{+} band-termination state, of the proton-rich nucleus ^{52}Co (Z=27, N=25). This has in turn enabled a study of mirror energy differences in the A=52 odd-odd mirror nuclei, interpreted in terms of isospin-nonconserving (INC) forces in nuclei. The analysis demonstrates the importance of using a full set of J-dependent INC terms to explain the experimental observations.

Half-life systematics across the N=126 shell closure: role of first-forbidden transitions in the ß decay of heavy neutron-rich nuclei.

This Letter reports on a systematic study of ß-decay half-lives of neutron-rich nuclei around doubly magic (208)Pb. The lifetimes of the 126-neutron shell isotone (204)Pt and the neighboring (200-202)Ir, (203)Pt, (204)Au are presented together with other 19 half-lives measured during the "stopped beam" campaign of the rare isotope investigations at GSI collaboration. The results constrain the main nuclear theories used in calculations of r-process nucleosynthesis. Predictions based on a statistical macroscopic description of the first-forbidden ß strength reveal significant deviations for most of the nuclei with N<126. In contrast, theories including a fully microscopic treatment of allowed and first-forbidden transitions reproduce more satisfactorily the trend in the measured half-lives for the nuclei in this region, where the r-process pathway passes through during ß decay back to stability.

Mirror energy differences at large isospin studied through direct two-nucleon knockout.

The first spectroscopy of excited states in 52Ni (T(z)=-2) and 51Co (T(z)=-3/2) has been obtained using the highly selective two-neutron knockout reaction. Mirror energy differences between isobaric analogue states in these nuclei and their mirror partners are interpreted in terms of isospin nonconserving effects. A comparison between large-scale shell-model calculations and data provides the most compelling evidence to date that both electromagnetic and an additional isospin nonconserving interactions for J=2 couplings, of unknown origin, are required to obtain good agreement.

New isomers in the full seniority scheme of neutron-rich lead isotopes: the role of effective three-body forces.

The neutron-rich lead isotopes, up to (216)Pb, have been studied for the first time, exploiting the fragmentation of a primary uranium beam at the FRS-RISING setup at GSI. The observed isomeric states exhibit electromagnetic transition strengths which deviate from state-of-the-art shell-model calculations. It is shown that their complete description demands the introduction of effective three-body interactions and two-body transition operators in the conventional neutron valence space beyond (208)Pb.

Gamma-ray fast-timing coincidence measurements from the 18O+18O fusion-evaporation reaction using a mixed LaBr3-HPGe array.

We report on a gamma-ray coincidence analysis using a mixed array of hyperpure germanium and cerium-doped lanthanum tri-bromide (LaBr3:Ce) scintillation detectors to study nuclear electromagnetic transition rates in the pico-to-nanosecond time regime in 33,34P and 33S following fusion-evaporation reactions between an 18O beam and an isotopically enriched 18O implanted tantalum target. Energies from decay gamma-rays associated with the reaction residues were measured in event-by-event coincidence mode, with the measured time difference information between the pairs of gamma-rays in each event also recorded using the ultra-fast coincidence timing technique. The experiment used the good full-energy peak resolution of the LaBr3:Ce detectors coupled with their excellent timing responses in order to determine the excited state lifetime associated with the lowest lying, cross-shell, Iπ=4- "intruder" state previously reported in the N=19 isotone 34P. The extracted lifetime is consistent with a mainly single-particle M2 multipolarity associated with a f7/2→d5/2 single particle transition.

Observation of isomeric decays in the r-process waiting-point nucleus 130Cd82.

The gamma decay of excited states in the waiting-point nucleus (130)Cd(82) has been observed for the first time. An 8(+) two-quasiparticle isomer has been populated both in the fragmentation of a (136)Xe beam as well as in projectile fission of 238U, making (130)Cd the most neutron-rich N = 82 isotone for which information about excited states is available. The results, interpreted using state-of-the-art nuclear shell-model calculations, show no evidence of an N = 82 shell quenching at Z = 48. They allow us to follow nuclear isomerism throughout a full major neutron shell from (98)Cd(50) to (130)Cd(82) and reveal, in comparison with (76)Ni(48) one major proton shell below, an apparently abnormal scaling of nuclear two-body interactions.

Lower limb muscle strength and physical activity in healthy individuals approaching retirement.

The purpose of this study was to examine knee extensor/flexor muscle strength and physical activity in healthy males and females approaching retirement. Peak torques of the knee extensor and knee flexor muscle groups were measured bilaterally in 95 individuals (mean age 59.4 years) using an isokinetic dynamometer. Isokinetic concentric contractions were performed at angular velocities of 1.05 and 3.14 rad x s(-1). Physical activity, including household, leisure, and sporting activities, was assessed. The results show that the average peak torques exhibited were lower than previously reported in studies using the same methodology with different populations of similar age and body size. Over one-third of the participants were sedentary, with just 13% being active enough to obtain health benefits. The poor muscle strength and low physical activity of this self selecting group of healthy working adults were surprising, and potentially a cause for concern. The combination of retirement being a potential watershed for a decrease in physical activity and the known age-related decline in physical performance indicates that some of these participants are at risk of losing their functional independence fairly early in the retirement stage. We recommend the introduction of effective health promotion interventions for individuals approaching retirement, encouraging them to become more physically active.

Gender differences in balance performance at the time of retirement.

BACKGROUND: Impairments in balance performance are a commonly accepted risk factor for falling in older people. Since there is a higher reported incidence of falling in women, it is of interest to test whether this correlates with poorer balance performance in women than men at the time of retirement in order to plan health promotional strategies. The purpose of this study was to investigate whether any gender differences exist in balance performance in people approaching retirement age. METHODS: Ninety-seven healthy volunteers (44 males, 53 females) planning to retire shortly were enrolled in the study (age range 50-67 years). Balance assessments during quiet standing were performed under various conditions; feet together eyes open, feet together eyes closed and single limb stance eyes open. The range of centre of pressure displacement in both the anterior-posterior and medial-lateral planes was collected for each task using a force platform. FINDINGS: For several of the balance tasks the men exhibited a statistically significant larger range of centre of pressure displacement than the women (P<0.01). However, after normalising the data for height, no gender differences were seen. Over half of the group failed to complete all three single limb stance trials on both limbs. INTERPRETATION: When the data was normalised for height, no differences were found in static balance performance between men and women of retirement age. A number of participants demonstrated balance impairments whilst performing the single limb stance likely to affect functional activities. Health promotional messages should be targeted equally at men and women.

Lifetime Measurements in (178)Hf.

Lifetimes of levels from K(π) = 2(+), K(π) = 4(+) and several K(π) = 0(+) bands have been measured in the (178)Hf nucleus using the GRID technique. Lifetimes of the 2(+) and 3(+) levels were measured within the K(π) = 2(+) γ band. A lower limit was established for the lifetime of the 4(+) level of the K(π) = 4(+) band. The resulting upper limits for the absolute B(E2) values exclude collective transitions from the K(π) = 4(+) to the ground state band but not to the K(π)= 2(+) band. Level lifetimes were also measured for several states within three separate K(π)= 0(+) bands. Evidence is presented for a previously unobserved case of two excited K(π)= 0(+) bands being connected via collective E2 transitions.

Estimation of the incidence of late bladder and rectum complications after high-dose (70-78 GY) conformal radiotherapy for prostate cancer, using dose-volume histograms.

PURPOSE: To investigate whether Dose-Volume Histogram (DVH) parameters can be used to identify risk groups for developing late gastrointestinal (GI) and genitourinary (GU) complications after conformal radiotherapy for prostate cancer. METHODS AND MATERIALS: DVH parameters were analyzed for 130 patients with localized prostate cancer, treated with conformal radiotherapy in a dose-escalating protocol (70-78 Gy, 2 Gy per fraction). The incidence of late (>6 months) GI and GU complications was classified using the RTOG/EORTC and the SOMA/LENT scoring system. In addition, GI complications were divided in nonsevere and severe (requiring one or more laser treatments or blood transfusions) rectal bleeding. The median follow-up time was 24 months. We investigated whether rectal and bladder wall volumes, irradiated to various dose levels, correlated with the observed actuarial incidences of GI and GU complications, using volume as a continuous variable. Subsequently, for each dose level in the DVH, the rectal wall volumes were dichotomized using different volumes as cutoff levels. The impact of the total radiation dose, and the maximum radiation dose in the rectal and bladder wall was analyzed as well. RESULTS: The actuarial incidence at 2 years for GI complications > or =Grade II was 14% (RTOG/EORTC) or 20% (SOMA/LENT); for GU complications > or =Grade III 8% (RTOG/EORTC) or 21% (SOMA/LENT). Neither for GI complications > or =Grade II (RTOG/EORTC or SOMA/LENT), nor for GU complications > or =Grade III (RTOG/EORTC or SOMA/LENT), was a significant correlation found between any of the DVH parameters and the actuarial incidence of complications. For severe rectal bleeding (actuarial incidence at 2 years 3%), four consecutive volume cutoff levels were found, which significantly discriminated between high and low risk. A trend was observed that a total radiation dose > or = 74 Gy (or a maximum radiation dose in the rectal wall >75 Gy) resulted in a higher incidence of severe rectal bleeding (p = 0.07). CONCLUSIONS: These data show that dose escalation up to 78 Gy, using a conformal technique, is feasible. However, these data have also demonstrated that the incidence of severe late rectal bleeding is increased above certain dose-volume thresholds.

Evidence for early and persistent impairment of salivary gland excretion after irradiation of head and neck tumours.

Salivary gland scintigraphy with technetium-99m pertechnetate was used to follow changes in the excretion and uptake function of the major salivary glands until 1 year after irradiation. Twenty-five patients who received radiotherapy for head and neck tumours were included in the study. Seventy-nine salivary glands (39 parotid and 40 submandibular) were evaluated in relation to the average received radiation dose. Salivary gland scintigraphy was performed before and 1, 6 and 12 months after radiotherapy. For each gland the excretion response to carbachol, evaluated by calculation of the salivary excretion fraction (SEF), the cumulative gland uptake (CGU) and the absolute excreted activity (AEA) at various intervals after radiotherapy were compared with the baseline values. The excretion response decreased in 20 of 25 patients at 1 month after radiotherapy. One month after radiotherapy both SEF and AEA decreased significantly in relation to the radiation dose. These decreases in excretion parameters persisted during the follow-up period. Parotid excretion was affected significantly more than submandibular excretion. CGU values did not change significantly until 6 months after radiotherapy, but at 12 months a significant decrease related to radiation dose was observed. Xerostomia was assessed during radiotherapy and on the days of the scintigraphic tests. The incidence of xerostomia did not correspond to the effects observed in the scintigraphic studies. It is concluded that radiotherapy induces early and persistent impairment of salivary gland excretion, related to the radiation dose. This impairment is stronger in parotid glands than in submandibular glands.

Variation in volumes, dose-volume histograms, and estimated normal tissue complication probabilities of rectum and bladder during conformal radiotherapy of T3 prostate cancer.

PURPOSE: To determine the pattern of changes of rectum and bladder structures during conformal therapy of T3 prostate cancer and the impact of these changes on the accuracy of the dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) of these organs, based on the planning computed tomography (CT) scan only. METHODS AND MATERIALS: For 11 T3 prostate cancer patients treated with conformal therapy, three repeat CT scans were made in Weeks 2, 4, and 6 of the treatment. The bony anatomy was aligned with the planning CT scan, using three dimensional (3D) chamfer matching. The internal and external surfaces of rectum and bladder were contoured in each scan. Three volumes were calculated for each organ: solid organ (including filling), filling, and wall volume. DVHs and NTCPs were calculated for all structures. RESULTS: The solid organ and filling volumes varied considerably between patients and within a patient and they decreased with increasing treatment time. The largest patient variation was seen for patients with large initial filling volumes. The variations of rectum and bladder wall volumes during treatment were 9 and 17% (1 standard deviation (SD)), respectively, with no time trend. The changes of the high dose (> 80 and 90% of the prescribed dose) volumes of the rectum in response to rectum filling differences were proportional to the whole rectum volume changes. The variation of the high-dose rectum wall volume was relatively small (14%, 1 SD). As a result, the NTCPs of rectum and rectum wall were the same overall and the variation of the NTCPs during treatment was about 14% (1 SD) and not correlated with rectum filling. The variation of the high-dose bladder volumes (about 14%, 1 SD) was smaller than the variation of the whole bladder volumes (30%, 1 SD). The high-dose bladder wall volume decreased significantly due to wall distention as the bladder filling increased. As a result of this complex pattern, the variation of NTCPs of bladder (85%, 1 SD) and bladder wall (88%, 1 SD) during treatment was large and significantly correlated with bladder filling. CONCLUSIONS: The planning CT scan overestimates rectum and bladder filling during treatment. Furthermore, the variation of filling is so large that only the wall structures have relatively constant volumes during treatment. For the rectum wall, the DVHs and NTCPs, as estimated from the initial scan, are representative for the whole treatment, because no correlation was seen between these parameters and organ filling. For the bladder wall, however, such a correlation was present and consequently, the initial bladder wall DVHs and NTCPs can only be representative for the whole treatment, if the bladder filling can be kept reasonably constant during treatment.

Time-course of the antihypertensive and autonomic effects of regular endurance exercise in human subjects.

To assess the role of different factors on the long-term antihypertensive effect of regular exercise we examined the time course of changes in haemodynamics, oxygen consumption and plasma noradrenaline in 10 normal healthy subjects. For 12 weeks, subjects performed alternating months of training and detraining in a random order. Training involved 40 min of bicycle exercise three times per week at 60-70% of maximum work. Steady-state changes at the end of 1 month's exercise were: (1) falls in resting blood pressure when supine and erect by 8/5 and 10/6 mmHg, respectively (P less than 0.01); (2) a reduction in the total peripheral resistance index of 14%; (3) an increase in maximum oxygen consumption of 14% (P less than 0.005); and (4) a fall in plasma noradrenaline of 21% (P less than 0.05). A significant fall in blood pressure occurred at the third training bout (P less than 0.005), at the beginning of the second week, and no further reduction occurred beyond the fourth bout of exercise. The reduction in plasma noradrenaline concentration was confined to the second half of the month in which exercise took place and lagged behind the blood pressure changes. There were significant differences between the rates of the initial fall of blood pressure and noradrenaline, and the times taken for the maximum changes to occur (P less than 0.05). During detraining, blood pressure remained low for 1-2 weeks after cessation of exercise, as did plasma noradrenaline. Both then rose gradually towards the initial sedentary levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Electroretinograms in microcephaly with chorioretinal degeneration.

We recorded full-field electroretinograms from a family with two daughters with microcephaly and chorioretinal degeneration and a third daughter and mother with microcephaly without chorioretinal degeneration. The two siblings with inferior chorioretinal degeneration showed electroretinographic responses to 0.5-Hz white light that were reduced 60% to 70% below normal, suggesting that the loss of photoreceptor function exceeded the areas of visible atrophy. The mother and third daughter had normal electroretinograms. The two siblings, ages 12 and 21 years, had virtually the same electroretinographic amplitudes. In a second family, a man with microcephaly and inferior chorioretinal degeneration, examined at ages 9 and 23 years, also showed 60% to 70% reduction in electroretinographic responses to 0.5-Hz white light and showed no change in amplitudes over the 14-year interval. These findings suggest that the chorioretinal degeneration sometimes associated with microcephaly is stable in young adult life, although the long-term prognosis remains to be defined.