Advanced crystallisation methods for small organic molecules.

Molecular materials based on small organic molecules often require advanced structural analysis, beyond the capability of spectroscopic techniques, to fully characterise them. In such cases, diffraction methods such as single crystal X-ray diffraction (SCXRD), are one of the most powerful tools available to researchers, providing molecular and structural elucidation at atomic level resolution, including absolute stereochemistry. However SCXRD, and related diffraction methods, are heavily dependent on the availability of suitable, high-quality crystals, thus crystallisation often becomes the major bottleneck in preparing samples. Following a summary of classical methods for the crystallisation of small organic molecules, this review will focus on a number of recently developed advanced methods for crystalline material sample preparation for SCXRD. This review will cover two main areas of modern small organic molecule crystallisation, namely the inclusion of molecules within host complexes (e.g., "crystalline sponge" and tetraaryladamantane based inclusion chaperones) and the use of high-throughput crystallisation, employing "under-oil" approaches (e.g., microbatch under-oil and ENaCt). Representative examples have been included for each technique, together with a discussion of their relative advantages and limitations to aid the reader in selecting the most appropriate technique to overcome a specific analytical challenge.

Real-world treatment sequencing and survival in previously treated advanced renal cell carcinoma patients receiving nivolumab monotherapy: a UK retrospective cohort study.

BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.

A model for occupational stress amongst paediatric and adult critical care staff during COVID-19 pandemic.

PURPOSE: The coronavirus 2019 pandemic has placed all intensive care unit (ICU) staff at increased risk of psychological distress. To date, measurement of this distress has largely been by means of validated assessment tools. We believe that qualitative data may provide a richer view of staff experiences during this pandemic. METHODS: We conducted a cross-sectional, observational study using online and written questionnaires to all ICU staff which consisted of validated tools to measure psychological distress (quantitative findings) and open-ended questions with free-text boxes (qualitative findings). Here, we report our qualitative findings. We asked four questions to explore causes of stress, need for supports and barriers to accessing supports. A conventional content analysis was undertaken. RESULTS: In total, 269 of the 408 respondents (65.9%) gave at least one response to a free-text question. Seven overarching themes were found, which contribute to our proposed model for occupational stress amongst critical care staff. The work environment played an important role in influencing the perceived psychological impact on healthcare workers. Extra-organisational factors, which we termed the "home-work interface" and uncertainty about the future, manifested as anticipatory anxiety, had a proportionally larger influence on worker well-being than would be expected in non-pandemic conditions. CONCLUSION: Our findings have important implications for appropriate allocation of resources and ensuring well-being of the ICU multidisciplinary team for this and future pandemics.

C-reactive protein trajectory to predict colorectal anastomotic leak: PREDICT Study.

BACKGROUND: Anastomotic leak is a common complication after colorectal surgery, associated with increased morbidity and mortality, and poorer long-term survival after oncological resections. Early diagnosis improves short-term outcomes, and may translate into reduced cancer recurrence. Multiple studies have attempted to identify biomarkers to enable earlier diagnosis of anastomotic leak. One study demonstrated that the trajectory of C-reactive protein (CRP) levels was highly predictive of anastomotic leak requiring intervention, with an area under the curve of 0·961. The aim of the present study was to validate this finding externally. METHODS: This was a prospective international multicentre observational study of adults undergoing elective colorectal resection with an anastomosis. CRP levels were measured before operation and for 5 days afterwards, or until day of discharge if earlier than this. The primary outcome was anastomotic leak requiring operative or radiological intervention. RESULTS: Between March 2017 and July 2018, 933 patients were recruited from 20 hospitals across Australia, New Zealand, England and Scotland. Some 833 patients had complete CRP data and were included in the primary analysis, of whom 41 (4·9 per cent) developed an anastomotic leak. A change in CRP level exceeding 50 mg/l between any two postoperative days had a sensitivity of 0·85 for detecting a leak, and a high negative predictive value of 0·99 for ruling it out. A change in CRP concentration of more than 50 mg/l between either days 3 and 4 or days 4 and 5 after surgery had a high specificity of 0·96-0·97, with positive likelihood ratios of 4·99-6·44 for a leak requiring intervention. CONCLUSION: This study confirmed the value of CRP trajectory in accurately ruling out an anastomotic leak after colorectal resection.

ANTECEDENTES: La fuga anastomótica es una complicación frecuente después de la cirugía colorrectal que se asocia con morbilidad y mortalidad, con una peor supervivencia a largo plazo tras resecciones oncológicas. El diagnóstico precoz mejora los resultados a corto plazo y puede traducirse en una reducción de la recidiva del cáncer. Múltiples estudios han tratado de identificar biomarcadores para lograr un diagnóstico precoz de la fuga anastomótica. Un estudio demostró que la evolución de la proteína C reactiva (PCR) era altamente predictiva de una fuga anastomótica que requería intervención, con un área bajo la curva de 0,961. Nuestro estudio tuvo como objetivo validar externamente este hallazgo. MÉTODOS: Se llevó a cabo un estudio internacional prospectivo observacional y multicéntrico de pacientes adultos sometidos a resección colorrectal electiva con anastomosis. Los niveles de PCR se midieron antes de la operación y diariamente hasta el día 5 después de la cirugía, o hasta el día del alta si fue anterior. El criterio de valoración principal fue la fuga anastomótica que requirió intervención quirúrgica o radiológica. RESULTADOS: Entre marzo de 2017 y julio de 2018, se reclutaron 933 pacientes de 20 hospitales de Australia, Nueva Zelanda, Inglaterra y Escocia. Se obtuvieron datos completos de PCR en 833 pacientes y se incluyeron en el análisis primario, de los cuales 41 (4,9%) presentaron una fuga anastomótica. Un aumento de la PCR > 50 mg/L entre dos días del postoperatorio fue sensible para detectar una fuga (0,85) y tuvo un alto valor predictivo negativo para descartarla (0,99). El porcentaje de cambio de PCR > 50 mg/L por día entre los días 3-4 o 4-5 después de la operación fue altamente específico (0,96) con un cociente de probabilidad positivo > 5,0 para las fugas que requirieron una intervención. CONCLUSIÓN: Este estudio confirma la utilidad de la evolución de la PCR para descartar con precisión una fuga anastomótica después de una resección colorrectal.

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.

Competition between Allowed and First-Forbidden ß Decay: The Case of

The ß decay of ^{208}Hg into the one-proton hole, one neutron-particle _{81}^{208}Tl_{127} nucleus was investigated at CERN-ISOLDE. Shell-model calculations describe well the level scheme deduced, validating the proton-neutron interactions used, with implications for the whole of the N>126, Z<82 quadrant of neutron-rich nuclei. While both negative and positive parity states with spin 0 and 1 are expected within the Q_{ß} window, only three negative parity states are populated directly in the ß decay. The data provide a unique test of the competition between allowed Gamow-Teller and Fermi, and first-forbidden ß decays, essential for the understanding of the nucleosynthesis of heavy nuclei in the rapid neutron capture process. Furthermore, the observation of the parity changing 0^{+}→0^{-}ß decay where the daughter state is core excited is unique, and can provide information on mesonic corrections of effective operators.

Biopsychosocial factors associated with depression and anxiety in older adults with intellectual disability: results of the wave 3 Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing.

BACKGROUND: Depression and anxiety are amongst the most prevalent mental health disorders in the older population with intellectual disability (ID). There is a paucity of research that pertains to associative biopsychosocial factors for depression and anxiety in this population. The aim of this study is to determine the biopsychosocial factors associated with depression and anxiety in a population of older adults with ID in Ireland. METHODS: The study was part of 'The Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing'. Depressive symptoms were assessed using the Glasgow Depression Scale for people with a Learning Disability. Anxiety symptoms were measured using the Glasgow Anxiety Scale for people with a Learning Disability. The cross-sectional associations of depression and anxiety with biopsychosocial parameters were measured using a variety of self-report and proxy-completed questionnaires. RESULTS: For the study population, 9.97% met the criteria for depression, and 15.12% met the criteria for an anxiety disorder. Participants meeting criteria for depression were more likely to be taking regular mood stabiliser medications and to exhibit aggressive challenging behaviour. Participants meeting criteria for anxiety were more likely to have sleep difficulties and report loneliness. Participants meeting criteria for either/both depression and anxiety were more likely to report loneliness. CONCLUSIONS: This study identified both treatable and modifiable, as well as unmodifiable, biopsychosocial factors associated with depression and/or anxiety in older adults with ID. A longitudinal study follow-up will further develop our knowledge on the causality and direction of associated biopsychosocial factors with depression and anxiety in older adults with ID and better inform management strategies, prevention policies and funding of services.

Maternal titanium dioxide nanomaterial inhalation exposure compromises placental hemodynamics.

The fetal consequences of gestational engineered nanomaterial (ENM) exposure are unclear. The placenta is a barrier protecting the fetus and allowing transfer of substances from the maternal circulation. The purpose of this study was to determine the effects of maternal pulmonary titanium dioxide nanoparticle (nano-TiO2) exposure on the placenta and umbilical vascular reactivity. We hypothesized that pulmonary nano-TiO2 inhalation exposure increases placental vascular resistance and impairs umbilical vascular responsiveness. Pregnant Sprague-Dawley rats were exposed via whole-body inhalation to nano-TiO2 with an aerodynamic diameter of 188 ±â€¯0.36 nm. On gestational day (GD) 11, rats began inhalation exposures (6 h/exposure). Daily lung deposition was 87.5 ±â€¯2.7 µg. Animals were exposed for 6 days for a cumulative lung burden of 525 ±â€¯16 µg. On GD 20, placentas, umbilical artery and vein were isolated, cannulated, and treated with acetylcholine (ACh), angiotensin II (ANGII), S-nitroso-N-acetyl-DL-penicillamine (SNAP), or calcium-free superfusate (Ca2+-free). Mean outflow pressure was measured in placental units. ACh increased outflow pressure to 53 ±â€¯5 mmHg in sham-controls but only to 35 ±â€¯4 mmHg in exposed subjects. ANGII decreased outflow pressure in placentas from exposed animals (17 ±â€¯7 mmHg) compared to sham-controls (31 ±â€¯6 mmHg). Ca2+-free superfusate yielded maximal outflow pressures in sham-control (63 ±â€¯5 mmHg) and exposed (30 ±â€¯10 mmHg) rats. Umbilical artery endothelium-dependent dilation was decreased in nano-TiO2 exposed fetuses (30 ±â€¯9%) compared to sham-controls (58 ±â€¯6%), but ANGII sensitivity was increased (-79 ±â€¯20% vs -36 ±â€¯10%). These results indicate that maternal gestational pulmonary nano-TiO2 exposure increases placental vascular resistance and impairs umbilical vascular reactivity.

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.

Phenome-wide association study identifies dsDNA as a driver of major organ involvement in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), dsDNA antibodies are associated with renal disease. Less is known about comorbidities in patients without dsDNA or other autoantibodies. Using an electronic health record (EHR) SLE cohort, we employed a phenome-wide association study (PheWAS) that scans across billing codes to compare comorbidities in SLE patients with and without autoantibodies. We used our validated algorithm to identify SLE subjects. Autoantibody status was defined as ever positive for dsDNA, RNP, Smith, SSA and SSB. PheWAS was performed in antibody positive vs. negative SLE patients adjusting for age and race and using a false discovery rate of 0.05. We identified 1097 SLE subjects. In the PheWAS of dsDNA positive vs. negative subjects, dsDNA positive subjects were more likely to have nephritis ( p = 2.33 × 10-9) and renal failure ( p = 1.85 × 10-5). After adjusting for sex, race, age and other autoantibodies, dsDNA was independently associated with nephritis and chronic kidney disease. Those patients negative for dsDNA, RNP, SSA and SSB negative subjects were all more likely to have billing codes for sleep, pain and mood disorders. PheWAS uncovered a hierarchy within SLE-specific autoantibodies with dsDNA having the greatest impact on major organ involvement.

The LAPLAP study: a randomized placebo-controlled clinical trial assessing postoperative functional recovery using intraperitoneal local anaesthetic in laparoscopic colorectal surgery.

AIM: Postoperative pain remains a major factor in recovery from colorectal resection. There is increasing interest in opioid-sparing analgesia, and intraperitoneal local anaesthetic (IPLA) has recently been shown to be useful in minor laparoscopic and open colorectal procedures. The aim of this study was to evaluate the impact of IPLA on functional recovery following major laparoscopic surgery. In this controlled trial, mobility, as measured by the De Morton Mobility Index (DEMMI), was used as a surrogate for postoperative functional recovery. METHOD: Patients undergoing laparoscopic colorectal resection were randomized either to continuous ropivacaine (0.2% at 4-6 ml/h) or to saline (0.9%) which were administered via intraperitoneal catheter for 3 days postoperatively. Results were analysed in a double-blind manner. DEMMIs were assessed on postoperative days 1, 2, 3, 7 and 30, and data on pain, opioid consumption, gut and respiratory function, length of stay (LOS) and complications were recorded. RESULTS: Ninety-six patients were recruited. There was no difference in primary outcome (i.e., functional recovery) between IPLA and placebo groups. Opioid consumption and LOS were similar between groups, and no differences were found for any secondary outcome measure. There were no adverse events related to ropivacaine. CONCLUSION: Infusional intraperitoneal local anaesthetic appears to be safe but does not improve functional recovery or analgesic consumption following elective laparoscopic colorectal surgery, in the setting of an established enhanced recovery programme.

The association of life events and mental ill health in older adults with intellectual disability: results of the wave 3 Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing.

BACKGROUND: Exposures to life events are associated with emotional, psychological and behavioural problems in those with intellectual disability (ID). Older adults with ID may experience different life events given differences in living circumstances, cognitive decline, greater dependency on others and less autonomy. This study examines the relationship of life events and mental ill health in an older ID population in Ireland. METHODS: The study was part of 'The Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing'. The frequency of life events was assessed using a 20-item checklist, and the level of stress experienced was assessed using a three-point Likert scale measuring the burden of the life event. The associations of life events with factors associated with mental ill health were measured using a variety of self-report and proxy completed questionnaires. RESULTS: For the study population, 88.1% had been exposed to at least one life event in the preceding 12 months and 64.5% to two or more life events. Frequency and burden of life events were significantly higher in individuals living in institutional settings and in individuals with any current psychiatric condition, increased depressive and anxiety symptoms, challenging behaviour and reported poorer self-rated mental and physical health. More life events were significantly associated with new psychiatric diagnoses as well as initiation and increased dosage of mood stabilising, hypnotic and sedative medications. CONCLUSIONS: Life events are significantly associated with mental ill health in the older ID population. Service providers must focus on limiting the exposure to these events and, in situations where they cannot be avoided, should support and manage individuals compassionately and effectively, prioritising their mental and physical well-being.

Intermittent fasting in Type 2 diabetes mellitus and the risk of hypoglycaemia: a randomized controlled trial.

AIMS: To establish whether the risk of hypoglycaemia is greater with 2 consecutive days of very-low-calorie diet compared with 2 non-consecutive days of very-low-calorie diet in people with Type 2 diabetes. METHODS: This was a non-blinded randomized parallel group interventional trial of intermittent fasting in adults. The participants had a BMI of 30-45 kg/m2 , Type 2 diabetes treated with metformin and/or hypoglycaemic medications and an HbA1c concentration of 50-86 mmol/mol (6.7-10%). The participants followed a 2092-2510-kJ diet on 2 days per week for 12 weeks. A total of 41 participants were randomized 1:1 to consecutive (n=19) or non-consecutive (n=22) day fasts, of whom 37 (n=18 and n=19, respectively) were included in the final analysis. The primary outcome was difference in the rate of hypoglycaemia between the two study arms. Secondary outcomes included change in diet, quality of life, weight, lipid, glucose and HbA1c levels, and liver function. RESULTS: The mean hypoglycaemia rate was 1.4 events over 12 weeks. Fasting increased the rate of hypoglycaemia despite medication reduction (RR 2.05, 95% CI 1.17 to 3.52). There was no difference between fasting on consecutive days and fasting on non-consecutive days (RR 1.54, 95% CI 0.35 to 6.11). Improvements in weight, HbA1c , fasting glucose and quality of life were experienced by participants in both arms. CONCLUSIONS: In individuals with Type 2 diabetes on hypoglycaemic medications, fasting of any type increased the rate of hypoglycaemia. With education and medication reduction, fewer than expected hypoglycaemic events occurred. Although it was not possible to determine whether fasting on consecutive days increased the risk of hypoglycaemia, an acceptable rate was observed in both arms.

Avian parental behavior and nest success influenced by temperature fluctuations.

Behavioral adjustments and parental decisions during reproduction can influence the thermal environment at nests, yet our understanding into how environmental factors (i.e., temperature and precipitation) constrain an adult's ability to balance self-maintenance and incubation demands is limited. To expand our understanding of how species respond to environmental factors, we investigated the reproductive ecology of two ground-nesting species (northern bobwhite [Colinus virginianus] and scaled quail [Callipepla squamata]) in a region (i.e., the Southern Great Plains) prone to thermal variability (i.e., extreme hot and cold temperatures). Specifically, our objective was to examine how temperature and precipitation directly influenced behavioral adjustments (i.e., off-bout duration, frequency, and nest attentiveness) and parental decisions (i.e., nest site selection), and indirectly influenced nest fate. Overall, we found that parents chose to nest in sites that were significantly cooler in temperature than randomly selected sites, and parents further altered the thermal environment experienced by embryos through incubation behavior. Daily precipitation and average ambient temperature and/or their interaction best predicted incubation behaviors, yet each species differed in the timing (i.e., morning vs. evening), frequency, and duration of off-bouts. Furthermore, successful nests were associated with cooler nest site temperatures for bobwhite and warmer nest site temperatures for scaled quail. Our finding of relatively stable (35.5 °C) incubation temperature for developing embryos of both species suggests that ground-nesting birds are able to regulate microclimate through behavioral adjustments and parental decisions even under extreme temperature fluctuations. Nevertheless, the ability for a ground-nesting species to effectively modify behavioral adjustments and decisions may be altered during long periods of enhanced physiological and environmental stress.

Maternal-engineered nanomaterial exposure disrupts progeny cardiac function and bioenergetics.

Nanomaterial production is expanding as new industrial and consumer applications are introduced. Nevertheless, the impacts of exposure to these compounds are not fully realized. The present study was designed to determine whether gestational nano-sized titanium dioxide exposure impacts cardiac and metabolic function of developing progeny. Pregnant Sprague-Dawley rats were exposed to nano-aerosols (~10 mg/m3, 130- to 150-nm count median aerodynamic diameter) for 7-8 nonconsecutive days, beginning at gestational day 5-6 Physiological and bioenergetic effects on heart function and cardiomyocytes across three time points, fetal (gestational day 20), neonatal (4-10 days), and young adult (6-12 wk), were evaluated. Functional analysis utilizing echocardiography, speckle-tracking based strain, and cardiomyocyte contractility, coupled with mitochondrial energetics, revealed effects of nano-exposure. Maternal exposed progeny demonstrated a decrease in E- and A-wave velocities, with a 15% higher E-to-A ratio than controls. Myocytes isolated from exposed animals exhibited ~30% decrease in total contractility, departure velocity, and area of contraction. Bioenergetic analysis revealed a significant increase in proton leak across all ages, accompanied by decreases in metabolic function, including basal respiration, maximal respiration, and spare capacity. Finally, electron transport chain complex I and IV activities were negatively impacted in the exposed group, which may be linked to a metabolic shift. Molecular data suggest that an increase in fatty acid metabolism, uncoupling, and cellular stress proteins may be associated with functional deficits of the heart. In conclusion, gestational nano-exposure significantly impairs the functional capabilities of the heart through cardiomyocyte impairment, which is associated with mitochondrial dysfunction.NEW & NOTEWORTHY Cardiac function is evaluated, for the first time, in progeny following maternal nanomaterial inhalation. The findings indicate that exposure to nano-sized titanium dioxide (nano-TiO2) during gestation negatively impacts cardiac function and mitochondrial respiration and bioenergetics. We conclude that maternal nano-TiO2 inhalation contributes to adverse cardiovascular health effects, lasting into adulthood.

Estimation of radiation risk in presence of classical additive and Berkson multiplicative errors in exposure doses.

In this paper, the influence of measurement errors in exposure doses in a regression model with binary response is studied. Recently, it has been recognized that uncertainty in exposure dose is characterized by errors of two types: classical additive errors and Berkson multiplicative errors. The combination of classical additive and Berkson multiplicative errors has not been considered in the literature previously. In a simulation study based on data from radio-epidemiological research of thyroid cancer in Ukraine caused by the Chornobyl accident, it is shown that ignoring measurement errors in doses leads to overestimation of background prevalence and underestimation of excess relative risk. In the work, several methods to reduce these biases are proposed. They are new regression calibration, an additive version of efficient SIMEX, and novel corrected score methods.

Altered circadian feeding behavior and improvement of metabolic syndrome in obese Tac1-deficient mice.

BACKGROUND: Metabolic function is regulated by the interplay of central and peripheral factors that ultimately regulate food intake (FI) and energy expenditure. The tachykinin substance P (SP) has been identified as a novel regulator of energy balance, however, the mechanisms underlying this effect are ill-defined and conflicting data regarding the role of SP on FI have been reported by different groups. OBJECTIVE: To further characterize the metabolic role of the Tac1 gene products (SP and neurokinin A) in mice through a series of genetic, metabolic and behavioral studies in Tac1-deficient mice. RESULTS: Tac1-/- mice are leaner than controls and display reduced FI and altered feeding circadian rhythm, supported by disrupted expression of the clock genes Cry1/2, Per1/2 in the suprachiasmatic nucleus, mediobasal hypothalamus (MBH) and liver, as well as increased proopiomelanocortin expression in the MBH. Tac1 ablation induced resistance to obesity, improved glucose tolerance, prevented insulin resistance under high-fat diet, increased activation of brown adipose tissue and improved hepatic steatosis. Moreover, deletion of Tac1 in ob/ob mice ameliorated body weight gain in females only but was sufficient to decrease fat and triglyceride content in the liver of males. CONCLUSIONS: These results provide further evidence that Tac1 controls circadian feeding behavior and metabolism in mice through mechanisms that involve the regulation of the melanocortin system. In addition, these studies suggest that the blockade of SP may offer a new method to treat metabolic syndrome.

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.

Anomalies in the Charge Yields of Fission Fragments from the

Fast-neutron-induced fission of ^{238}U at an energy just above the fission threshold is studied with a novel technique which involves the coupling of a high-efficiency γ-ray spectrometer (MINIBALL) to an inverse-kinematics neutron source (LICORNE) to extract charge yields of fission fragments via γ-γ coincidence spectroscopy. Experimental data and fission models are compared and found to be in reasonable agreement for many nuclei; however, significant discrepancies of up to 600% are observed, particularly for isotopes of Sn and Mo. This indicates that these models significantly overestimate the standard 1 fission mode and suggests that spherical shell effects in the nascent fission fragments are less important for low-energy fast-neutron-induced fission than for thermal neutron-induced fission. This has consequences for understanding and modeling the fission process, for experimental nuclear structure studies of the most neutron-rich nuclei, for future energy applications (e.g., Generation IV reactors which use fast-neutron spectra), and for the reactor antineutrino anomaly.

Shape Evolution in Neutron-Rich Krypton Isotopes Beyond N=60: First Spectroscopy of

We report on the first γ-ray spectroscopy of low-lying states in neutron-rich ^{98,100}Kr isotopes obtained from ^{99,101}Rb(p,2p) reactions at ∼220 MeV/nucleon. A reduction of the 2_{1}^{+} state energies beyond N=60 demonstrates a significant increase of deformation, shifted in neutron number compared to the sharper transition observed in strontium and zirconium isotopes. State-of-the-art beyond-mean-field calculations using the Gogny D1S interaction predict level energies in good agreement with experimental results. The identification of a low-lying (0_{2}^{+}, 2_{2}^{+}) state in ^{98}Kr provides the first experimental evidence of a competing configuration at low energy in neutron-rich krypton isotopes consistent with the oblate-prolate shape coexistence picture suggested by theory.