Role of TLR4 in the induction of inflammatory changes in adipocytes and macrophages.

In obesity, high levels of saturated fatty acids (SFAs) contribute to adipose tissue inflammation and dysfunction. Obesity-induced macrophage infiltration leads to insulin resistance, but the adipocyte itself may play a role in generating the inflammatory milieu. Given our recent findings of the role of TLR4 in myeloid biasing in obesity, we next investigated the role of TLR4 in adipocyte generated inflammatory responses to SFAs and lipopolysaccharides. We used WT and Tlr4-/- ear mesenchymal stem cell derived adipocytes (EMSC Ad) and bone marrow dendritic cells (BMDCs) to evaluate cell specific responses. Our work demonstrates a role for TLR4 in adipocyte- immune cell crosstalk and that SFA derived metabolites from adipocytes may induce proinflammatory stimulation of immune cells in a TLR4 independent manner.

Color, composition, and thermal environment of Kuiper Belt object (486958) Arrokoth.

The outer Solar System object (486958) Arrokoth (provisional designation 2014 MU69) has been largely undisturbed since its formation. We studied its surface composition using data collected by the New Horizons spacecraft. Methanol ice is present along with organic material, which may have formed through irradiation of simple molecules. Water ice was not detected. This composition indicates hydrogenation of carbon monoxide-rich ice and/or energetic processing of methane condensed on water ice grains in the cold, outer edge of the early Solar System. There are only small regional variations in color and spectra across the surface, which suggests that Arrokoth formed from a homogeneous or well-mixed reservoir of solids. Microwave thermal emission from the winter night side is consistent with a mean brightness temperature of 29 ± 5 kelvin.

The geology and geophysics of Kuiper Belt object (486958) Arrokoth.

The Cold Classical Kuiper Belt, a class of small bodies in undisturbed orbits beyond Neptune, is composed of primitive objects preserving information about Solar System formation. In January 2019, the New Horizons spacecraft flew past one of these objects, the 36-kilometer-long contact binary (486958) Arrokoth (provisional designation 2014 MU69). Images from the flyby show that Arrokoth has no detectable rings, and no satellites (larger than 180 meters in diameter) within a radius of 8000 kilometers. Arrokoth has a lightly cratered, smooth surface with complex geological features, unlike those on previously visited Solar System bodies. The density of impact craters indicates the surface dates from the formation of the Solar System. The two lobes of the contact binary have closely aligned poles and equators, constraining their accretion mechanism.

The solar nebula origin of (486958) Arrokoth, a primordial contact binary in the Kuiper Belt.

The New Horizons spacecraft's encounter with the cold classical Kuiper Belt object (486958) Arrokoth (provisional designation 2014 MU69) revealed a contact-binary planetesimal. We investigated how Arrokoth formed and found that it is the product of a gentle, low-speed merger in the early Solar System. Its two lenticular lobes suggest low-velocity accumulation of numerous smaller planetesimals within a gravitationally collapsing cloud of solid particles. The geometric alignment of the lobes indicates that they were a co-orbiting binary that experienced angular momentum loss and subsequent merger, possibly because of dynamical friction and collisions within the cloud or later gas drag. Arrokoth's contact-binary shape was preserved by the benign dynamical and collisional environment of the cold classical Kuiper Belt and therefore informs the accretion processes that operated in the early Solar System.

Programming effects of maternal and gestational obesity on offspring metabolism and metabolic inflammation.

With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of this on offspring. The purpose of this study is to investigate the programming effects of maternal obesity during preconception and the preconception/gestational period on adiposity and adipose tissue inflammation in offspring using an animal model. Adult female C57Bl/6J mice were assigned either normal diet, high fat diet (HFD) prior to pregnancy, or HFD prior to and through pregnancy. Some offspring were maintained on normal diet while others started HFD later in life. Offspring were assessed for body composition and metabolic responses. Lipid storing tissues were evaluated for expansion and inflammation. Male offspring from the preconception group had the greatest weight gain, most subcutaneous adipose tissue, and largest liver mass when introduced to postnatal HFD. Male offspring of the preconception/gestation group had worsened glucose tolerance and an increase in resident (CD11c-) adipose tissue macrophages (ATMs) when exposed to postnatal HFD. Female offspring had no significant difference in any parameter between the diet treatment groups. In conclusion, this study demonstrates that prenatal and pregnancy windows have independent programming effects on offspring. Preconception exposure affects body composition and adiposity while gestation exposure affects metabolism and tissue immune cell phenotypes.

Detection of ammonia on Pluto's surface in a region of geologically recent tectonism.

We report the detection of ammonia (NH3) on Pluto's surface in spectral images obtained with the New Horizons spacecraft that show absorption bands at 1.65 and 2.2 µm. The ammonia signature is spatially coincident with a region of past extensional tectonic activity (Virgil Fossae) where the presence of H2O ice is prominent. Ammonia in liquid water profoundly depresses the freezing point of the mixture. Ammoniated ices are believed to be geologically short lived when irradiated with ultraviolet photons or charged particles. Thus, the presence of NH3 on a planetary surface is indicative of a relatively recent deposition or possibly through exposure by some geological process. In the present case, the areal distribution is more suggestive of cryovolcanic emplacement, however, adding to the evidence for ongoing geological activity on Pluto and the possible presence of liquid water at depth today.

Impact craters on Pluto and Charon indicate a deficit of small Kuiper belt objects.

The flyby of Pluto and Charon by the New Horizons spacecraft provided high-resolution images of cratered surfaces embedded in the Kuiper belt, an extensive region of bodies orbiting beyond Neptune. Impact craters on Pluto and Charon were formed by collisions with other Kuiper belt objects (KBOs) with diameters from ~40 kilometers to ~300 meters, smaller than most KBOs observed directly by telescopes. We find a relative paucity of small craters ≲13 kilometers in diameter, which cannot be explained solely by geological resurfacing. This implies a deficit of small KBOs (≲1 to 2 kilometers in diameter). Some surfaces on Pluto and Charon are likely ≳4 billion years old, thus their crater records provide information on the size-frequency distribution of KBOs in the early Solar System.

The formation of Charon's red poles from seasonally cold-trapped volatiles.

A unique feature of Pluto's large satellite Charon is its dark red northern polar cap. Similar colours on Pluto's surface have been attributed to tholin-like organic macromolecules produced by energetic radiation processing of hydrocarbons. The polar location on Charon implicates the temperature extremes that result from Charon's high obliquity and long seasons in the production of this material. The escape of Pluto's atmosphere provides a potential feedstock for a complex chemistry. Gas from Pluto that is transiently cold-trapped and processed at Charon's winter pole was proposed as an explanation for the dark coloration on the basis of an image of Charon's northern hemisphere, but not modelled quantitatively. Here we report images of the southern hemisphere illuminated by Pluto-shine and also images taken during the approach phase that show the northern polar cap over a range of longitudes. We model the surface thermal environment on Charon and the supply and temporary cold-trapping of material escaping from Pluto, as well as the photolytic processing of this material into more complex and less volatile molecules while cold-trapped. The model results are consistent with the proposed mechanism for producing the observed colour pattern on Charon.

Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity.

It is well known in clinical and animal studies that women and men have different disease risk as well as different disease physiology. Women of reproductive age are protected from metabolic and cardiovascular disease compared with postmenopausal women and men. Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses.

The small satellites of Pluto as observed by New Horizons.

The New Horizons mission has provided resolved measurements of Pluto's moons Styx, Nix, Kerberos, and Hydra. All four are small, with equivalent spherical diameters of ~40 kilometers for Nix and Hydra and ~10 kilometers for Styx and Kerberos. They are also highly elongated, with maximum to minimum axis ratios of ~2. All four moons have high albedos (~50 to 90%) suggestive of a water-ice surface composition. Crater densities on Nix and Hydra imply surface ages of at least 4 billion years. The small moons rotate much faster than synchronous, with rotational poles clustered nearly orthogonal to the common pole directions of Pluto and Charon. These results reinforce the hypothesis that the small moons formed in the aftermath of a collision that produced the Pluto-Charon binary.

Surface compositions across Pluto and Charon.

The New Horizons spacecraft mapped colors and infrared spectra across the encounter hemispheres of Pluto and Charon. The volatile methane, carbon monoxide, and nitrogen ices that dominate Pluto's surface have complicated spatial distributions resulting from sublimation, condensation, and glacial flow acting over seasonal and geological time scales. Pluto's water ice "bedrock" was also mapped, with isolated outcrops occurring in a variety of settings. Pluto's surface exhibits complex regional color diversity associated with its distinct provinces. Charon's color pattern is simpler, dominated by neutral low latitudes and a reddish northern polar region. Charon's near-infrared spectra reveal highly localized areas with strong ammonia absorption tied to small craters with relatively fresh-appearing impact ejecta.

Computer-aided combined movement examination of the lumbar spine and manual therapy implications: Case report.

Combined movement examination (CME) of the lumbar spine has been recommended for clinical examination as it confers information about mechanical pain patterns. However, little quantitative study has been undertaken to validate its use in manual therapy practice. This study used computer aided CME to develop a normal reference range, and to guide provisional diagnosis and management. Two cases were assessed, before and after manual therapy using CME, a pain Visual Analogue Scale, the Roland Morris Low Back Pain and Disability Questionnaire and the Short Form (SF-12) Health Survey. Diagnosis and management were guided by comparing each CME pattern with the age and gender matched reference range. Self-reports data and CME total change scores were markedly improved for both cases, particularly for the most painful and restricted CME directions. This report describes how computer-aided CME and a normal reference range may be used objectively to inform a diagnosis and as an outcome measure in cases of mechanical LBP. Future investigations of cases with specific lumbar pathologies are required to validate this concept.

Low back pain misdiagnosis or missed diagnosis: Core principles.

Consensus guidelines for the management of low back pain recommend that the clinician use contemporary best practice for assessment and treatment, consider biopsychosocial factors and, if chronic, use a multimodal and multi-disciplinary approach. Where guidelines are not followed and basic assessment is inadequate the diagnosis may be compromised and the sequelae of errors compounded. Factors such as a lack of knowledge or recognition of the common structure specific pain referral patterns, poor clinical reasoning, inappropriate referral and predilection for popular management approaches also contribute to mis-diagnosis and mis-management. This report describes two cases of chronic low back pain with lengthy histories of multiple failed interventions to highlight the consequences of focussing on a singular approach to the exclusion of evidence based pathways and the resulting risk of a missed diagnosis. The eventual management to mitigate these problems is reported with the aid of low back pain outcome measures, computer-aided combined movement examination, disability and pain questionnaires and health quality of life surveys.

Assessing the clinical utility of combined movement examination in symptomatic degenerative lumbar spondylosis.

OBJECTIVES: The aim of this study is to report the development and validation of a low back computer-aided combined movement examination protocol in normal individuals and record treatment outcomes of cases with symptomatic degenerative lumbar spondylosis. DESIGN: Test-retest, following intervention. BACKGROUND: Self-report assessments and combined movement examination were used to record composite spinal motion, before and following neurosurgical and pain medicine interventions. METHODS: 151 normal individuals aged from 20 years to 69 years were assessed using combined movement examination between L1 and S1 spinal levels to establish a reference range. Cases with degenerative low back pain and sciatica were assessed before and after therapeutic interventions with combined movement examination and a battery of self-report pain and disability questionnaires. Change scores for combined movement examination and all outcome measures were derived. FINDINGS: Computer-aided combined movement examination validation and intraclass correlation coefficient with 95% confidence interval and least significant change scores indicated acceptable reliability of combined movement examination when recording lumbar movement in normal subjects. In both clinical cases lumbar spine movement restrictions corresponded with self-report scores for pain and disability. Post-intervention outcomes all showed significant improvement, particularly in the most restricted combined movement examination direction. INTERPRETATION: This study provides normative reference data for combined movement examination that may inform future clinical studies of the technique as a convenient objective surrogate for important clinical outcomes in lumbar degenerative spondylosis. It can be used with good reliability, may be well tolerated by individuals in pain and appears to change in concert with validated measures of lumbar spinal pain, functional limitation and quality of life.

Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites.

Antigen-mediated cross-linking of Immunoglobulin E (IgE) bound to mast cells/basophils via FcɛRI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FcɛRI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FcɛRI signals for DC function remain poorly understood. We show that humanized mice that express FcɛRI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FcɛRI cross-linking fails to induce maturation or production of inflammatory mediators in human DCs and FcɛRI-humanized DCs. Furthermore, conferring expression of FcɛRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcɛRI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcɛRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast cell-dependent allergic phenotype observed in FcɛRI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.

Referrer and service provider beliefs and attitudes towards rehabilitation in the home; factors related to utilisation of Early Supported Discharge.

PURPOSE: To investigate the attitudes and beliefs held by referrers and service providers of an Australian Early Supported Discharge (ESD) service called "Rehabilitation in the Home" (RITH); with particular consideration of factors that may influence referral to RITH. METHODS: A cross-sectional online survey based on the Theory of Planned Behaviour was undertaken. RESULTS: There were 113 respondents; 90 referrers and 23 service providers. Referrers and RITH staff had a moderately favourable attitude towards RITH. The majority of referrers, and, to a greater degree, RITH staff members, understood and appreciated the advantages ascribed to ESD. However, views varied with regard to some of the factors upon which the decision to refer to RITH rests. Two-fifths of referrers did not think that RITH provided hospital equivalent therapy intensity and over one-fifth of referrers had concerns about the capability of the RITH service to provide specialist stroke rehabilitation. Opinion of RITH staff was also varied on these topics. CONCLUSIONS: This study provides evidence that there was a level of uncertainty amongst referrers and RITH service providers regarding issues directly and indirectly related to patient eligibility and RITH service capability. This uncertainty needs to be explored in future research. IMPLICATIONS FOR REHABILITATION: Differences in views held by referrers and ESD service providers were identified in this study that could lead to inconsistencies in patient selection for, and under-utilization of, ESD services. Improved communication between referrers and ESD service providers, for instance attendance of RITH staff at inpatient team meetings, could ameliorate some of these misconceptions. On-going education of referrers about service capability is essential to ensure timely transfer of appropriate clients to ESD services.

Nanoscale heat engine beyond the Carnot limit.

We consider a quantum Otto cycle for a time-dependent harmonic oscillator coupled to a squeezed thermal reservoir. We show that the efficiency at maximum power increases with the degree of squeezing, surpassing the standard Carnot limit and approaching unity exponentially for large squeezing parameters. We further propose an experimental scheme to implement such a model system by using a single trapped ion in a linear Paul trap with special geometry. Our analytical investigations are supported by Monte Carlo simulations that demonstrate the feasibility of our proposal. For realistic trap parameters, an increase of the efficiency at maximum power of up to a factor of 4 is reached, largely exceeding the Carnot bound.