Treatment of type 2 diabetes with the designer cytokine IC7Fc.

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.

Cyclic and Linear Tetrablock Copolymers Synthesized at Speed and Scale by Lewis Pair Polymerization of a One-Pot (Meth)acrylic Mixture and Characterized at Multiple Levels.

Cyclic block copolymers (cBCP) are fundamentally intriguing materials, but their synthetic challenges that demand precision in controlling both the monomer sequence and polymer topology limit access to AB and ABC block architectures. Here, we show that cyclic ABAB tetra-BCPs (cABAB) and their linear counterpart (lABAB) can be readily obtained at a speed and scale from one-pot (meth)acrylic monomer mixtures, through coupling the Lewis pair polymerization's unique compounded-sequence control with its precision in topology control. This approach achieves fast (<15 min) and quantitative (>99%) conversion to tetra-BCPs of predesignated linear or cyclic topology at scale (40 g) in a one-pot procedure, precluding the needs for repeated chain extensions, stoichiometric addition steps, dilute conditions, and postsynthetic modifications, and/or postsynthetic ring-closure steps. The resulting lABAB and cABAB have essentially identical molecular weights (Mn = 165-168 kg mol-1) and block degrees/symmetry, allowing for direct behavioral comparisons in solution (hydrodynamic volume, intrinsic viscosity, elution time, and refractive indices), bulk (thermal transitions), and film (thermomechanical and rheometric properties and X-ray scattering patterns) states. To further the morphological characterizations, allylic side-chain functionality is exploited via the thiol-ene click chemistry to install crystalline octadecane side chains and promote phase separation between the A and B blocks, allowing visualization of microdomain formation.

Hybrid Monomer Design Synergizing Property Trade-offs in Developing Polymers for Circularity and Performance.

Current search for more sustainable plastics seeks to redesign polymers possessing both chemical recyclability to monomer for a circular plastics economy and desirable performance that can rival or even exceed today's non-recyclable or hard-to-recycle petroleum-based incumbents. However, within a traditional monomer framework it is challenging to optimize, concurrently, contrasting polymerizability/depolymerizability and recyclability/performance properties. Here, we highlight the emerging hybrid monomer design strategy to develop intrinsically circular polymers with tunable performance properties, aiming to unify desired, but otherwise conflicting, properties in a single monomer. Conceptually, this design hybridizes parent monomer pairs of contrasting, mismatching, or matching properties into offspring monomers that not only unify the above-described conflicting properties but also radically alter the resultant polymer properties far beyond the limits of what either parent homopolymers or their copolymers can achieve.

Meningeal Lymphatic vasculature in health and disease.

PURPOSE OF REVIEW: The recent (re)discovery of the meningeal lymphatic has brought a new player in brain neurophysiology. This review highlights the state of the current research on the meningeal lymphatic vasculature, from its specific physiology to its increasing implication in normal and pathological brain function. RECENT FINDINGS: Growing evidence are emerging about the uniqueness of the meningeal lymphatic vasculature and its implication in multiple neurological and neurotraumatic disorders. SUMMARY: These studies are highlighting a new and unexpected role for the lymphatic vasculature in brain function and a potential new therapeutic target for neurological disorders.

Compounded Interplay of Kinetic and Thermodynamic Control over Comonomer Sequences by Lewis Pair Polymerization.

The design of facile synthetic routes to well-defined block copolymers (BCPs) from direct polymerization of one-pot comonomer mixtures, rather than traditional sequential additions, is both fundamentally and technologically important. Such synthetic methodologies often leverage relative monomer reactivity toward propagating species exclusively and therefore are rather limited in monomer scope and control over copolymer structure. The recently developed compounded sequence control (CSC) by Lewis pair polymerization (LPP) utilizes synergistically both thermodynamic (Keq) and kinetic (kp) differentiation to precisely control BCP sequences and suppress tapering and misincorporation errors. Here, we present an in-depth study of CSC by LPP, focusing on the complex interplay of the fundamental Keq and kp parameters, which enable the unique ability of CSC-LPP to precisely control comonomer sequences across a variety of polar vinyl monomer classes. Individual Lewis acid equilibrium and polymerization rate parameters of a range of commercially relevant monomers were experimentally quantified, computationally validated, and rationalized. These values allowed for the judicious design of copolymerizations which probed multiple hypotheses regarding the constructive vs conflicting nature of the relationship between Keq and kp biases, which arise during CSC-LPP of comonomer mixtures. These relationships were thoroughly explored and directly correlated with resultant copolymer microstructures. Several examples of higher-order BCPs are presented, further demonstrating the potential for materials innovation offered by this methodology.

Mechanism of Spatial and Temporal Control in Precision Cyclic Vinyl Polymer Synthesis by Lewis Pair Polymerization.

In typical cyclic polymer synthesis via ring-closure, chain growth and cyclization events are competing with each other, thus affording cyclic polymers with uncontrolled molecular weight or ring size and high dispersity. Here we uncover a mechanism by which Lewis pair polymerization (LPP) operates on polar vinyl monomers that allows the control of where and when cyclization takes place, thereby achieving spatial and temporal control to afford precision cyclic vinyl polymers or block copolymers with predictable molecular weight and low dispersity (≈1.03). A combined experimental and theoretical study demonstrates that cyclization occurs only after all monomers have been consumed (when) via conjugate addition of the propagating chain end to the specific site of the initiating chain end (where), allowing the cyclic polymer formation steps to be regulated and executed with precision in space and time.

Oleate disrupts cAMP signaling, contributing to potent stimulation of pancreatic ß-cell autophagy.

Autophagy is critical for maintaining cellular function via clearance of excess nutrients and damaged organelles. In pancreatic ß-cells, it helps counter the endoplasmic reticulum (ER) stress that impairs insulin secretory capacity during Type 2 diabetes. Chronic exposure of ß-cells to saturated fatty acids (FAs) such as palmitate stimulates ER stress and modulates autophagy, but the effects of unsaturated FAs such as oleate, which are also elevated during obesity, are less well understood. We therefore treated MIN6 cells and mouse islets for 8-48 h with either palmitate or oleate, and then monitored autophagic flux, signaling pathways, lysosomal biology, and phospholipid profiles. Compared with palmitate, oleate more effectively stimulated both autophagic flux and clearance of autophagosomes. The flux stimulation occurred independently of ER stress, nutrient-sensing (mTOR) and signaling pathways (protein kinases A, C, and D). Instead the mechanism involved the exchange factor directly activated by cAMP 2 (EPAC2). Oleate reduced cellular cAMP, and its effects on autophagic flux were reproduced or inhibited, respectively, by Epac2 knockdown or activation. Oleate also increased lysosomal acidity and increased phospholipid saturation, consistent with improved autophagosomal fusion with lysosomes. We conclude that a potent stimulation of autophagy might help explain the known benefits of unsaturated FAs in countering the toxicity of saturated FAs in ß-cells during obesity and lipid loading.

Regulation of mitochondrial metabolism in murine skeletal muscle by the medium-chain fatty acid receptor Gpr84.

Fatty acid receptors have been recognized as important players in glycaemic control. This study is the first to describe a role for the medium-chain fatty acid (MCFA) receptor G-protein-coupled receptor (Gpr) 84 in skeletal muscle mitochondrial function and insulin secretion. We are able to show that Gpr84 is highly expressed in skeletal muscle and adipose tissue. Mice with global deletion of Gpr84 [Gpr84 knockout (KO)] exhibit a mild impairment in glucose tolerance when fed a MCFA-enriched diet. Studies in mice and pancreatic islets suggest that glucose intolerance is accompanied by a defect in insulin secretion. MCFA-fed KO mice also exhibit a significant impairment in the intrinsic respiratory capacity of their skeletal muscle mitochondria, but at the same time also exhibit a substantial increase in mitochondrial content. Changes in canonical pathways of mitochondrial biogenesis and turnover are unable to explain these mitochondrial differences. Our results show that Gpr84 plays a crucial role in regulating mitochondrial function and quality control.-Montgomery, M. K., Osborne, B., Brandon, A. E., O'Reilly, L., Fiveash, C. E., Brown, S. H. J., Wilkins, B. P., Samsudeen, A., Yu, J., Devanapalli, B., Hertzog, A., Tolun, A. A., Kavanagh, T., Cooper, A. A., Mitchell, T. W., Biden, T. J., Smith, N. J., Cooney, G. J., Turner, N. Regulation of mitochondrial metabolism in murine skeletal muscle by the medium-chain fatty acid receptor Gpr84.

High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice.

AIMS/HYPOTHESIS: Defective beta cell function during lipid oversupply and type 2 diabetes is associated with dysregulation of lysosomal function and autophagy. Whether this dysregulation represents augmentation or inhibition is unclear because of technical limitations in assaying autophagy. The current aim was to determine the effects of high-fat feeding on true autophagic flux in beta cells in vivo in mice, and to establish the relationship between autophagy, endoplasmic reticulum (ER) stress and apoptosis. METHODS: Green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) mice were fed chow or high-fat diets for 8-10 weeks and injected with 100 mg kg(-1) day(-1) chloroquine for 5 days, prior to being killed, to block clearance of autophagic markers. Pancreases and livers were fixed and GFP-LC3 aggregates or autophagosomes were detected by fluorescence or electron microscopy, respectively. Independently, islets isolated from chow or high-fat-fed mice were treated for 2 h with chloroquine ex vivo, and immunoblotting was performed for markers of autophagy (LC3 lipidation - LC3II and p62/SQSTM1), ER stress (C/EBP homology protein [CHOP], phosphorylated eukaryotic initiation factor 2α [p-eIFα] and inositol requiring enzyme 1α [p-IRE1α]) and apoptosis (cleaved caspase-3). RESULTS: Numbers of autophagosomes and GFP puncta were increased in beta cells by combined high-fat feeding and chloroquine injection, indicative of enhanced autophagic flux. By contrast, GFP puncta were attenuated in liver under the same conditions. Relative to chow-fed controls, islets isolated from fat-fed mice exhibited higher LC3II levels when treated ex vivo with chloroquine. The combination of high-fat feeding and acute chloroquine treatment induced CHOP, p-eIF2α and caspase-3, but not either treatment alone. CONCLUSIONS/INTERPRETATION: We provide the first in vivo demonstrations that high-fat feeding increases autophagic flux in pancreatic beta cells, and that this serves to protect against induction of terminal ER stress. We also highlight an approach for monitoring dietary alterations in autophagic flux using ex vivo manipulation of isolated islets.

Proton-triggered topological transformation in superbase-mediated selective polymerization enables access to ultrahigh-molar-mass cyclic polymers.

The selective synthesis of ultrahigh-molar-mass (UHMM, >2 million Da) cyclic polymers is challenging as an exceptional degree of spatiotemporal control is required to overcome the possible undesired reactions that can compete with the desired intramolecular cyclization. Here we present a counterintuitive synthetic methodology for cyclic polymers, represented here by polythioesters, which proceeds via superbase-mediated ring-opening polymerization of gem-dimethylated thiopropiolactone, followed by macromolecular cyclization triggered by protic quenching. This proton-triggered linear-to-cyclic topological transformation enables selective, linear polymer-like access to desired cyclic polythioesters, including those with UHMM surpassing 2 MDa. In addition, this method eliminates the need for stringent conditions such as high dilution to prevent or suppress linear polymer contaminants and presents the opposite scenario in which protic-free conditions are required to prevent cyclic polymer formation, which is capitalized to produce cyclic polymers on demand. Furthermore, such UHMM cyclic polythioester exhibits not only much enhanced thermostability and mechanical toughness, but it can also be quantitatively recycled back to monomer under mild conditions due to its gem-disubstitution.

Frailty in an Adult Acute Hospital Population: Predictors, Prevalence, and Outcomes.

Frailty is common among older hospital inpatients. While studies describe frailty prevalence in acute hospitals, it is usually based upon retrospective hospital-coded data or brief screening on admission rather than comprehensive geriatric assessment (CGA). Further, little is known about differences between pre-admission and current frailty status. Given this, we investigated the prevalence of pre-frailty and frailty among adult inpatients in a large university hospital after CGA. Of the 410 inpatients available, 398 were included in the study, with a median age of 70 years; 56% were male. The median length of stay (LOS) at review was 8 days. The point prevalence of frailty was 30% versus 14% for pre-frailty. The median Clinical Frailty Scale score pre-admission was 3/9, which was significantly lower than at review, which was 4/9 (p < 0.001). After adjusting for age and sex, frailty was associated with greater odds of prolonged LOS (odds ratio [OR] 1.7, p = 0.045), one-year mortality (OR 2.1, p = 0.006), and one-year institutionalisation (OR 9, p < 0.001) but not re-admission. Frailty was most prevalent on medical and orthopaedic wards. In conclusion, CGA is an important risk assessment for hospitalised patients. Frailty was highly prevalent and associated with poor healthcare outcomes. Frailty status appears to worsen significantly during admission, likely reflecting acute illness, and it may not reflect a patient's true frailty level. The development of frailty clinical care pathways is recommended in order to address the poor prognosis associated with a diagnosis of frailty in this setting.

Recurrent or unusual infections in children - when to worry about inborn errors of immunity.

Recurrent infections are a common presenting feature in paediatrics and, while most times considered part of normal growing up, they are also a classical hallmark of inborn errors of immunity (IEI). We aimed to outline the value of currently used signs for IEI and the influence of the changing epidemiology of infectious diseases due to implementation of new vaccines and the effect of the COVID-19 pandemic on the assessment of children with recurrent infections. Warning signs for IEI have been developed, but the supporting evidence for their effectiveness is limited, and immune dysregulation is more commonly recognised as a feature for IEI, making reliable identification of children who should be screened for IEI on clinical grounds difficult. In addition, the epidemiology of infectious diseases is changing due to restrictions related to Covid-19 as well as immunisations, which may change the threshold to screen children for IEI. Treatments for IEI are evolving and are often more effective and less complicated when started early. Screening for IEI can be initiated by the non-immunologist and should be considered early to ensure optimal treatment outcomes.

An analysis of time-varying dynamics in electrically sensitive arthropod hairs to understand real-world electrical sensing.

With increasing evidence of electroreception in terrestrial arthropods, an understanding of receptor level processes is vital to appreciating the capabilities and limits of this sense. Here, we examine the spatio-temporal sensitivity of mechanoreceptive filiform hairs in detecting electrical fields. We first present empirical data, highlighting the time-varying characteristics of biological electrical signals. After which, we explore how electrically sensitive hairs may respond to such stimuli. The main findings are: (i) oscillatory signals (elicited by wingbeats) influence the spatial sensitivity of hairs, unveiling an inextricable spatio-temporal link; (ii) wingbeat direction modulates spatial sensitivity; (iii) electrical wingbeats can be approximated by sinusoidally modulated DC signals; and (iv) for a moving point charge, maximum sensitivity occurs at a faster timescale than a hair's frequency-based tuning. Our results show that electro-mechanical sensory hairs may capture different spatio-temporal information, depending on an object's movement and wingbeat and in comparison with aero-acoustic stimuli. Crucially, we suggest that electrostatic and aero-acoustic signals may provide distinguishable channels of information for arthropods. Given the pervasiveness of electric fields in nature, our results suggest further study to understand electrostatics in the ecology of arthropods and to reveal unknown ecological relationships and novel interactions between species.

ß-cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFß receptor signaling.

We have exploited islet-associated macrophages (IAMs) as a model of resident macrophage function, focusing on more physiological conditions than the commonly used extremes of M1 (inflammation) versus M2 (tissue remodeling) polarization. Under steady state, murine IAMs are metabolically poised between aerobic glycolysis and oxidative phosphorylation, and thereby exert a brake on glucose-stimulated insulin secretion (GSIS). This is underpinned by epigenetic remodeling via the metabolically regulated histone demethylase Kdm5a. Conversely, GSIS is enhanced by engaging Axl receptors on IAMs, or by augmenting their oxidation of glucose. Following high-fat feeding, efferocytosis is stimulated in IAMs in conjunction with Mertk and TGFß receptor signaling. This impairs GSIS and potentially contributes to ß-cell failure in pre-diabetes. Thus, IAMs serve as relays in many more settings than currently appreciated, fine-tuning insulin secretion in response to dynamic changes in the external environment. Intervening in this nexus might represent a means of preserving ß-cell function during metabolic disease.

Observed electric charge of insect swarms and their contribution to atmospheric electricity.

The atmosphere hosts multiple sources of electric charge that influence critical processes such as the aggregation of droplets and the removal of dust and aerosols. This is evident in the variability of the atmospheric electric field. Whereas these electric fields are known to respond to physical and geological processes, the effect of biotic sources of charge has not hitherto been considered. Here, we combine theoretical and empirical evidence to demonstrate that honeybee swarms directly contribute to atmospheric electricity, in proportion to the swarm density. We provide a quantitative assessment of this finding, by comparing the electrical contribution of various swarming insect species with common abiotic sources of charge. This reveals that the charge contribution of some insect swarms will be comparable with that of meteorologically induced variations. The observed transport of charge by insects therefore demonstrates an unexplored role of biogenic space charge for physical and ecological processes in the atmosphere.

ARTP statement on pulmonary function testing 2020.

The Association for Respiratory Technology & Physiology (ARTP) last produced a statement on the performance of lung function testing in 1994. At that time the focus was on a practical statement for people working in lung function laboratories. Since that time there have been many technological advances and alterations to best practice in the measurement and interpretation of lung function assessments. In light of these advances an update was warranted. ARTP, therefore, have provided within this document, where available, the most up-to-date and evidence-based recommendations for the most common lung function assessments performed in laboratories across the UK. These recommendations set out the requirements and considerations that need to be made in terms of environmental and patient factors that may influence both the performance and interpretation of lung function tests. They also incorporate procedures to ensure quality assured diagnostic investigations that include those associated with equipment, the healthcare professional conducting the assessments and the results achieved by the subject. Each section aims to outline the common parameters provided for each investigation, a brief principle behind the measurements (where applicable), and suggested acceptability and reproducibility criteria.

Deaf moths employ acoustic Müllerian mimicry against bats using wingbeat-powered tymbals.

Emitting ultrasound upon hearing an attacking bat is an effective defence strategy used by several moth taxa. Here we reveal how Yponomeuta moths acquire sophisticated acoustic protection despite being deaf themselves and hence unable to respond to bat attacks. Instead, flying Yponomeuta produce bursts of ultrasonic clicks perpetually; a striated patch in their hind wing clicks as the beating wing rotates and bends. This wing structure is strikingly similar to the thorax tymbals with which arctiine moths produce their anti-bat sounds. And indeed, Yponomeuta sounds closely mimic such arctiine signals, revealing convergence in form and function. Because both moth taxa contain noxious compounds, we conclude they are mutual Müllerian acoustic mimics. Yponomeuta's perpetual clicking would however also attract bat predators. In response, their click amplitude is reduced and affords acoustic protection just as far as required, matching the distance over which bat biosonar would pick up Yponomeuta echoes anyway - advanced acoustic defences for a deaf moth.

Comparison of Frailty Screening Instruments in the Emergency Department.

Early identification of frailty through targeted screening can facilitate the delivery of comprehensive geriatric assessment (CGA) and may improve outcomes for older inpatients. As several instruments are available, we aimed to investigate which is the most accurate and reliable in the Emergency Department (ED). We compared the ability of three validated, short, frailty screening instruments to identify frailty in a large University Hospital ED. Consecutive patients aged ≥70 attending ED were screened using the Clinical Frailty Scale (CFS), Identification of Seniors at Risk Tool (ISAR), and the Programme on Research for Integrating Services for the Maintenance of Autonomy 7 item questionnaire (PRISMA-7). An independent CGA using a battery of assessments determined each patient's frailty status. Of the 280 patients screened, complete data were available for 265, with a median age of 79 (interquartile ±9); 54% were female. The median CFS score was 4/9 (±2), ISAR 3/6 (±2), and PRISMA-7 was 3/7 (±3). Based upon the CGA, 58% were frail and the most accurate instrument for separating frail from non-frail was the PRISMA-7 (AUC 0.88; 95% CI:0.83-0.93) followed by the CFS (AUC 0.83; 95% CI:0.77-0.88), and the ISAR (AUC 0.78; 95% CI:0.71-0.84). The PRISMA-7 was statistically significantly more accurate than the ISAR (p = 0.008) but not the CFS (p = 0.15). Screening for frailty in the ED with a selection of short screening instruments, but particularly the PRISMA-7, is reliable and accurate.

Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance.

Protein kinase C epsilon (PKCɛ) activation in the liver is proposed to inhibit insulin action through phosphorylation of the insulin receptor. Here, however, we demonstrated that global, but not liver-specific, deletion of PKCɛ in mice protected against diet-induced glucose intolerance and insulin resistance. Furthermore, PKCɛ-dependent alterations in insulin receptor phosphorylation were not detected. Adipose-tissue-specific knockout mice did exhibit improved glucose tolerance, but phosphoproteomics revealed no PKCɛ-dependent effect on the activation of insulin signaling pathways. Altered phosphorylation of adipocyte proteins associated with cell junctions and endosomes was associated with changes in hepatic expression of several genes linked to glucose homeostasis and lipid metabolism. The primary effect of PKCɛ on glucose homeostasis is, therefore, not exerted directly in the liver as currently posited, and PKCɛ activation in this tissue should be interpreted with caution. However, PKCɛ activity in adipose tissue modulates glucose tolerance and is involved in crosstalk with the liver.