Periodic fever due to a novel TNFRSF1A mutation in a heterozygous Chinese carrier of MEFV E148Q

SIR, The hereditary periodic fever syndromes are characterizedby recurrent episodes of fever due to multisystemic inflammation.In the case of autosomal dominantly inherited tumour necrosisfactor (TNF) receptor-associated periodic syndrome (TRAPS),these attacks are associated with severe abdominal pain, localizedmyalgia, painful migratory erythematous skin rash, conjunctivitisand/or periorbital oedema. TRAPS is caused by sequence alterationsin the TNFRSF1A gene, which encodes the 55-kDa TNF receptor[1]. Familial Mediterranean fever (FMF) is the most common autosomalrecessively inherited periodic fever syndrome. Attacks of FMFare of 1–3 days’     

The rotational and divergent components of atmospheric circulation on tidally locked planets

Tidally locked exoplanets likely host global atmospheric circulations with a superrotating equatorial jet, planetary-scale stationary waves, and thermally driven overturning circulation. In this work, we show that each of these features can be separated from the total circulation by using a Helmholtz decomposition, which splits the circulation into rotational (divergence-free) and divergent (vorticity-free) components. This technique is applied to the simulated circulation of a terrestrial planet and a gaseous hot Jupiter. For both planets, the rotational component comprises the equatorial jet and stationary waves, and the divergent component contains the overturning circulation. Separating out each component allows us to evaluate their spatial structure and relative contribution to the total flow. In contrast with previous work, we show that divergent velocities are not negligible when compared with rotational velocities and that divergent, overturning circulation takes the form of a single, roughly isotropic cell that ascends on the day side and descends on the night side. These conclusions are drawn for both the terrestrial case and the hot Jupiter. To illustrate the utility of the Helmholtz decomposition for studying atmospheric processes, we compute the contribution of each of the circulation components to heat transport from day side to night side. Surprisingly, we find that the divergent circulation dominates day–night heat transport in the terrestrial case and accounts for around half of the heat transport for the hot Jupiter. The relative contributions of the rotational and divergent components to day–night heat transport are likely sensitive to multiple planetary parameters and atmospheric processes and merit further study.

Exoplanets, which are planets orbiting stars other than the Sun, have revealed a variety of novel forms of atmospheric circulation. The most notable of these is the circulation of tidally locked planets, which are close enough to their host star that tidal stresses between planet and star cause the planet’s orbital and rotational periods to synchronize (1, 2). These planets always present the same side to their star, yielding a permanent day side and night side.Understanding the global circulation of tidally locked planets is vital to interpreting observations of their atmospheres and studying their atmospheric stability and habitability. The circulation transports heat, chemical species, and clouds around the planet. This affects the observable “phase curve,” which is the light emitted or reflected by the planet as it rotates (3–5). Accurate retrievals of chemical composition and cloud structure depend on understanding the temperature structure of the atmosphere, which is determined by the circulation (6–9). Vertical motion in the atmosphere affects the transport and distribution of chemical species and clouds (10, 11), which will also have observable effects. In addition, the circulation may be crucial to supporting a habitable atmosphere on a terrestrial (rocky) planet, with sufficient heat transport needed to prevent volatile species from condensing on the cold night side and leading to atmospheric collapse (12–15).Previous work has shown that the circulation on tidally locked planets is driven by the strong heating/cooling gradient between their day sides and night sides (16–19). The day–night forcing generates overturning circulation, which features air rising on the day side and sinking on the night side (16). This vertical motion then leads to the generation of stationary waves (20, 21), which in turn can accelerate a prograde (superrotating) equatorial jet (21–24). However, the relative contribution of each of these components to the total circulation is poorly understood, as no study has shown how they can be isolated from one another.In this study we address this issue by showing how the overturning circulation, stationary waves, and superrotating jet can be separated out from the total circulation using a Helmholtz decomposition, which uniquely divides the total circulation u=(u,v) into divergent (“vorticity-free”) and rotational (“divergence-free”) components (25):u=ud+ur[1]=−∇χ+k×∇ψ.[2]Above, χ is the velocity potential function, and ψ is a streamfunction. χ and ψ are obtained from∇2χ=δ[3]∇2ψ=ζ,[4]where δ is the divergence and ζ is the vorticity. We apply the Helmholtz decomposition to the horizontal velocity fields output from two well-studied general circulation model (GCM) simulations of tidally locked atmospheres, one representing a terrestrial planet (26) and the other a giant gaseous planet (a “hot Jupiter”) (27). Details of the numerical procedure used to invert Eqs. 3 and 4 are provided in Materials and Methods. The Helmholtz decomposition has been used extensively to study the Earth’s atmospheric circulation (25). We apply it for the first time to the atmospheric circulation of tidally locked planets.Fig. 1 shows the global circulation of the terrestrial planet and hot Jupiter simulations that we analyze in this study. The terrestrial simulation was run using the GCM Exo-FMS (24, 26), using parameters appropriate for typical terrestrial tidally locked planets, such as those in the Trappist-1 system (29). The hot Jupiter simulation was run using the GCM THOR (27, 30), configured with parameters appropriate for the planet HD 189733b (31). In both simulations, the substellar point is located at 0° longitude, 0° latitude. Model details and parameters are described in Materials and Methods for both cases. The data for the THOR simulation were provided to us by the developers of THOR.Open in a separate windowFig. 1.The global circulation of the idealized tidally locked planets simulated in Exo-FMS and THOR. (Left column) Terrestrial simulation, showing the height and velocity fields at 0.4 bar and the zonal-mean zonal velocity. (Right column) Hot Jupiter simulation, showing the temperature and velocity fields at 0.02 bar and the zonal-mean zonal velocity. Both simulations have the eastward equatorial jet and eastward hot-spot shift typical of tidally locked planets. For both simulations, the substellar point is located at (0°,0°). We show the height field for the terrestrial case and the temperature field for the gaseous case for consistency with the original publications where their overall circulation was analyzed (26, 27). In both atmospheres, the height and temperature fields have the same qualitative structure as the thickness of a hydrostatic layer between two pressure levels is proportional to its temperature (22). This relationship is expressed by the hypsometric equation (28).Fig. 1, Left column shows the circulation of the terrestrial planet simulation. Fig. 1, Top Left shows the height and velocity field at 0.4 bar, and Fig. 1, Bottom Left shows the zonal-mean zonal velocity. These fields show the key features of its circulation: a “hot spot” shifted eastward of the substellar point, stationary planetary-scale waves, and an eastward equatorial jet produced by these waves (22–24). Fig. 1, Right column shows the hot Jupiter. Temperature and velocity fields at 0.02 bar are shown in Fig. 1, Top Right, and the zonal-mean zonal velocity is shown in Fig. 1, Bottom Right. This atmosphere has the same key features as the terrestrial case, despite its much higher temperature, larger size, and faster rotation rate. In this study we decompose the velocity fields of our two simulations into two physically distinct circulations and show how they relate to these key features.     

Integrins protect sensory neurons in models of paclitaxel-induced peripheral sensory neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent adverse effect of treatment in cancer patients and survivors (1). CIPN significantly impacts quality of life as damage to sensory nerves may be permanent, and is often a dose-limiting factor during cancer treatment (2–4). Patients with CIPN report pain-related symptoms, including allodynia, hyper- or hypoalgesia, or pain that can be more severe than the pain associated with the original cancer (4). Despite increasing data on agents that protect sensory nerves, our limited understanding of the mechanisms of CIPN impedes effective treatment (5). Studies from model systems may be helpful in identifying molecules that protect sensory neuron morphology and function from the effects of chemotherapeutics.In the present study, we explored the mechanisms of CIPN induced by paclitaxel using two established models: Drosophila larval nociceptive neurons (6, 7) and primary dorsal root ganglia (DRG) neurons isolated from adult mouse (8). Similar to other peripheral neuropathies, CIPN models using paclitaxel, bortezomib, oxaliplatin, and vincristine report changes in unmyelinated intraepidermal nerve fibers (IENFs) that detect painful or noxious stimuli (9–14). These small fibers are embedded in the epidermis, and continuously turn over coincident with the turnover of skin (9, 15). Drosophila class IV nociceptive neurons are a favored model for genetic studies of nociceptive neuron development and signaling mechanisms (16). Prior studies showed that class IV neuron morphology is sensitive to paclitaxel and demonstrated morphological changes of nociceptive neurons at the onset and the end stage of paclitaxel-induced pathology (6, 7). Specifically, chronic treatment of high doses (30 μM) induce fragmentation and simplification of branching of sensory terminals (6). Additionally, acute treatments of moderate doses (10 to 20 μM) induced hyperbranching of sensory arbors without changing the branch patterns or degeneration (7). Nociceptive neurons in Drosophila larvae detect multiple qualities of noxious stimuli (17, 18), and project naked nerve terminals that are partially embedded in the epidermis (19, 20). Larvae have a stereotyped behavioral response toward noxious stimuli that can serve as a readout of nociceptive neuron function (17, 21). Nociceptive neurons in Drosophila larvae may therefore serve as a good in vivo model to study morphological and functional changes to sensory neurons induced by chemotherapeutics.Paclitaxel binds to tubulin and prevents microtubule disassembly. It is a commonly used chemotherapeutic drug for treatment of solid cancers, such as breast, ovarian, and lung cancers, by virtue of its ability to inhibit cell division. Paclitaxel causes chronic sensory neuropathy in patients and animal models (22–24). Several CIPN animal and in vitro models have also revealed acute effects of paclitaxel (7, 8, 24–26). While the mechanisms of acute and chronic neurodegeneration are likely to be distinct (27), how long-term treatment of paclitaxel can affect sensory neuron morphology and function, and how neuronal arbors can be protected against long-term toxicity is not understood.Several studies have shown that nociceptive sensory terminals share a close relationship with specific extracellular structures, most notably epidermal cells and the extracellular matrix (ECM). Thus, in addition to direct effects on neurons, paclitaxel could conceivably destabilize terminals by disrupting relationships with the extracellular environment. Indeed, a study in zebrafish indicates that epidermal cells are directly affected by paclitaxel and that epidermal changes precede neuronal degradation, indicating that degradation of neuronal substrates contributes to degeneration of adjacent arbors (25). For the most part, however, extracellular contributions to neuropathy induced by chemotherapeutics are still poorly characterized. It is therefore important to determine how sensory terminals are maintained in the context of a dynamic extracellular environment that itself may be sensitive to chemotherapeutics. Integrins are a key mediator of the interaction between cells and the ECM, and impact dendrite stabilization and maintenance in both vertebrate and invertebrate systems (20, 28, 29). Prior studies in other systems indicate that integrin levels at the surface are maintained by continuous recycling via tight regulation of the endosomal pathway rather than degradation and de novo synthesis (30). Decreased recycling or increased degradation could lead to depletion of the surface receptors (31, 32) responsible for arbor maintenance and, in turn, degeneration of nociceptive terminals. We therefore explored whether integrin–ECM interactions may impact sensory neuron maintenance upon paclitaxel-induced toxicity and how the endosomal–lysosomal pathway may be linked to the maintenance of sensory neurons.Here, we have used Drosophila and isolated mouse DRG neurons to investigate the pathological effect of paclitaxel in sensory neurons. Morphological changes in Drosophila neurons occurred at paclitaxel doses that also caused changes in thermal nociceptive behaviors. Cell-specific overexpression of integrins protected nociceptive neurons from morphological alterations and prevented the thermal nociceptive behavior deficits caused by paclitaxel in Drosophila. Transduction of integrins also protected adult mouse DRG sensory neurons from paclitaxel-induced toxicity in vitro, indicating that integrin-mediated protection is conserved in a vertebrate model of CIPN. We provide evidence that paclitaxel alters intracellular trafficking in both Drosophila and mouse models of CIPN. Furthermore, our biochemical analysis indicates a reduction of integrin surface availability, suggesting paclitaxel-induced recycling defects in mouse DRG neurons in vitro. Our study suggests that altered interactions between sensory neurons and their extracellular environment are an important contributor to paclitaxel-induced neuronal pathology, and that preventing these changes may offer a therapeutic approach.     

An overview of the endocrinology of skeletal muscle.

Endocrine regulation of the balance between skeletal muscle anabolism and catabolism has been investigated extensively. Factors determining whether hormones exert anabolic or catabolic influences are multifaceted and often unclear. Testosterone, growth hormone, insulin and insulin-like growth factor-I have complex anabolic effects, some of which have only recently been elucidated, and are important regulators of muscle remodeling, whereas glucocorticoids have direct catabolic effects and induce muscle protein loss. The effects of estrogen are poorly understood and warrant further study. We review recent literature and evaluate the hormones driving skeletal muscle anabolism and catabolism, which ultimately dictate the endocrinology and metabolism of skeletal muscle in humans. Understanding hormonal regulation of skeletal muscle remodeling might facilitate development of improved hormone-mediated therapies for muscle wasting conditions.     

Designer broad-spectrum polyimidazolium antibiotics

For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.

AMPs and AMP mimics have attracted considerable attention as candidates for therapeutic development (1). The basic design elements include a region of charged residues, generally cationic residues, enabling interaction with bacterial cell surfaces, combined with a hydrophobic nature in AMPs (2). Unfortunately, AMPs and related polymers, in general, have one or more issues that limit their use as broad-spectrum antibiotics. Some are quite toxic to human cells, the potency of some is not adequate for human administration, others are sensitive to salt at levels present in human fluids, and some are too difficult and expensive to synthesize (3, 4). One broad-spectrum antimicrobial peptide, CST has seen increased recent use as a last resort antibiotic. CST is believed to kill bacteria by virtue of its ability to disrupt membrane integrity (5). This antibiotic requires intravenous administration and is nephrotoxic (6). The emergence of CST-resistant pathogens has also become a significant problem (7). We are unaware of any new broad-spectrum AMPs that have advanced to clinical trials.Imidazolium (IM) salts are antimicrobials (8), and there is an emerging literature on antimicrobial activity of side-chain and main-chain polyimidazolium (PIM) salts with chemical structures that are in some ways similar to those we describe. Although PIMs are potent antimicrobials, there are biocompatibility problems hindering their development, and some have somewhat limited activity spectra. As with other AMPs, there have been toxicity issues, potency issues, and delivery issues as many have large molecular masses, and there is little known about mammalian cell toxicity or mechanism of action (9–12).Here we show that members of a series of PIMs we designed and synthesized are potent broad-spectrum antibacterial compounds. We selected two for further analysis and showed they retain activity even against pan-antibiotic-resistant bacteria. Unlike CST and many other AMPs, which disrupt bacterial membranes, our model PIM is bactericidal without disrupting bacterial membranes. Our experiments provide insights about mechanism of action, the potential for the emergence of PIM resistance, and indicate PIMs are effective against a model gram-negative and a model gram-positive pathogen in murine infection models.     

Low density lipoprotein receptor activity in freshly isolated human blood monocytes and lymphocytes

Circulating human monocytes and lymphocytes were isolated by counterflow and density gradient centrifugation. Binding and degradation of low density lipoprotein (LDL) occurred predominantly in monocytes and to a much lesser extent in lymphocytes. The findings are consistent with greater LDL receptor activity in freshly isolated monocytes than lymphocytes, in keeping with differences in other cell surface receptors between these two cell types. Therefore, when freshly isolated mixed mononuclear cells are used to study LDL receptor activity in vivo in humans, careful attention needs to be given to the proportions of monocytes and lymphocytes, or alternatively, relatively pure preparations of monocytes should be used.