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Intracellular compartmentalization plays a pivotal role in cellular function, with membrane-bound organelles and membrane-less biomolecular “condensates” playing key roles. These condensates, formed through liquid–liquid phase separation (LLPS), enable selective compartmentalization without the barrier of a lipid bilayer, thereby facilitating rapid formation and dissolution in response to stimuli. Intrinsically disordered proteins (IDPs) or proteins with intrinsically disordered regions (IDRs), which are often rich in charged and polar amino acid sequences, scaffold many condensates, often in conjunction with RNA.

Solutions of oppositely charged polyelectrolytes and surfactants can undergo phase separation, in a charge-driven process known as complex coacervation. These materials are widely used in a variety of applications because of their useful rheological and structural properties. It is understood that these properties are related to the assembly of the surfactants into micelles, which then undergo complexation with the oppositely charged polyelectrolytes to form the coacervate phase. However, there remain challenges in understanding how the molecular features of the components give rise to this useful phase behavior, with a still-nascent understanding of how electrostatics, micelle structure, composition, and steric interactions interplay to govern coacervation. In this paper, we used a combination of experiment and a recently developed hybrid simulation/theory model to understand polyelectrolyte–surfactant coacervates. We used mixtures of ionic and neutral surfactants to systematically vary the micelle surface charge density, along with PEG side-chains on the neutral surfactants to vary the steric repulsions between nearby micelles. Finally, we altered the polyelectrolyte charge density to tune the polymer-mediated attractions between micelles. By mapping the phase behavior of these solutions, we showed that higher charge density on the polymer or micelle, or decreasing steric repulsion, facilitates coacervation. We considered analogous quantities in our simulation/theory model, which makes predictions for both the thermodynamics and the structure of the micelle–polyelectrolyte rich coacervate and micelle–polyelectrolyte poor supernatant phases. By varying the micelle surface charge density and the correlation-based polymer–micelle interaction energy, we showed phase separation behaviors consistent with experiments.

THE POISON BED By Elizabeth Fremantle King James I was, said his contemporaries, ''the wisest fool in Christendom.'' A scholar from his teens, he sponsored the authorized version of the [...]

English novelist Sarah Perry's previous two books include The Essex Serpent SELECTION Sept/Oct 2017), which was named the Water-stones Book of the Year in 2016, and Melmoth (**** Jan/Feb 2019), [...]

When teaching children with disabilities, the home–school music connection can be the key to keeping our students engaged and motivated while increasing students’ self-regulation and positive interactions with peers. This article aims to shed light on classroom experiences with popular music of two third-grade students with sensory processing disorder and on how ‘music sharing turns’ influenced their overall engagement and ability to self-regulate in music classes. Music sharing turns, a weekly music ‘show and tell’, provided opportunities to bring popular music and activities they enjoy at home into the classroom. The results show that the participants were easily engaged and experienced greater self-regulation and awareness of others during music sharing turns. Music sharing turns also provided a predictable environment for peer interaction with opportunities to take on leadership roles within the classroom while remaining open-ended in a way participants could make their own.

Odorants interact with receptors expressed in specialized olfactory neurons, and neurons of the same class send their axons to distinct glomeruli in the brain. The stereotypic spatial glomerular activity map generates recognition and the behavioral response for the odorant. The valence of an odorant changes with concentration, typically becoming aversive at higher concentrations. Interestingly, in Drosophila larvae, the odorant (E)-2-hexenal is aversive at low concentrations and attractive at higher concentrations. We investigated the molecular and neural basis of this phenomenon, focusing on how activities of different olfactory neurons conveying opposing effects dictate behaviors. We identified the repellant neuron in the larvae as one expressing the olfactory receptor Or7a, whose activation alone at low concentrations of (E)-2-hexenal elicits an avoidance response in an Or7a-dependent manner. We demonstrate that avoidance can be overcome at higher concentrations by activation of additional neurons that are known to be attractive, most notably odorants that are known activators of Or42a and Or85c. These findings suggest that in the larval stage, the attraction-conveying neurons can overcome the aversion-conveying channels for (E)-2-hexenal.

AbstractRATIONALE: Sleep disordered breathing (SDB) is associated with adverse health consequences that can be mitigated through timely and effective management. Guidelines provide wait time targets, but the evidence supporting them is unclear. The purpose of this systematic review was to explore the relationship between interventions to improve wait times for SDB and the effects on patient or provider outcomes.METHODS: A targeted search of medical databases was performed from database inception to June 2017. Included studies described an intervention intended to reduce wait times for the diagnosis or treatment of SDB and reported on a patient- or provider-level outcome.RESULTS: The search produced 2,944 abstracts and 51 articles underwent full text review. Ten articles were included in the final review. Five trials reported wait times to diagnosis and treatment, 3 studies described wait times for diagnosis only and 2 studies discussed time to treatment exclusively. All studies were of moderate methodological quality. Wait times were improved in most studies, but due to short follow-up periods a clear relationship with improved health outcomes was rarely established. The variety of interventions limited the characterization of specific wait-times reduction strategies that could reliably improve outcomes.CONCLUSIONS: This review highlights the scarcity of studies but suggests a possible clinical benefit of interventions to reduce wait times. However, generalizability is limited and the short follow-up periods likely underestimate potential positive impacts of reduced wait times. Further studies are needed to better characterize this relationship and to identify additional interventions to deliver more timely patient care.

Recently, Margossian et al. reported pH-responsive complex coacervates formed by a polyzwitterion and a polyelectrolyte in Nature Communications, which remain intact under acidic conditions (pH≤3) yet dissolve with increasing pH, suggesting the potential for oral delivery to the gastrointestinal tract.

The Heavens by Sandra Newman Granta, 12.99 [pounds sterling], pp. 257 The Heavens is Sandra Newman's eighth book. It follows novels featuring, variously, sex addiction, Buddhism and a post-apocalyptic teen [...]

The electrospinning field is dominated by studies that investigate parameters, such as polymer concentration and chain length, to identify conditions where the polymer chains are sufficiently entangled to facilitate fiber formation. Here, we report the first demonstration that linear, nonentangled, oligomeric polyelectrolytes can be electrospun into fibers using a traditional single-nozzle setup. Previously, we have demonstrated that the associative phase separation phenomenon known as complex coacervation facilitates the electrospinning of polyelectrolyte complex fibers directly from water. In this work, we synthesized polycations and polyanions with degrees of polymerization ranging from ∼500 down to <10, representing average molecular weights on the order of 100 to 1 kg/mol. We then quantified the phase behavior and viscosity of our various coacervate samples as a function of both chain length and salt concentration. Our results confirm that the polymer concentration in all samples was near or above the estimated value for the overlap concentration and that only the longest polymer samples were expected to experience entanglements. However, we were able to electrospin fibers from all of our coacervate samples, even oligomers. Thus, the electrospinnability of coacervates is fundamentally different from the traditional electrospinning of linear, neutral polymers or solutions composed of polyelectrolytes mixed with neutral polymers. In the same way that coacervation represents a novel way to enable the electrospinning of polyelectrolytes from water, the associative interactions driving phase separation eliminate the need for entanglements by slowing the timescale for relaxation. Our results suggest an alternative route that enables the electrospinning of novel solutions by decoupling chain-length requirements from other length-dependent parameters.

Objectives:Many children undergo surgery or an invasive procedure during their terminal hospital admission.1The types of procedures, patients, and the intent of the procedures has not been well defined. Understanding these details may help pediatric surgeons better determine the clinical settings in which certain procedures will not enhance palliation or survival. Methods:A retrospective single institution chart review was performed for patients age 14 days to 18 years with chronic conditions who died while inpatient from 2013–2017. Data was gathered on demographics, primary diagnosis, intubation status, palliative care involvement, duration of hospital stay, length of palliative care involvement, and total number of procedures. Negative binomial regression was used to assess association with number of procedures. Results:132 children met inclusion criteria. Most children were White and less than one year old. The most common type of diagnosis was cardiac in nature. Children underwent an average of three procedures. 75% were intubated and 77.5% had palliative care involved. Patients who were less than one year old at death were more likely to have been intubated, had longer terminal hospital stays, and had more procedures. Those who were intubated underwent more procedures and had longer hospital stays. Those with longer palliative care involvement had fewer procedures. Conclusions:Children undergo a significant number of surgical procedures during their terminal hospitalization. This may be influenced by age, intubation status, and length of stay. Ongoing study may help refine which procedures may have limited impact on survival in the chronically ill pediatric population.

Here, we explore the effect of copolymer chemistry on the phase behavior and viscoelasticity of complex coacervates. To this end, we utilized a library of methacrylate copolymers with varying charge densities and hydrophobicity. Our results show that changing the charge density and hydrophobicity drastically affects the phase behavior─with charge density dictating the salt stability and hydrophobicity controlling the polymer concentration of the coacervates. Small-amplitude oscillatory shear measurements were used to study the viscoelastic response of the coacervates, leveraging knowledge of the coacervate phase behavior in tandem with time-salt superposition to construct a series of time-salt-copolymer master curves that highlight the effects of polymer charge density and hydrophobicity. These combined data show evidence of charge-dominated and hydrophobicity-dominated regimes, allowing for an understanding of how copolymer chemistry can be used to tune the mechanical properties of complex coacervates.

FOR SAFETY, HEALTH AND environment managers, dealing with environmental issues is old news. Government regulations mean that the environment has been on the agenda since the 1980s, when saving the [...]

The Shiva Naipaul memorial prize is awarded annually to the contestant best able, like the late Shiva Naipaul, to describe a visit to a foreign place or people. It is […]

AbstractRATIONALE: Quality indicators have been published for the management of sleep-disordered breathing, but the extent to which quality of care is measured by Canadian sleep centers is unknown.OBJECTIVEThe objective of this study is to characterize the measurement of healthcare quality as reported by Canadian sleep centers.METHODSWe performed a national online survey of Canadian sleep centers. Surveys were distributed by Canadian respiratory and sleep specialty societies. Respondents reporting formal quality measurement were contacted to complete telephone interviews that characterized the process through which quality was assessed. Questions explored the indicators used, the process by which quality data was collected and reported and barriers and facilitators to effective quality measurement. Quality indicators were categorized based on the aspect of clinical care being evaluated and classified using the Institute of Medicine’s (IOM) quality dimensions (safe, effective, patient-centered, timely, efficient, equitable) and Donabedian’s structure-process-outcome framework.MEASUREMENTS AND MAIN RESULTS: Thirty-four survey responses were received, of which 20 sleep centers reported formal quality measurement. Interviews with 19 of these centers identified 61 indicators that were classified into 11 unique categories. The IOM dimensions of patient-centeredness, effectiveness and timeliness were most common while no centers evaluated equity and only one center measured efficiency. All centers used process measures, while most used outcome measures and only one used a structural quality measure.CONCLUSIONSAmong Canadian sleep centers that report formally assessing healthcare quality, measurement was highly variable. These findings highlight the need to identify and mitigate barriers to quality measurement to improve sleep-disordered breathing care.

The British Book Awards 2018 has launched with the introduction of two new awards for individuals, Author of the Year and Illustrator of the Year, as well as a new [...]

There was never any pop or rock music in the house when I grew up, so the idea of an album in the ordinary sense (parents playing the Beatles in [...]

Complex coacervates can form through the electrostatic complexation of oppositely charged polymers. The material properties of the resulting coacervates can change based on the polymer chemistry and the complex interplay between electrostatic interactions and water structure, controlled by salt. We examined the effect of varying the polymer backbone chemistry using methacryloyl- and acryloyl-based complex coacervates over a range of polymer chain lengths and salt conditions. We simultaneously quantified the coacervate phase behavior and the linear viscoelasticity of the resulting coacervates to understand the interplay between polymer chain length, backbone chemistry, polymer concentration, and salt concentration. Time-salt superposition analysis was used to facilitate a broader characterization and comparison of the stress relaxation behavior between different coacervate samples. Samples with mismatched polymer chain lengths highlighted the ways in which the shortest polymer chain can dominate the resulting coacervate properties. A comparison between coacervates formed from methacryloyl vs acryloyl polymers demonstrated that the presence of a backbone methyl group affects the phase behavior, and thus the rheology in such a way that coacervates formed from methacryloyl polymers have a similar phase behavior to those of acryloyl polymers with ∼10× longer polymer chains.

Widespread vaccine coverage for viral diseases could save the lives of millions of people each year. For viral vaccines to be effective, they must be transported and stored in a narrow temperature range of 2–8 °C. If temperatures are not maintained, the vaccine may lose its potency and would no longer be effective in fighting disease; this is called the cold storage problem. Finding a way to thermally stabilize a virus and end the need to transport and store vaccines at refrigeration temperatures will increase access to life-saving vaccines. We explore the use of polymer-rich complex coacervates to stabilize viruses. We have developed a method of encapsulating virus particles in liquid complex coacervates that relies on the electrostatic interaction of viruses with polypeptides. In particular, we tested the incorporation of two model viruses; a non-enveloped porcine parvovirus (PPV) and an enveloped bovine viral diarrhea virus (BVDV) into coacervates formed from poly(lysine) and poly(glutamate). We identified optimal conditions (i.e., the relative amount of the two polypeptides) for virus encapsulation, and trends in this composition matched differences in the isoelectric point of the two viruses. Furthermore, we were able to achieve a ∼103–104-fold concentration of virus into the coacervate phase, such that the level of virus remaining in the bulk solution approached our limit of detection. Lastly, we demonstrated a significant enhancement of the stability of non-enveloped PPV during an accelerated aging study at 60 °C over the course of a week. Our results suggest the potential for using coacervation to aid in the purification and formulation of both enveloped and non-enveloped viruses, and that coacervate-based formulations could help limit the need for cold storage throughout the transportation and storage of vaccines based on non-enveloped viruses.

Electrospun biopolyelectrolyte nanofibers hold potential for use in a range of biomedical applications, but eliminating toxic chemicals involved in their production remains a key challenge. In this study, we successfully electrospun nanofibers from an aqueous complex coacervate solution composed of chitosan and hyaluronic acid. Experimentally, we investigated the effect of added salt and electrospinning apparatus parameters, such as how applied voltage affected fiber formation. We also studied how the addition of alcohol cosolvents affected the properties of the coacervate solution and the resulting nanofibers. Overall, we observed a trade-off in how the addition of salt and alcohol affected the phase behavior and rheology of the coacervates and, consequently, the size of the resulting fibers. While salt served to weaken electrostatic associations within the coacervate and decrease the precursor solution viscosity, the addition of alcohol lowered the dielectric constant of the system and strengthened these interactions. We hypothesize that the optimized concentration of alcohol accelerated the solvent evaporation during the electrospinning process to yield desirable nanofiber morphology. The smallest average nanofiber diameter was determined to be 115 ± 30 nm when coacervate samples were electrospun using an aqueous solvent containing 3 wt % ethanol and an applied voltage of 24 kV. These results demonstrate a potentially scalable strategy to manufacture electrospun nanofibers from biopolymer complex coacervates that eliminate the need for toxic solvents and could enable the use of these materials across a range of biomedical applications.

Witnessing and enabling a teenager's successful head injury recovery has reaffirmed one nurse's philosophy of treating patients with head injuries in full confidence of a successful outcome. A 17-year-old college-bound high school student sustained an internal head injury during a car accident leaving him in a coma. Routine treatment and a positive attitude by the attending nurse and his family resulted in his steady improvement and eventual full recovery.

Background:Thiotepa-based autologous stem cell transplantation (ASCT) improves survival in primary central nervous system lymphoma (PCNSL) but up to 30-60% of patients are unable to receive ASCT after MATRix induction, frequently due to treatment-related adverse events. Common conditioning regimens such as thiotepa/BCNU or thiotepa/busulfan/cyclophosphamide have also been associated with risks of pulmonary toxicity or increased transplant-related mortality. Novel strategies to improve the utilization and tolerability of ASCT are therefore needed to maximize the curative potential of this therapy in PCNSL.

The effects of fecal and urinary double incontinence in older stroke survivors with relation to degree of soiling are presented.

Corticotomies are now an integral part of the orthodontist's therapeutic arsenal in adult orthodontics. In recent years, the number of publications about different surgical techniques has increased significantly. This shows that practitioners and patients have a common interest. It is now accepted that corticotomies cause a regional acceleratory phenomenon, which enables a faster dental movement, a reduction in treatment time, as well as a reduction in the risk of root resorption. The perspective of osteogenesis induced by corticotomies has already been mentioned in literature. It could provide a real advantage in maintaining the periodontium, reducing the risk of fenestration or dehiscence and the stability of long-term treatment by increasing the dental bone envelope. Through a clinical case, treated by mini- invasive surgical technique (as described in the previous article), we highlight the potential for osteogenesis induced by alveolar corticotomies and the utility of this procedure in adults.

Charged polymers are ubiquitous in biological systems because electrostatic interactions can drive complicated structure formation and respond to environmental parameters such as ionic strength and pH. In these systems, function emerges from sophisticated molecular design; for example, intrinsically disordered proteins leverage specific sequences of monomeric charges to control the formation and function of intracellular compartments known as membraneless organelles. The role of a charged monomer sequence in dictating the strength of electrostatic interactions remains poorly understood despite extensive evidence that sequence is a powerful tool biology uses to tune soft materials. In this article, we use a combination of theory, experiment, and simulation to establish the physical principles governing sequence-driven control of electrostatic interactions. We predict how arbitrary sequences of charge give rise to drastic changes in electrostatic interactions and correspondingly phase behavior. We generalize a transfer matrix formalism that describes a phase separation phenomenon known as “complex coacervation” and provide a theoretical framework to predict the phase behavior of charge sequences. This work thus provides insights into both how charge sequence is used in biology and how it could be used to engineer properties of synthetic polymer systems.

We present the first demonstration of the direct encapsulation of cargo into polyelectrolyte complex (PEC) fiber mats. This approach takes advantage of the intrinsic self-assembly characteristics of complex coacervates to simplify the formulation requirements to electrospin fibers containing a high loading and an even distribution of cargo. Two families of structurally similar fluorescent dyes were used as model cargo of varying hydrophobicity and charge and were encapsulated into coacervates of poly(4-styrenesulfonic acid, sodium salt) and poly(diallyldimethylammonium chloride). The coacervate phase behavior, dye partitioning, and resulting fibers were systematically investigated as a function of dye and salt concentration. Strong partitioning was facilitated by favorable electrostatic and π–π interactions but was adversely affected by increased salt. We further identified that dye and salt interactions can be treated as independent control parameters to modulate the properties and electrospinnability of the coacervate precursor solutions. These findings facilitate the use of electrospun PEC fibers in applications related to biomedicine, energy, and separations where cargo-loaded mats are needed.

At midnight today, the first snowflake fell Wandering through miles of clear December air. It blew onto my windowpane And lay there, a silent witness To the candlelight twinkling within [...]

The Critics: Arts From the beginning of the pandemic, unable to write the novel I had been working on, and at a loss to comprehend the scale and speed of the changes brought by coronavirus, I spoke often with my friend Dr Sam Guglani, an NHS consultant oncologist based in Cheltenham - where he manages patients with lung and brain tumours - and a novelist and writer for the Lancet. SP This idea that the response to the pandemic has privileged the privileged - and the statistics around the disproportionate deaths of BAME people have made this unignorable - is so vital, and, yes: it damages our shared humanity, absolutely. SP I have begun to see the virus as a kind of magnifying lens. [Extracted from the article]

Novel polymer amphiphiles with chemical structures designed as zwitterionic analogs of Pluronic block copolymers were prepared by controlled free radical polymerization of phosphorylcholine (PC) or choline phosphate (CP) methacrylate monomers from a difunctional poly(propylene oxide) (PPO) macroinitiator. Well-defined, water-dispersible zwitterionic triblock copolymers, or “zwitteronics”, were prepared with PC content ranging from 5 to 47 mol percent and composition-independent surfactant characteristics in water, which deviate from the properties of conventional Pluronic amphiphiles. These PC-zwitteronics assembled into nanoparticles in water, with tunable sizes and critical aggregation concentrations (CACs) based on their hydrophilic–lipophilic balance (HLB). Owing to the lower critical solution temperature (LCST) miscibility of the hydrophobic PPO block in water, PC-zwitteronics exhibited thermoreversible aqueous solubility tuned by block copolymer composition. The chemical versatility of this approach was demonstrated by embedding functionality, in the form of alkyne groups, directly into the zwitterion moieties. These alkynes proved ideal for cross-linking the zwitteronic nanoparticles and for generating nanoparticle-cross-linked hydrogels using UV-initiated thiol–yne “click” chemistry.

Biomolecules exist and function in cellular microenvironments that control their spatial organization, local concentration, and biochemical reactivity. Due to the complexity of native cytoplasm, the development of artificial bioreactors and cellular mimics to compartmentalize, concentrate, and control the local physico-chemical properties is of great interest. Here, we employ self-assembling polypeptide coacervates to explore the partitioning of the ubiquitous cytoskeletal protein actin into liquid polymer-rich droplets. We find that actin spontaneously partitions into coacervate droplets and is enriched by up to ∼30-fold. Actin polymerizes into micrometer-long filaments and, in contrast to the globular protein BSA, these filaments localize predominately to the droplet periphery. We observe up to a 50-fold enhancement in the actin filament assembly rate inside coacervate droplets, consistent with the enrichment of actin within the coacervate phase. Together these results suggest that coacervates can serve as a versatile platform in which to localize and enrich biomolecules to study their reactivity in physiological environments.

ObjectiveOmega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22).DesignA randomised, open-label, cross-over trial of 8 weeks’ treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week ‘washout’ period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry.ResultsBoth omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburiaand Lactobacilluswas observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects.ConclusionOmega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure.Trial registration numberISRCTN18662143.

Potential changes to the El Niño–Southern Oscillation (ENSO) resulting from climate change may have far reaching impacts through atmospheric teleconnections. Here ENSO temperature and precipitation teleconnections between the historical and high‐emission future simulations are compared in 40 models from phase 5 of the Coupled Model Intercomparison Project. Focusing on the global land area only, we show that there are robust increases in the spatial extent of ENSO teleconnections during austral summer in 2040–2089 of ~19% for temperature and ~12% for precipitation in the multimodel mean (MMM), relative to the 1950–1999 period. The MMM further shows that the expansion of ENSO teleconnection extent is at least partly related to a strengthening of ENSO teleconnections over continental regions; however, a consistent strengthening is not found across the individual models. This suggests that while more land may be affected by ENSO, the existing teleconnections may not be simply strengthened. The majority of CMIP5 models project robust increases in the spatial extent of ENSO temperature and precipitation teleconnections over landThe increase in area is related to the amplified ENSO‐driven precipitation across the equatorial Pacific in the futureDespite the robust increase in area over land, we do not find a consistent strengthening of these teleconnections in the individual models

Histone deacetylases (HDACs) have been extensively studied as drug targets in neurodegenerative diseases, but less is known about their role in healthy neurons. We tested zinc-dependent HDACs using RNAi in Drosophila melanogasterand found memory deficits with RPD3and HDAC6. We demonstrate that HDAC6 is required in both the larval and adult stages for normal olfactory memory retention. Neuronal expression of HDAC6rescued memory deficits, and we demonstrate that the N-terminal deacetylase (DAC) domain is required for this ability. This suggests that deacetylation of synaptic targets associated with the first DAC domain, such as the active-zone scaffold Bruchpilot, is required for memory retention. Finally, electrophysiological experiments at the neuromuscular junction reveal that HDAC6mutants exhibit a partial block of homeostatic plasticity, suggesting that HDAC6 may be required for the stabilization of synaptic strength. The learning deficit we observe in HDAC6mutants could be a behavioral consequence of these synaptic defects.

Auditory hair cells contain mechanotransduction channels that rapidly open in response to sound-induced vibrations. We report here that auditory hair cells contain two molecularly distinct mechanotransduction channels. One ion channel is activated by sound and is responsible for sensory transduction. This sensory transduction channel is expressed in hair cell stereocilia, and previous studies show that its activity is affected by mutations in the genes encoding the transmembrane proteins TMHS, TMIE, TMC1 and TMC2. We show here that the second ion channel is expressed at the apical surface of hair cells and that it contains the Piezo2 protein. The activity of the Piezo2-dependent channel is controlled by the intracellular Ca2+concentration and can be recorded following disruption of the sensory transduction machinery or more generally by disruption of the sensory epithelium. We thus conclude that hair cells express two molecularly and functionally distinct mechanotransduction channels with different subcellular distributions.

Encapsulation is a strategy that has been used to facilitate the delivery and increase the stability of proteins and viruses. Here, we investigate the encapsulation of viruses via complex coacervation, which is a liquid–liquid phase separation resulting from the complexation of oppositely charged polymers. In particular, we utilized polypeptide-based coacervates and explored the effects of peptide chemistry, chain length, charge patterning, and hydrophobicity to better understand the effects of the coacervating polypeptides on virus incorporation. Our study utilized two nonenveloped viruses, porcine parvovirus (PPV) and human rhinovirus (HRV). PPV has a higher charge density than HRV, and they both appear to be relatively hydrophobic. These viruses were compared to characterize how the charge, hydrophobicity, and patterning of chemistry on the surface of the virus capsid affects encapsulation. Consistent with the electrostatic nature of complex coacervation, our results suggest that electrostatic effects associated with the net charge of both the virus and polypeptide dominated the potential for incorporating the virus into a coacervate, with clustering of charges also playing a significant role. Additionally, the hydrophobicity of a virus appears to determine the degree to which increasing the hydrophobicity of the coacervating peptides can enhance virus uptake. Nonintuitive trends in uptake were observed with regard to both charge patterning and polypeptide chain length, with these parameters having a significant effect on the range of coacervate compositions over which virus incorporation was observed. These results provide insights into biophysical mechanisms, where sequence effects can control the uptake of proteins or viruses into biological condensates and provide insights for use in formulation strategies.

Ionotropic glutamate receptors (GluRs) are targets for modulation in Hebbian and homeostatic synaptic plasticity and are remodeled by development, experience, and disease. We have probed the impact of synaptic glutamate levels on the two postsynaptic GluR subtypes at the Drosophilaneuromuscular junction, GluRA and GluRB. We first demonstrate that GluRA and GluRB compete to establish postsynaptic receptive fields, and that proper GluR abundance and composition can be orchestrated in the absence of any synaptic glutamate release. However, excess glutamate adaptively tunes postsynaptic GluR abundance, echoing GluR scaling observed in mammalian systems. Furthermore, when GluRA vs. GluRB competition is eliminated, GluRB becomes insensitive to glutamate modulation. In contrast, GluRA is now homeostatically regulated by excess glutamate to maintain stable miniature activity, where Ca2+permeability through GluRA receptors is required. Thus, excess glutamate, GluR competition, and Ca2+signaling collaborate to selectively target GluR subtypes for homeostatic regulation at postsynaptic compartments.

Chronic kidney disease (CKD) remains an important comorbid condition in people living with HIV. However, data in children living with HIV/AIDS (CLWHA) in sub-Saharan Africa is limited. We sought to establish the prevalence and identify risk factors of CKD among CLWHA in SSA.

A nurse recalls an experience she had while caring for a woman who had died and whose husband consented to give up her organs for donation. Unlike most medical personnel assigned to care for such patients, the nurse still considered the woman as her patient. In addition, she tried to get to know the woman through pictures of her family. She tried also to console the woman's husband, reminding him about how his wife's organs will help further the lives of its recipients.

Using small-angle x-ray scattering (SAXS), we investigated the phase behavior of mesophases of monoolein (MO) mixed with additives commonly used for the crystallization of membrane proteins from lipidic mesophases. In particular, we examined the effect of sodium and potassium phosphate salts and the detergent β-octylglucoside (βOG) over a wide range of compositions relevant for the crystallization of membrane proteins in lipidic mesophases. We studied two types of systems: 1), ternary mixtures of MO with salt solutions above the hydration boundary; and 2), quaternary mixtures of MO with βOG and salt solutions over a wide range of hydration conditions. All quaternary mixtures showed highly regular lyotropic phase behavior with the same sequence of phases (Lα, Ia3d, and Pn3m) as MO/water mixtures at similar temperatures. The effects of additives in quaternary systems agreed qualitatively with those found in ternary mixtures in which only one additive is present. However, quantitative differences in the effects of additives on the lattice parameters of fully hydrated mesophases were found between ternary and quaternary mixtures. We discuss the implications of these findings for mechanistic investigations of membrane protein crystallization in lipidic mesophases and for studies of the suitability of precipitants for mesophase-based crystallization methods.

The c-Met protein is overexpressed in many gastrointestinal cancers. We explored EMI-137, a novel c-Met targeting fluorescent probe, for application in fluorescence-guided colon surgery, in HT-29 colorectal cancer (CRC) cell line and an in vivomurine model.

Perry: Seattle Genetics: Honoraria. Villa:Seattle Genetics: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria; AZ: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria. Gerrie:Sandoz: Consultancy; Roche: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding. Scott:Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding. Savage:Abbvie: Consultancy, Honoraria; Verastem: Honoraria; Takeda: Honoraria; Servier: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sehn:AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria.

The article discusses community learning programs sponsored by the Community Learning Innovation Fund (CLIF) in Great Britain, which was developed by the public organization Skills Funding Agency to promote adult education in 2012. Health, family, and employment education are discussed, as well as digital skills development, volunteering, and programs for homeless people.

We investigated the in vitro inspired dose and particle size distribution of albuterol delivered by a vibrating mesh nebulizer through the Vapotherm (Stevensville, MD) humidified high-flow nasal cannula system.

In this article, the authors discuss several issues on the relationship between religion and science. Sarah Perry said that religion turned oppressive on the issue of homosexuality and abortion. Dan Hindes, on the other hand, stressed the implication of religion as a core motivating factor in committing inhumane treatment to other members of the species. Moreover, Daniel F. Weisberg, evaluated the claims of Steve Salerno on the difference between hucksterism and positive psychology.

Chemical systems can show complex behaviour that is not seen in individual molecules or reactions. Helena S. Azevedo, Sarah L. Perry, Peter A. Korevaar, and Dibyendu Das report on the emergence of this complex behaviour, which was discussed at the Virtual Symposium on Systems Chemistry