Photochemically Driven Peptide Formation in Supersaturated Aerosol Droplets.

The condensation of amino acids into peptides plays a crucial role in protein synthesis and is thus essential for understanding the origins of life. However, the spontaneous formation of peptides from amino acids in bulk aqueous media is energetically unfavorable, posing a challenge for elucidating plausible abiotic mechanisms. In this study, we investigate the formation of amide bonds between amino acids within highly supersaturated aerosol droplets containing dicyandiamide (DCD), a cyanide derivative potentially present on primordial Earth. Metastable states, i.e. supersaturation, within individual micron-sized droplets are studied using both an optical trap and a linear quadrupole electrodynamic balance. When irradiated with intense visible light, amide bond formation is observed to occur and can be monitored using vibrational bands in Raman spectra. The reaction rate is found to be strongly influenced by droplet size and kinetic modelling suggests that it is driven by the photochemical product of a DCD self-reaction. Our results highlight the potential of atmospheric aerosol particles as reaction environments for peptide synthesis and have potential implications for the prebiotic chemistry of early Earth.

Bottlenose dolphins (Tursiops truncatus) display gaze alternation and referential communication in an impossible task.

Gaze cues play a vital role in conveying critical information about objects and locations necessary for survival, such as food sources, predators, and the attentional states of conspecific and heterospecific individuals. During referential intentional communication, the continuous alternation of gaze between a communicative partner and a specific object or point of interest attracts the partner's attention towards the target. This behaviour is considered by many as essential for understanding intentions and is thought to involve mental planning. Here, we investigated the behavioural responses of seven bottlenose dolphins (Tursiops truncatus) that were given an impossible task in the presence of two experimenters (a 'commanding experimenter' and a 'non-commanding experimenter'), whose attentional state towards the dolphins varied. We found that the dolphins spontaneously displayed gaze alternation, specifically triadic referential pointing, only when the human commanding experimenter was facing them. However, they ceased to alternate their gaze between the impossible object and the commanding experimenter when the experimenter had their back turned. Notably, the dolphins' behaviour differed from general pointing and gaze, as their triadic sequence occurred within a narrow time window. These findings suggest that the dolphins were sensitive to human attentional cues and utilized their own gaze cue (pointing) as a salient signal to attract the attention of the commanding experimenter towards a specific location.

Episodic-like memory in wild free-living blue tits and great tits.

Episodic-like memory in non-human animals represents the behavioral characteristics of human episodic memory-the ability to mentally travel backward in time to "re-live" past experiences. A focus on traditional model species of episodic-like memory may overlook taxa possessing this cognitive ability and consequently its evolution across species. Experiments conducted in the wild have the potential to broaden the scope of episodic-like memory research under the natural conditions in which they evolved. We combine two distinct yet complementary episodic-like memory tasks (the what-where-when memory and incidental encoding paradigms), each targeting a different aspect of human episodic memory, namely the content (what-where-when) and process (incidental encoding), to comprehensively test the memory abilities of wild, free-living, non-caching blue tits (Cyanistes caeruleus) and great tits (Parus major). Automated feeders with custom-built programs allowed for experimental manipulation of spatiotemporal experiences on an individual-level basis. In the what-where-when memory experiment, after learning individualized temporal feeder rules, the birds demonstrated their ability to recall the "what" (food type), "where" (feeder location), and "when" (time since their initial visit of the day) of previous foraging experiences. In the incidental encoding experiment, the birds showed that they were able to encode and recall incidental spatial information regarding previous foraging experiences ("where" test), and juveniles, but not adults, were also able to recall incidentally encoded visual information ("which" test). Consequently, this study presents multiple lines of converging evidence for episodic-like memory in a wild population of generalist foragers, suggesting that episodic-like memory may be more taxonomically widespread than previously assumed.

Gene expression and ultra-structural evidence for metabolic derangement in the primary mitral regurgitation heart.

Aims: Chronic neurohormonal activation and haemodynamic load cause derangement in the utilization of the myocardial substrate. In this study, we test the hypothesis that the primary mitral regurgitation (PMR) heart shows an altered metabolic gene profile and cardiac ultra-structure consistent with decreased fatty acid and glucose metabolism despite a left ventricular ejection fraction (LVEF) > 60%. Methods and results: Metabolic gene expression in right atrial (RA), left atrial (LA), and left ventricular (LV) biopsies from donor hearts (n = 10) and from patients with moderate-to-severe PMR (n = 11) at surgery showed decreased mRNA glucose transporter type 4 (GLUT4), GLUT1, and insulin receptor substrate 2 and increased mRNA hexokinase 2, O-linked N-acetylglucosamine transferase, and O-linked N-acetylglucosaminyl transferase, rate-limiting steps in the hexosamine biosynthetic pathway. Pericardial fluid levels of neuropeptide Y were four-fold higher than simultaneous plasma, indicative of increased sympathetic drive. Quantitative transmission electron microscopy showed glycogen accumulation, glycophagy, increased lipid droplets (LDs), and mitochondrial cristae lysis. These findings are associated with increased mRNA for glycogen synthase kinase 3ß, decreased carnitine palmitoyl transferase 2, and fatty acid synthase in PMR vs. normals. Cardiac magnetic resonance and positron emission tomography for 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake showed decreased LV [18F]FDG uptake and increased plasma haemoglobin A1C, free fatty acids, and mitochondrial damage-associated molecular patterns in a separate cohort of patients with stable moderate PMR with an LVEF > 60% (n = 8) vs. normal controls (n = 8). Conclusion: The PMR heart has a global ultra-structural and metabolic gene expression pattern of decreased glucose uptake along with increased glycogen and LDs. Further studies must determine whether this presentation is an adaptation or maladaptation in the PMR heart in the clinical evaluation of PMR.

Alpha-secretase inhibition impairs Group I metabotropic glutamate receptor-mediated protein synthesis, long-term potentiation and long-term depression.

Group I metabotropic glutamate receptors (Gp1-mGluRs) exert a host of effects on cellular functions, including enhancement of protein synthesis and the associated facilitation of long-term potentiation (LTP) and induction of long-term depression (LTD). However, the complete cascades of events mediating these events are not fully understood. Gp1-mGluRs trigger α-secretase cleavage of amyloid precursor protein, producing soluble amyloid precursor protein-α (sAPPα), a known regulator of LTP. However, the α-cleavage of APP has not previously been linked to Gp1-mGluR's actions. Using rat hippocampal slices, we found that the α-secretase inhibitor tumour necrosis factor-alpha protease inhibitor-1, which inhibits both disintegrin and metalloprotease 10 (ADAM10) and 17 (ADAM17) activity, blocked or reduced the ability of the Gp1-mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) to stimulate protein synthesis, metaplastically prime future LTP and elicit sub-maximal LTD. In contrast, the specific ADAM10 antagonist GI254023X did not affect the regulation of plasticity, suggesting that ADAM17 but not ADAM10 is involved in mediating these effects of DHPG. However, neither drug affected LTD that was strongly induced by either high-concentration DHPG or paired-pulse synaptic stimulation. Our data suggest that moderate Gp1-mGluR activation triggers α-secretase sheddase activity targeting APP or other membrane-bound proteins as part of a more complex signalling cascade than previously envisioned. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Eurasian jays (Garrulus glandarius) show episodic-like memory through the incidental encoding of information.

Episodic memory describes the conscious reimagining of our memories and is often considered to be a uniquely human ability. As these phenomenological components are embedded within its definition, major issues arise when investigating the presence of episodic memory in non-human animals. Importantly, however, when we as humans recall a specific experience, we may remember details from that experience that were inconsequential to our needs, thoughts, or desires at that time. This 'incidental' information is nevertheless encoded automatically as part of the memory and is subsequently recalled within a holistic representation of the event. The incidental encoding and unexpected question paradigm represents this characteristic feature of human episodic memory and can be employed to investigate memory recall in non-human animals. However, without evidence for the associated phenomenology during recall, this type of memory is termed 'episodic-like memory'. Using this approach, we tested seven Eurasian jays (Garrulus glandarius) on their ability to use incidental visual information (associated with observed experimenter made 'caches') to solve an unexpected memory test. The birds performed above chance levels, suggesting that Eurasian jays can encode, retain, recall, and access incidental visual information within a remembered event, which is an ability indicative of episodic memory in humans.

A pilot study to explore patterns and predictors of delayed kidney decline after cardiopulmonary bypass.

There is no current consensus on the follow up of kidney function in patients undergoing cardiopulmonary bypass (CPB). The main objectives of this pilot study is to collect preliminary data on kidney function decline encountered on the first postoperative visit of patients who have had CPB and to identify predictors of kidney function decline post hospital discharge. Design: Retrospective chart review. Adult patients undergoing open heart procedures utilizing CPB. Patient demographics, type of procedure, pre-, intra-, and postoperative clinical, hemodynamic echocardiographic, and laboratory data were abstracted from electronic medical records. Acute kidney disease (AKD), and chronic kidney disease (CKD) were diagnosed based on standardized criteria. Interval change in medications, hospital admissions, and exposure to contrast, from hospital discharge till first postoperative visit were collected. AKD, and CKD as defined by standardized criteria on first postoperative visit. 83 patients were available for analysis. AKD occurred in 27 (54%) of 50 patients and CKD developed in 12 (42%) out of 28 patients. Older age was associated with the development of both AKD and CKD. Reduction in right ventricular cardiac output at baseline was associated with AKD (OR: 0.5, 95% CI: 0.3, 0.79, P = 0.01). Prolongation of transmitral early diastolic filling wave deceleration time was associated with CKD (OR: 1.02, 95% CI: 1.01, 1.05, P = 0.03). In-hospital acute kidney injury (AKI) was a predictor of neither AKD nor CKD. AKD and CKD occur after CPB and may not be predicted by in-hospital AKI. Older age, right ventricular dysfunction and diastolic dysfunction are important disease predictors. An adequately powered longitudinal study is underway to study more sensitive predictors of delayed forms of kidney decline after CPB.

Structural and biophysical analysis of a Haemophilus influenzae tripartite ATP-independent periplasmic (TRAP) transporter.

Tripartite ATP-independent periplasmic (TRAP) transporters are secondary-active transporters that receive their substrates via a soluble-binding protein to move bioorganic acids across bacterial or archaeal cell membranes. Recent cryo-electron microscopy (cryo-EM) structures of TRAP transporters provide a broad framework to understand how they work, but the mechanistic details of transport are not yet defined. Here we report the cryo-EM structure of the Haemophilus influenzae N-acetylneuraminate TRAP transporter (HiSiaQM) at 2.99 Å resolution (extending to 2.2 Å at the core), revealing new features. The improved resolution (the previous HiSiaQM structure is 4.7 Å resolution) permits accurate assignment of two Na+ sites and the architecture of the substrate-binding site, consistent with mutagenic and functional data. Moreover, rather than a monomer, the HiSiaQM structure is a homodimer. We observe lipids at the dimer interface, as well as a lipid trapped within the fusion that links the SiaQ and SiaM subunits. We show that the affinity (KD) for the complex between the soluble HiSiaP protein and HiSiaQM is in the micromolar range and that a related SiaP can bind HiSiaQM. This work provides key data that enhances our understanding of the 'elevator-with-an-operator' mechanism of TRAP transporters.

Probing the evaporation dynamics of semi-volatile organic compounds to reveal the thermodynamics of liquid-liquid phase separated aerosol.

Liquid-liquid phase separation (LLPS) is a thermodynamically driven process that occurs in mixtures of low miscibility material. LLPS is an important process in chemical, biological, and environmental systems. In atmospheric chemistry, LLPS in aerosol containing internally-mixed organic and inorganic particles has been an area of significant interest, with particles separating to form organic-rich and aqueous phases on dehydration. This alters the optical properties of the particles, has been connected to changes in the cloud nucleation ability of the aerosol, and potentially changes the reactivity of particles towards gas-phase oxidants. Although the chemical systems that undergo LLPS have become quite well-characterized, the properties and processes of LLPS particles are quite poorly understood. In this work, we characterize LLPS in aerosol particles containing ammonium sulfate and triethylene glycol (3EG), a semi-volatile organic molecule. We explore the relative humidity (RH) conditions under which LLPS occurs and characterize the rate of evaporation of 3EG from well-mixed and LLPS particles as a function of RH. We show that the evaporation rates vary with RH due to changes in chemical activity, however no clear change in the dynamics following LLPS are observed. We interpret our observations using a thermodynamic model (AIOMFAC) coupled with an evaporation model and show that a significant increase in the activity coefficient of 3EG as the RH decreases, required for LLPS to occur, obscures a clear step-change in the evaporation rates following LLPS. By characterizing the evaporation rates, we estimate the composition of the organic-rich phase and compare our results to thermodynamic predictions. This study is the first to explore the connection between LLPS and the chemical evolution of aerosol particles via the evaporation of semi-volatile organic material. Ultimately, we reveal that the thermodynamics of non-ideal mixing are primarily responsible for the controlling both the rate of evaporation and the onset of LLPS, with LLPS itself having limited impact on the rate of evaporation in a fluid system. These results have significant implications for understanding and predicting the lifetime of aerosol particles, their effect on cloud formation, and the chemical evolution of multiphase systems by particle-gas partitioning and heterogeneous reactions.

Cerebral blood flow and neurocognition in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis.

Aims: Aortic valve stenosis (AS) results in higher systolic pressure to overcome resistance from the stenotic valve, leading to heart failure and decline in cardiac output. There has been no assessment of cerebral blood flow (CBF) association with neurocognition in AS or the effects of valve replacement. The goal was to determine if AS is associated with altered cerebral haemodynamics and impaired neurocognition, and whether transcatheter aortic valve replacement (TAVR) improves haemodynamics and cognition. Methods and results: In 42 patients with planned TAVR, transcranial Doppler (TCD) assessed bilateral middle cerebral artery (MCA) mean flow velocities (MFVs); abnormality was <34.45 cm/s. The neurocognitive battery assessed memory, language, attention, visual-spatial skills, and executive function, yielding a composite Z-score. Impairment was <1.5 SDs below the normative mean. The mean age was 78 years, 59% Male, and the mean valve gradient was 46.87 mm/Hg. Mean follow-up was 36 days post-TAVR (range 27-55). Pre-TAVR, the mean MFV was 42.36 cm/s (SD = 10.17), and the mean cognitive Z-score was -0.22 SDs (range -1.99 to 1.08) below the normative mean. Among the 34 patients who returned after TAVR, the MFV was 41.59 cm/s (SD = 10.42), not different from baseline (P = 0.66, 2.28-3.67). Post-TAVR, average Z-scores were 0.17 SDs above the normative mean, not meeting the pre-specified threshold for a clinically significant 0.5 SD change. Conclusion: Among patients with severe AS, there was little impairment of MFV on TCD and no correlation with cognition. Transcatheter aortic valve replacement did not affect MFV or cognition. Assumptions about diminished CBF and improvement after TAVR were not supported.

Sustainability in the IVF laboratory: recommendations of an expert panel.

The healthcare industry is a major contributor to greenhouse gas emissions. Assisted reproductive technology is part of the larger healthcare sector, with its own heavy carbon footprint. The social, economic and environmental costs of this collective carbon footprint are becoming clearer, as is the impact on human reproductive health. Alpha Scientists in Reproductive Medicine and the International IVF Initiative collaborated to seek and formulate practical recommendations for sustainability in IVF laboratories. An international panel of experts, enthusiasts and professionals in reproductive medicine, environmental science, architecture, biorepository and law convened to discuss the topics of importance to sustainability. Recommendations were issued on how to build a culture of sustainability in the workplace, implement green design and building, use life cycle analysis to determine the environmental impact, manage cryostorage more sustainably, and understand and manage laboratory waste with prevention as a primary goal. The panel explored whether the industry supporting IVF is sustainable. An example is provided to illustrate the application of green principles to an IVF laboratory through a certification programme. The UK legislative landscape surrounding sustainability is also discussed and a few recommendations on 'Green Conferencing' are offered.

TRAPs: the 'elevator-with-an-operator' mechanism.

Tripartite ATP-independent periplasmic (TRAP) transporters are nutrient-uptake systems found in bacteria and archaea. These evolutionary divergent transporter systems couple a substrate-binding protein (SBP) to an elevator-type secondary transporter, which is a first-of-its-kind mechanism of transport. Here, we highlight breakthrough TRAP transporter structures and recent functional data that probe the mechanism of transport. Furthermore, we discuss recent structural and biophysical studies of the ion transporter superfamily (ITS) members and highlight mechanistic principles that are relevant for further exploration of the TRAP transporter system.

Social influences on delayed gratification in New Caledonian crows and Eurasian jays.

Self-control underlies goal-directed behaviour in humans and other animals. Delayed gratification - a measure of self-control - requires the ability to tolerate delays and/or invest more effort to obtain a reward of higher value over one of lower value, such as food or mates. Social context, in particular, the presence of competitors, may influence delayed gratification. We adapted the 'rotating-tray' paradigm, where subjects need to forgo an immediate, lower-quality (i.e. less preferred) reward for a delayed, higher-quality (i.e. more preferred) one, to test social influences on delayed gratification in two corvid species: New Caledonian crows and Eurasian jays. We compared choices for immediate vs. delayed rewards while alone, in the presence of a competitive conspecific and in the presence of a non-competitive conspecific. We predicted that, given the increased risk of losing a reward with a competitor present, both species would similarly, flexibly alter their choices in the presence of a conspecific compared to when alone. We found that species differed: jays were more likely to select the immediate, less preferred reward than the crows. We also found that jays were more likely to select the immediate, less preferred reward when a competitor or non-competitor was present than when alone, or when a competitor was present compared to a non-competitor, while the crows selected the delayed, highly preferred reward irrespective of social presence. We discuss our findings in relation to species differences in socio-ecological factors related to adult sociality and food-caching (storing). New Caledonian crows are more socially tolerant and moderate cachers, while Eurasian jays are highly territorial and intense cachers that may have evolved under the social context of cache pilfering and cache protection strategies. Therefore, flexibility (or inflexibility) in delay of gratification under different social contexts may relate to the species' social tolerance and related risk of competition.

A Smart, Textile-Driven, Soft Exosuit for Spinal Assistance.

Work-related musculoskeletal disorders (WMSDs) are often caused by repetitive lifting, making them a significant concern in occupational health. Although wearable assist devices have become the norm for mitigating the risk of back pain, most spinal assist devices still possess a partially rigid structure that impacts the user's comfort and flexibility. This paper addresses this issue by presenting a smart textile-actuated spine assistance robotic exosuit (SARE), which can conform to the back seamlessly without impeding the user's movement and is incredibly lightweight. To detect strain on the spine and to control the smart textile automatically, a soft knitting sensor that utilizes fluid pressure as a sensing element is used. Based on the soft knitting hydraulic sensor, the robotic exosuit can also feature the ability of monitoring and rectifying human posture. The SARE is validated experimentally with human subjects (N = 4). Through wearing the SARE in stoop lifting, the peak electromyography (EMG) signals of the lumbar erector spinae are reduced by 22.8% ± 12 for lifting 5 kg weights and 27.1% ± 14 in empty-handed conditions. Moreover, the integrated EMG decreased by 34.7% ± 11.8 for lifting 5 kg weights and 36% ± 13.3 in empty-handed conditions. In summary, the artificial muscle wearable device represents an anatomical solution to reduce the risk of muscle strain, metabolic energy cost and back pain associated with repetitive lifting tasks.

Ancient genomic linkage couples metabolism with erythroid development.

Generation of mature cells from progenitors requires tight coupling of differentiation and metabolism. During erythropoiesis, erythroblasts are required to massively upregulate globin synthesis then clear extraneous material and enucleate to produce erythrocytes1-3. Nprl3 has remained in synteny with the α-globin genes for >500 million years4, and harbours the majority of the α-globin enhancers5. Nprl3 is a highly conserved inhibitor of mTORC1, which controls cellular metabolism. However, whether Nprl3 itself serves an erythroid role is unknown. Here, we show that Nprl3 is a key regulator of erythroid metabolism. Using Nprl3-deficient fetal liver and adult competitive bone marrow - fetal liver chimeras, we show that NprI3 is required for sufficient erythropoiesis. Loss of Nprl3 elevates mTORC1 signalling, suppresses autophagy and disrupts erythroblast glycolysis and redox control. Human CD34+ progenitors lacking NPRL3 produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Finally, we show that the α-globin enhancers upregulate NprI3 expression, and that this activity is necessary for optimal erythropoiesis. Therefore, the anciently conserved linkage of NprI3, α-globin and their associated enhancers has enabled coupling of metabolic and developmental control in erythroid cells. This may enable erythropoiesis to adapt to fluctuating nutritional and environmental conditions.

Pioneer activity distinguishes activating from non-activating SOX2 binding sites.

Genome-wide transcriptional activity involves the binding of many transcription factors (TFs) to thousands of sites in the genome. Pioneer TFs are a class of TFs that maintain open chromatin and allow non-pioneer TFs access to their target sites. Determining which TF binding sites directly drive transcription remains a challenge. Here, we use acute protein depletion of the pioneer TF SOX2 to establish its functionality in maintaining chromatin accessibility. We show that thousands of accessible sites are lost within an hour of protein depletion, indicating rapid turnover of these sites in the absence of the pioneer factor. To understand the relationship with transcription, we performed nascent transcription analysis and found that open chromatin sites that are maintained by SOX2 are highly predictive of gene expression, in contrast to all other SOX2 binding sites. We use CRISPR-Cas9 genome editing in the Klf2 locus to functionally validate a predicted regulatory element. We conclude that the regulatory activity of SOX2 is exerted mainly at sites where it maintains accessibility and that other binding sites are largely dispensable for gene regulation.

MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.

Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.