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Extracellular vesicles (EVs) are membrane-bound vesicles released by cells and act as media for transfer of proteins, small RNAs and mRNAs to distant sites. They can be isolated by different methods. However, the biological activities of the purified EVs have seldom been studied. In this study, we compared the use of ultracentrifugation (UC), ultra-filtration (UF), polymer-based precipitation (PBP), and PBP with size-based purification (PBP+SP) for isolation of EVs from human endometrial cells and mouse uterine luminal fluid (ULF). Electron microscopy revealed that the diameters of the isolated EVs were similar among the tested methods. UF recovered the highest number of EVs followed by PBP, while UC and PBP+SP were significantly less efficient (P<0.05). Based on the number of EVs-to-protein ratios, PBP had the least protein contamination, significantly better than the other methods (P<0.05). All the isolated EVs expressed exosome-enriched proteins CD63, TSG101 and HSP70. Incubation of the trophoblast JEG-3 cells with an equal amount of the fluorescence-labelled EVs isolated by the studied methods showed that many of the PBP-EVs treated cells were fluorescence positive but only a few cells were labelled in the UC- and UF-EVs treated groups. Moreover, the PBP-EVs could transfer significantly more miRNA to the recipient cells than the other 3 methods (P<0.05). The PBP method could isolate EVs from mouse ULF; the diameter of the isolated EVs was 62±19 nm and expressed CD63, TSG101 and HSP70 proteins. In conclusion, PBP could best preserve the activities of the isolated EVs among the 4 methods studied and was able to isolate EVs from a small volume of sample. The simple setup and low equipment demands makes PBP the most suitable method for rapid EV assessment and isolation of EVs in clinical and basic research settings.

Physical activity improves well-being and reduces the risk of heart disease, cancer and type 2 diabetes mellitus in the general population. In individuals with established type 2 diabetes, physical activity improves glucose and lipid levels, reduces weight and improves insulin resistance. In type 1 diabetes mellitus, however, the benefits of physical activity are less clear. There is poor evidence for a beneficial effect of physical activity on glycaemic control and microvascular complications, and significant risk of harm through hypoglycaemia. Here we review the literature relating to physical activity and health in type 1 diabetes. We examine its effect on a number of outcomes, including glycaemic control, lipids, blood pressure, diabetic complications, well-being and overall mortality. We conclude that whilst there is sufficient evidence to recommend physical activity in the management of type 1 diabetes, it is still unclear as to what form, duration and intensity should be recommended and whether there is benefit for many of the outcomes examined.

The multi-messenger detection of the gravitational-wave signal GW170817, the corresponding kilonova AT2017gfo and the short gamma-ray burst GRB170817A, as well as the observed afterglow has delivered a scientific breakthrough. For an accurate interpretation of all these different messengers, one requires robust theoretical models that describe the emitted gravitational-wave, the electromagnetic emission, and dense matter reliably. In addition, one needs efficient and accurate computational tools to ensure a correct cross-correlation between the models and the observational data. For this purpose, we have developed the Nuclear-physics and Multi-Messenger Astrophysics framework NMMA. The code allows incorporation of nuclear-physics constraints at low densities as well as X-ray and radio observations of isolated neutron stars. In previous works, the NMMA code has allowed us to constrain the equation of state of supranuclear dense matter, to measure the Hubble constant, and to compare dense-matter physics probed in neutron-star mergers and in heavy-ion collisions, and to classify electromagnetic observations and perform model selection. Here, we show an extension of the NMMA code as a first attempt of analyzing the gravitational-wave signal, the kilonova, and the gamma-ray burst afterglow simultaneously. Incorporating all available information, we estimate the radius of a 1.4 M ⊙ neutron star to be R = 11.9 8 − 0.40 + 0.35 km. The Nuclear-physics and Multi-Messenger Astrophysics framework, NMMA, combines multiple information from neutron stars and neutron star mergers. Here, the authors show an update of the NMMA framework to constrain neutron star equation of state by simultaneously analyzing multi-messenger observations.

The activation of a population of hippocampal neurons thought to encode a specific fear memory is shown to elicit freezing behaviour in mice. Neural representation of a memory Several studies have used ablation strategies to demonstrate that certain neuronal populations in the brain are needed for memory expression, but whether a particular ensemble is sufficient to elicit a behavioural outcome from a particular memory has remained unexplored. Now, Susumu Tonegawa and colleagues use optogenetics to demonstrate that a particular, targeted memory 'engram', or group of cells, that was active during fear-learning is sufficient to drive freezing behaviour in mice during subsequent reactivations. A specific memory is thought to be encoded by a sparse population of neurons 1 , 2 . These neurons can be tagged during learning for subsequent identification 3 and manipulation 4 , 5 , 6 . Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) 7 , 8 and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.

An advanced LIGO and Virgo’s third observing run brought another binary neutron star merger (BNS) and the first neutron-star black hole mergers. While no confirmed kilonovae were identified in conjunction with any of these events, continued improvements of analyses surrounding GW170817 allow us to project constraints on the Hubble Constant (H 0), the Galactic enrichment from r-process nucleosynthesis, and ultra-dense matter possible from forthcoming events. Here, we describe the expected constraints based on the latest expected event rates from the international gravitational-wave network and analyses of GW170817. We show the expected detection rate of gravitational waves and their counterparts, as well as how sensitive potential constraints are to the observed numbers of counterparts. We intend this analysis as support for the community when creating scientifically driven electromagnetic follow-up proposals. During the next observing run O4, we predict an annual detection rate of electromagnetic counterparts from BNS of 0.43−0.26+0.58 ( 1.97−1.2+2.68 ) for the Zwicky Transient Facility (Rubin Observatory).

In mammals, the sperm deliver mRNA of unknown function into the oocytes during fertilization. The role of sperm microRNAs (miRNAs) in preimplantation development is unknown. miRNA profiling identified six miRNAs expressed in the sperm and the zygotes but not in the oocytes or preimplantation embryos. Sperm contained both the precursor and the mature form of one of these miRNAs, miR-34c. The absence of an increased level of miR-34c in zygotes derived from α-amanitin—treated oocytes and in parthenogenetic oocytes supported a sperm origin of zygotic miR-34c. Injection of miR-34c inhibitor into zygotes inhibited DNA synthesis and significantly suppressed first cleavage division. A 3′ UTR luciferase assay and Western blotting demonstrated that miR-34c regulates B-cell leukemia/lymphoma 2 (Bcl-2) expression in the zygotes. Coinjection of anti—Bcl-2 antibody in zygotes partially reversed but injection of Bcl-2 protein mimicked the effect of miR-34c inhibition. Oocyte activation is essential for the miR-34c action in zygotes, as demonstrated by a decrease in 3′ UTR luciferase reporter activity and Bcl-2 expression after injection of precursor miR-34c into parthenogenetic oocytes. Our findings provide evidence that sperm-borne miR-34c is important for the first cell division via modulation of Bcl-2 expression.

Previous studies on paternal epigenetic inheritance have shown that sperm RNAs play a role in this type of inheritance. The microinjection of sperm small noncoding RNAs into fertilised mouse oocytes induces reprogramming of the early embryo, which is thought to be responsible for the differences observed in adult phenotype. While sperm long noncoding RNAs (lncRNAs) have also been investigated in a previous study, their microinjection into fertilised oocytes did not yield conclusive results regarding their role in modulating brain development and adult behavioural phenotypes. Therefore, in the current study we sought to investigate this further. We used our previously established paternal corticosterone (stress hormone) model to assess sperm lncRNA expression using CaptureSeq, a sequencing technique that is more sensitive than the ones used in other studies in the field. Paternal corticosterone exposure led to dysregulation of sperm long noncoding RNA expression, which encompassed lncRNAs, circular RNAs and transposable element transcripts. Although they have limited functional annotation, bioinformatic approaches indicated the potential of these lncRNAs in regulating brain development and function. We then separated and isolated the sperm lncRNAs and performed microinjections into fertilised oocytes, to generate embryos with modulated lncRNA populations. We observed that the resulting adult offspring had lower body weight and altered anxiety and affective behavioural responses, demonstrating roles for lncRNAs in modulating development and brain function. This study provides novel insights into the roles of lncRNAs in epigenetic inheritance, including impacts on brain development and behaviours of relevance to affective disorders.

Key Points Mature neurotrophins bind preferentially to Trk receptor tyrosine kinases. By contrast, proneurotrophins (neurotrophin precursors) bind with high affinity to the p75 neurotrophin receptor (p75 NTR ). Interaction of mature neurotrophins with Trk receptors leads to cell survival, whereas binding of pro-nerve growth factor (proNGF) to p75 NTR leads to apoptosis. The 'yin and yang' effects of neurotrophins are, therefore, controlled by the proteolytic cleavage of proneurotrophins. Proneurotrophins can be cleaved intracellularly by furin or prohormone convertases 1 and 2 (PC1/2), and extracellularly by proteases such as tissue plasminogen activator (tPA)/plasmin and matrix metalloproteinases 3 and 7 (MMP3/7). NGF is secreted mainly in the mature form, whereas brain-derived neurotrophic factor (BDNF) is secreted predominantly in the pro- form. The pro-domain of BDNF is involved in the correct folding and intracellular trafficking of BDNF. The mature domain of BDNF contains a structural motif that interacts with the sorting receptor carboxypeptidase E (CPE) to sort BDNF into the regulated secretory pathway. In the hippocampus, BDNF has 'yin and yang' effects on long-term synaptic plasticity by activating p75 NTR and TrkB, respectively. Mature BDNF facilitates hippocampal early-phase long-term potentiation (E-LTP) through presynaptic mechanisms. In addition, the conversion of pro- to mature BDNF by the tPA/plasmin system is crucial for the expression of late-phase LTP (L-LTP) at hippocampal synapses. ProBDNF, on the other hand, selectively promotes the NMDA ( N -methyl- D -aspartate)-receptor-dependent form of long-term depression (LTD) in the hippocampus. This is achieved by p75 NTR -mediated expression of NR2B, a subunit of the NMDA receptor that is uniquely involved in LTD. Studying yin–yang aspects of neurotrophin function should generate important advances in our understanding of how neurotrophins regulate bidirectional processes at the cellular level, and how this affects a range of cognitive processes. Neurotrophins have diverse functions in the CNS. Initially synthesized as precursors (proneurotrophins), they are cleaved to produce mature proteins, which promote neuronal survival and enhance synaptic plasticity by activating Trk receptor tyrosine kinases. Recent studies indicate that proneurotrophins serve as signalling molecules by interacting with the p75 neurotrophin receptor (p75 NTR ). Interestingly, proneurotrophins often have biological effects that oppose those of mature neurotrophins. Therefore, the proteolytic cleavage of proneurotrophins represents a mechanism that controls the direction of action of neurotrophins. New insights into the 'yin and yang' of neurotrophin activity have profound implications for our understanding of the role of neurotrophins in a wide range of cellular processes.

With GW170817 being the only multimessenger gravitational-wave (GW) event with an associated kilonova detected so far, there exists a pressing need for realistic estimation of the GW localization uncertainties and rates, as well as optimization of available telescope time to enable the detection of new kilonovae. We simulate GW events assuming a data-driven distribution of binary parameters for the LIGO/Virgo/KAGRA fourth and fifth observing runs (O4 and O5). We map the binary neutron star (BNS) and neutron star–black hole (NSBH) properties to the kilonova optical light curves. We use the simulated population of kilonovae to generate follow-up observing plans, with the primary goal of optimizing detection with the Gravitational Wave Multi-Messenger Astronomy DECam Survey. We explore the dependence of kilonova detectability on the mass, distance, inclination, and spin of the binaries. Assuming that no BNS was detected during O4 until the end of 2024, we present updated GW BNS (NSBH) merger detection rates. We expect to detect BNS (NSBH) kilonovae with DECam at a per-year rate of 0–2.0 (0) in O4 and 2.0–19 (0–1.0) in O5. We expect the majority of BNS detections and also those accompanied by a detectable kilonova to produce a hypermassive NS remnant, with a significant fraction of the remaining BNSs promptly collapsing to a BH. We release GW simulations and depths required to detect kilonovae based on our predictions to support the astronomical community in their multimessenger follow-up campaigns and analyses.

Whilst regular exercise is advocated for people with type 1 diabetes, the benefits of this therapy are poorly delineated. Our objective was to review the evidence for a glycaemic benefit of exercise in type 1 diabetes. Electronic database searches were carried out in MEDLINE, Embase, Cochrane's Controlled Trials Register and SPORTDiscus. In addition, we searched for as yet unpublished but completed trials. Glycaemic benefit was defined as an improvement in glycosylated haemoglobin (HbA1c). Both randomised and non-randomised controlled trials were included. Thirteen studies were identified in the systematic review. Meta-analysis of twelve of these (including 452 patients) demonstrated an HbA1c reduction but this was not statistically significant (standardised mean difference (SMD) -0.25; 95% CI, -0.59 to 0.09). This meta-analysis does not reveal evidence for a glycaemic benefit of exercise as measured by HbA1c. Reasons for this finding could include increased calorie intake, insulin dose reductions around the time of exercise or lack of power. We also suggest that HbA1c may not be a sensitive indicator of glycaemic control, and that improvement in glycaemic variability may not be reflected in this measure. Exercise does however have other proven benefits in type 1 diabetes, and remains an important part of its management.