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Neovascular retinopathies are major causes of vision loss; yet treatments to prevent the condition are inadequate. The role of regulatory T cells in neovascular retinopathy is unknown. Here we show that in retinopathy regulatory T cells are transiently increased in lymphoid organs and the retina, but decline when neovascularization is established. The decline is prevented following regulatory T cells expansion with an IL-2/anti-IL-2 mAb complex or the adoptive transfer of regulatory T cells. Further, both approaches reduce vasculopathy (vaso-obliteration, neovascularization, vascular leakage) and alter the activation of Tmem119 + retinal microglia. Our in vitro studies complement these findings, showing that retinal microglia co-cultured with regulatory T cells exhibit a reduction in co-stimulatory molecules and pro-inflammatory mediators that is attenuated by CTLA-4 blockade. Collectively, we demonstrate that regulatory T cells are recruited to the retina and, when expanded in number, repair the vasculature. Manipulation of regulatory T cell numbers is a previously unrecognized, and promising avenue for therapies to prevent blinding neovascular retinopathies. The local immune responses in the eye are attenuated to preserve sight. Surprisingly, Deliyanti et al. show that regulatory T cells (Tregs) take an active role in protecting the eye from neovascularization in oxygen-induced retinopathy, and that interventions that augment the retinal Treg numbers reduce neovascular retinopathy in mice.

This study presents an optimised cultured ELISpot protocol for detecting central memory T-cell interferon gamma (IFNγ) responses against SARS-CoV-2 peptides following an initial priming with either peptides, or whole spike protein. Key variations optimised include the culture length, timing of exogenous survival signals (IL-2), and endpoint analysis modality and cell density to enhance assay sensitivity without compromising specificity for central memory T-cell IFNγ recall responses to cognate antigen. We noted a culture duration of 10 days, combined with a delayed IL-2 administration on day 5 to enhance assay sensitivity while maintaining response specificity towards cognate antigen when compared with shorter culture periods or earlier exogenous survival signal provision. With regards to lower-frequency T-cell interactions, as we observed with our donor SARS-CoV-2 epitope responses, our findings suggest Fluorospot to be preferable to the chromogenic ELISpot modality, and an immediate cell washing after culture collection to better facilitate cognate antigen responses. Fluorospot enabled a higher cell density while minimising the generation of visual artefacts, meanwhile immediate cell washing was critical for improving endpoint assay sensitivity. CCR7+ cell depletion was used to demonstrate our optimised protocol to selectively demonstrate central memory T-cell responses. Lastly, we provide evidence for the capacity of our assay to delineate individual responding peptides following peptide pool priming, and to explore cross-reactivity between viral variant peptides. This work advances the methodology for investigating T-cell immunity, particularly in the context of SARS-CoV-2, and emphasises the balance between enhancing specific cognate central memory responses while limiting non-specific activation.

Vision loss in diabetic retinopathy features damage to the blood–retinal barrier and neovascularization, with hypertension and the renin–angiotensin system (RAS) having causal roles. We evaluated if finerenone, a non-steroidal mineralocorticoid receptor (MR) antagonist, reduced vascular pathology and inflammation in diabetic and neovascular retinopathy. Diabetic and hypertensive transgenic (mRen-2)27 rats overexpressing the RAS received the MR antagonist finerenone (10 mg/kg/day, oral gavage) or the angiotensin-converting enzyme inhibitor perindopril (10 mg/kg/day, drinking water) for 12 weeks. As retinal neovascularization does not develop in diabetic rodents, finerenone (5 mg/kg/day, i.p.) was evaluated in murine oxygen-induced retinopathy (OIR). Retinal vasculopathy was assessed by measuring gliosis, vascular leakage, neovascularization, and VEGF. Inflammation was investigated by quantitating retinal microglia/macrophages, pro-inflammatory mediators, and anti-inflammatory regulatory T-cells (Tregs). In diabetes, both treatments reduced systolic blood pressure, gliosis, vascular leakage, and microglial/macrophage density, but only finerenone lowered VEGF, ICAM-1, and IL-1ß. In OIR, finerenone reduced neovascularization, vascular leakage, and microglial density, and increased Tregs in the blood, spleen, and retina. Our findings, in the context of the FIDELIO-DKD and FIGARO-DKD trials reporting the benefits of finerenone on renal and cardiovascular outcomes in diabetic kidney disease, indicate the potential of finerenone as an effective oral treatment for diabetic retinopathy.

Analysis of synergistic muscle activations during locomotion and anatomical tracing of muscle synergy representations in the rodent spinal cord guide the development of a new spinal implant for neuromodulation therapy. In multiple rodent models of spinal cord injury, spatiotemporal stimulation that mimics naturalistic muscle activation patterns promotes improved functional recovery over previously described continuous stimulation protocols. Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

We report the detection of Kepler-47, a system consisting of two planets orbiting around an eclipsing pair of stars. The inner and outer planets have radii 3.0 and 4.6 times that of Earth, respectively. The binary star consists of a Sun-like star and a companion roughly one-third its size, orbiting each other every 7.45 days. With an orbital period of 49.5 days, 18 transits of the inner planet have been observed, allowing a detailed characterization of its orbit and those of the stars. The outer planet's orbital period is 303.2 days, and although the planet is not Earth-like, it resides within the classical \"habitable zone,\" where liquid water could exist on an Earth-like planet. With its two known planets, Kepler-47 establishes that close binary stars can host complete planetary systems.

We report the detection of a planet whose orbit surrounds a pair of low-mass stars. Data from the Kepler spacecraft reveal transits of the planet across both stars, in addition to the mutual eclipses of the stars, giving precise constraints on the absolute dimensions of all three bodies. The planet is comparable to Saturn in mass and size and is on a nearly circular 229-day orbit around its two parent stars. The eclipsing stars are 20 and 69% as massive as the Sun and have an eccentric 41-day orbit. The motions of all three bodies are confined to within 0.5° of a single plane, suggesting that the planet formed within a circumbinary disk.

Two double-sun exoplanets have been discovered by the Kepler spacecraft, establishing a new class of ‘circumbinary’ exoplanets and suggesting that at least several million such systems exist in our Galaxy. Dual 'Suns' a common phenomenon The Kepler spacecraft's haul of newly discovered extrasolar planets continues to grow. Most Sun-like stars in the Milky Way are found in gravitationally bound pairs or binaries. The discovery of exoplanet Kepler-16 b showed that planets can exist in orbits around a binary, and now two further such 'circumbinary' planets have been found: Kepler-34 b and Kepler-35 b. Each is a low-density gas giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 b orbits two Sun-like stars every 289 days, and Kepler-35 b orbits a pair of smaller stars every 131 days. The observed rate of circumbinary planets implies that 1% of close binary stars have giant planets in nearly coplanar orbits, equivalent to a population of at least several million such bodies in the Milky Way. Most Sun-like stars in the Galaxy reside in gravitationally bound pairs of stars 1 , 2 (binaries). Although long anticipated 3 , 4 , 5 , 6 , 7 , 8 , the existence of a ‘circumbinary planet’ orbiting such a pair of normal stars was not definitively established until the discovery 9 of the planet transiting (that is, passing in front of) Kepler-16. Questions remained, however, about the prevalence of circumbinary planets and their range of orbital and physical properties. Here we report two additional transiting circumbinary planets: Kepler-34 (AB)b and Kepler-35 (AB)b, referred to here as Kepler-34 b and Kepler-35 b, respectively. Each is a low-density gas-giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 b orbits two Sun-like stars every 289 days, whereas Kepler-35 b orbits a pair of smaller stars (89% and 81% of the Sun’s mass) every 131 days. The planets experience large multi-periodic variations in incident stellar radiation arising from the orbital motion of the stars. The observed rate of circumbinary planets in our sample implies that more than ∼1% of close binary stars have giant planets in nearly coplanar orbits, yielding a Galactic population of at least several million.

When an extrasolar planet passes in front of (transits) its star, its radius can be measured from the decrease in starlight and its orbital period from the time between transits. Multiple planets transiting the same star reveal much more: period ratios determine stability and dynamics, mutual gravitational interactions reflect planet masses and orbital shapes, and the fraction of transiting planets observed as multiples has implications for the planarity of planetary systems. But few stars have more than one known transiting planet, and none has more than three. Here we report Kepler spacecraft observations of a single Sun-like star, which we call Kepler-11, that reveal six transiting planets, five with orbital periods between 10 and 47 days and a sixth planet with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases. The degree of coplanarity and proximity of the planetary orbits imply energy dissipation near the end of planet formation. Edge-on view of Kepler-11 planetary system NASA's Kepler mission, a space observatory designed to detect and study extrasolar planets that transit across the disk of their host star, has hit the jackpot with the discovery of a six-planet system orbiting a Sun-like star now named Kepler-11. Five of the planets have orbital periods of between 10 and 47 days, and these are among the smallest for which size and mass have both been measured. The sixth and outermost transiting planet has been less well characterized thus far. Only one other star has more than one confirmed transiting planet (Kepler-9, which has three). This newly discovered system resembles our own Solar System in being close to coplanar, but Kepler-11's planets orbit much closer to their star. Kepler is due to continue to return data on Kepler-11 and its planets for some time yet, and it should provide many valuable constraints on models of the formation and evolution of solar systems in general. When an extrasolar planet passes in front of its star (transits), its radius can be measured from the decrease in starlight and its orbital period from the time between transits. This study reports Kepler spacecraft observations of a single Sun-like star that reveal six transiting planets, five with orbital periods between 10 and 47 days plus a sixth one with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases.

Whole brain segmentation from structural magnetic resonance imaging (MRI) is a prerequisite for most morphological analyses, but is computationally intense and can therefore delay the availability of image markers after scan acquisition. We introduce QuickNAT, a fully convolutional, densely connected neural network that segments a MRI brain scan in 20 s. To enable training of the complex network with millions of learnable parameters using limited annotated data, we propose to first pre-train on auxiliary labels created from existing segmentation software. Subsequently, the pre-trained model is fine-tuned on manual labels to rectify errors in auxiliary labels. With this learning strategy, we are able to use large neuroimaging repositories without manual annotations for training. In an extensive set of evaluations on eight datasets that cover a wide age range, pathology, and different scanners, we demonstrate that QuickNAT achieves superior segmentation accuracy and reliability in comparison to state-of-the-art methods, while being orders of magnitude faster. The speed up facilitates processing of large data repositories and supports translation of imaging biomarkers by making them available within seconds for fast clinical decision making. [Display omitted] •Introduces a deep learning based whole brain segmentation tool called QuickNAT, processing each 3D MRI T1 brain scans in 20 secs.•The high segmentation accuracy of QuickNAT was evaluated on 5 different benchmark datasets, containing a wide age range, subjects with different pathologies (AD, MCI and CN), and different scanners (1.5T and 3.0T).•QuickNAT can be effectively used for longitudinal studies as it performs well in test-retest and multi-center experiments.

Fluorescent calcium indicators are often used to investigate neural dynamics, but the relationship between fluorescence and action potentials (APs) remains unclear. Most APs can be detected when the soma almost fills the microscope’s field of view, but calcium indicators are used to image populations of neurons, necessitating a large field of view, generating fewer photons per neuron, and compromising AP detection. Here, we characterized the AP-fluorescence transfer function in vivo for 48 layer 2/3 pyramidal neurons in primary visual cortex, with simultaneous calcium imaging and cell-attached recordings from transgenic mice expressing GCaMP6s or GCaMP6f. While most APs were detected under optimal conditions, under conditions typical of population imaging studies, only a minority of 1 AP and 2 AP events were detected (often <10% and ~20–30%, respectively), emphasizing the limits of AP detection under more realistic imaging conditions. Neurons, the cells that make up the nervous system, transmit information using electrical signals known as action potentials or spikes. Studying the spiking patterns of neurons in the brain is essential to understand perception, memory, thought, and behaviour. One way to do that is by recording electrical activity with microelectrodes. Another way to study neuronal activity is by using molecules that change how they interact with light when calcium binds to them, since changes in calcium concentration can be indicative of neuronal spiking. That change can be observed with specialized microscopes know as two-photon fluorescence microscopes. Using calcium indicators, it is possible to simultaneously record hundreds or even thousands of neurons. However, calcium fluorescence and spikes do not translate one-to-one. In order to interpret fluorescence data, it is important to understand the relationship between the fluorescence signals and the spikes associated with individual neurons. The only way to directly measure this relationship is by using calcium imaging and electrical recording simultaneously to record activity from the same neuron. However, this is extremely challenging experimentally, so this type of data is rare. To shed some light on this, Huang, Ledochowitsch et al. used mice that had been genetically modified to produce a calcium indicator in neurons of the visual cortex and simultaneously obtained both fluorescence measurements and electrical recordings from these neurons. These experiments revealed that, while the majority of time periods containing multi-spike neural activity could be identified using calcium imaging microscopy, on average, less than 10% of isolated single spikes were detectable. This is an important caveat that researchers need to take into consideration when interpreting calcium imaging results. These findings are intended to serve as a guide for interpreting calcium imaging studies that look at neurons in the mammalian brain at the population level. In addition, the data provided will be useful as a reference for the development of activity sensors, and to benchmark and improve computational approaches for detecting and predicting spikes.