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Transient cortical circuits match spontaneous and sensory-driven activity during development

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A moment in time

As the brain develops, it does not simply get bigger. Like a building that depends on temporary scaffolds as its structures are assembled, the developing brain sets up the circuits that characterize the adult brain. Molnár et al. review the current state of knowledge about how brain connections are built and how autonomously established patterns are reshaped by activity from the sensory periphery. With the help of a transient population of neurons, the spontaneous activity of early circuits is molded by increasing inputs from the external world. When these normal developmental interactions are disrupted, consequent miswiring drives dysfunction in the adult brain.

Science, this issue p. eabb2153

Structured Abstract

BACKGROUND

During early mammalian brain development, transient neurons and circuits form the scaffold for the development of neuronal networks. In the immature cerebral cortex, subplate neurons in the lower cortical layer and Cajal-Retzius cells in the marginal zone lay the foundations for cortical organization in horizontal layers and translaminar radial circuits (“cortical columns”). Patterns of spontaneous activity during early development synchronize local and large-scale cortical networks, which form the functional template for generation of cortical architecture and guide establishment of global thalamocortical and intracortical networks. These networks become established in an autonomous fashion before the arrival of signals from the sensory periphery and before the maturation of cortical circuits. The subplate, which is a transient structure located below the developing cortical plate, orchestrates alignment of these autonomously established pathways by integrating spontaneous and sensory-driven activity patterns during critical stages of early development.

ADVANCES

The subplate contains heterogeneous neuronal populations with distinct characteristics, such as origin, birthdate, neurotransmitters, receptor expression, morphology, projections, firing properties, and their participation in specific intra- and extracortical connectivity. The transformation of this early subplate-driven circuit to the adult-like cortex requires patterned spontaneous activity and depends on the awakening of silent synapses in the cortical plate when thalamic inputs are progressively integrated. Moreover, a subpopulation of the glutamatergic and GABAergic (GABA, γ-aminobutyric acid) subplate neurons has widespread axonal projections that establish early large-scale networks. The early circuits are remodeled when Cajal-Retzius and subplate neurons largely disappear by programmed cell death. Both the programmed cell death and the remodeling of circuits may be also controlled by the transition from spontaneous synchronized burst to sensory-driven activity.

OUTLOOK

Functional impairments of these transient circuits (that include both transient and more permanent cell types) have great clinical relevance. Genetic abnormalities or early pathological conditions such as in utero infection, inflammation, exposure to pharmacological compounds, or hypoxia-ischemia induce functional disturbances in early microcircuits, which may lead to cortical miswiring at later stages and subsequent neurological and psychiatric conditions. A better understanding of the transition from early transient to permanent neuronal circuits will clarify mechanisms driving abnormal distribution and persistence of subplate neurons as interstitial white matter cells in pathophysiological conditions. Exploring the transition from transient to permanent circuits helps us to understand causal foundations of certain pharmaco-resistant epilepsies and psychiatric conditions and to consider new therapeutic strategies to treat such disorders.

Early spontaneous synchronized neuronal activity sculpts cortical architecture.

(A) Schematic outlines of brain development from the embryonic stage to adult. (B and C) Prenatal cortical circuits are dominated by early-generated, largely transient neurons in the subplate (SP) and marginal zone (MZ) before maturation of cortical plate (CP) neurons. (D to H) Transformation of early subplate-driven circuits to the adult-like six-layered cortex requires spontaneous synchronized burst activity (D) that also controls programmed cell death (apoptosis), arrangement of neurites and axons, and formation and awakening of synapses. Most subplate neurons disappear with development; a few survive in rodents as layer (L) 6b neurons or in primates as interstitial white matter (WM) cells (G). During prenatal and early postnatal stages, pathophysiological conditions such as hypoxia-ischemia, drugs, infection or inflammation may alter spontaneous activity [(E) and (F)]. These altered activity patterns may disturb subsequent developmental programs, including apoptosis (H). Surviving subplate neurons that persist in white matter or L6b may support altered circuits that could cause neurological or psychiatric disorders.

Abstract

At the earliest developmental stages, spontaneous activity synchronizes local and large-scale cortical networks. These networks form the functional template for the establishment of global thalamocortical networks and cortical architecture. The earliest connections are established autonomously. However, activity from the sensory periphery reshapes these circuits as soon as afferents reach the cortex. The early-generated, largely transient neurons of the subplate play a key role in integrating spontaneous and sensory-driven activity. Early pathological conditions—such as hypoxia, inflammation, or exposure to pharmacological compounds—alter spontaneous activity patterns, which subsequently induce disturbances in cortical network activity. This cortical dysfunction may lead to local and global miswiring and, at later stages, can be associated with neurological and psychiatric conditions.

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Intel is providing the smarts for the first satellite with local AI processing on board

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Intel detailed today its contribution to PhiSat-1, a new tiny small satellite that was launched into sun-synchronous orbit on September 2. PhiSat-1 has a new kind of hyperspectral-thermal camera on board, and also includes a Movidius Myriad 2 Vision Processing Unit. That VPU is found in a number of consumer devices on Earth, but this is its first trip to space – and the first time it’ll be handling large amounts of local data, saving researchers back on Earth precious time and satellite downlink bandwidth.

Specifically, the AI on board the PhiSat-1 will be handling automatic identification of cloud cover – images where the Earth is obscured in terms of what the scientists studying the data actually want to see. Getting rid of these images before they’re even transmitted means that the satellite can actually realize a bandwidth savings of up to 30%, which means more useful data is transmitted to Earth when it is in range of ground stations for transmission.

The AI software that runs on the Intel Myriad 2 on PhiSat-1 was created by startup Ubotica, which worked with the hardware maker behind the hyperspectral camera. It also had to be tuned to compensate for the excess exposure to radiation, though a bit surprisingly testing at CERN found that the hardware itself didn’t have to be modified in order to perform within the standards required for its mission.

Computing at the edge takes on a whole new meaning when applied to satellites on orbit, but it’s definitely a place where local AI makes a ton of sense. All the same reasons that companies seek to handle data processing and analytics at the site of sensors hear on Earth also apply in space – but magnified exponentially in terms of things like network inaccessibility and quality of connections, so expect to see a lot more of this.

PhiSat-1 was launched in September as part of Arianspace’s first rideshare demonstration mission, which it aims to use to show off its ability to offer launch services to smaller startups for smaller payloads at lower costs.

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This 14-Year-Old’s Discovery Could Lead to a Cure for COVID-19

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With no clear end in sight to the pandemic, there is an urgent need for a cure to COVID-19. As scientists around the world work to develop possible vaccines, one 14-year-old girl from Texas has made a new discovery that could lead to a potential treatment.

On Wednesday, Anika Chebrolu from Frisco, Texas was named the winner of the 3M Young Scientist Challenge after discovering a molecule that can selectively bind to the spike protein of the SARS-COV-2 virus, which causes COVID-19.

The competition opened in December 2019 and invited students in grades five to eight to find a unique solution to an everyday problem. Anika won $25,000, a special destination trip, and the title of “America’s Top Young Scientist” for her achievement.

Her discovery could lead to important developments in COVID-19 research. By binding to the spike protein in the coronavirus, the molecule she found can potentially prevent virus entry into the host cell, and can be used in creating a potential drug to cure COVID-19.

Anika used in-silico methodology — methods and experiments that make use of computers — to screen millions of small molecules. She originally planned for her project to focus on the influenza virus, but pivoted once COVID-19 hit and she realized the severity of the pandemic. Anika was in eighth grade when she submitted the project.

She told CNN that she hopes to work with other scientists and researchers to develop her discovery into an actual cure for the virus.

At the moment, the World Health Organization (WHO) is tracking over 170 candidate vaccines around the world. However, since many of them are still in early development, the effectiveness of these vaccines are still unknown. Vaccines go through multiple stages of testing and experts predict that a vaccine will only be available to the public in 2021, at the earliest.

In August, Russia was the first country to claim to have developed a vaccine for COVID-19. However, many were skeptical as President Vladimir Putin had ordered to speed up clinical trials. The vaccine, which was not subject to the extensive Phase III testing, was registered after less than two months of human testing. Experts have said that the vaccine is based on a common cold virus, which many people have been exposed to, potentially limiting its effectiveness. Other countries working on vaccines include the United Kingdom, Germany, and China.

At the moment, there are no specific vaccines or drugs for COVID-19. Developing one to prevent or cure infection from the novel coronavirus could help decrease the number of fatalities and help hospitals manage patients better.

As of posting, there have been a total of over 40 million cases of COVID-19 and 1.1 million deaths around the world. The United States and India have the most number of cases, with 8.1 million and 7.5 million total COVID-19 cases respectively. Few places across the globe have successfully managed  the virus, including New Zealand, Taiwan, and Singapore.

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Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense

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Cells drop a bomb on pathogens

Lipid droplets (LDs) accumulate in cells to serve as lipid storage organelles. They are also an attractive source of nutrients for many pathogens. Bosch et al. show that various proteins involved in innate immunity form complexes on LDs in response to bacterial lipopolysaccharide (see the Perspective by Green). Upon activation, LDs became physically uncoupled from mitochondria, driving a shift in cells from oxidative phosphorylation to aerobic glycolysis. This work highlights the ability of LDs both to kill pathogens directly and to establish a metabolic environment conducive to host defense. This may inform future antimicrobial strategies in the age of antibiotic resistance.

Science, this issue p. eaay8085; see also p. 294

Structured Abstract

INTRODUCTION

In all eukaryotic cells, lipid droplets (LDs) store and supply essential lipids to produce signaling molecules, membrane building blocks, and metabolic energy. The LD monolayer also accommodates proteins not obviously related to lipids, such as transcription factors, chromatin components, and toxic proteins.

Common parasites (such as trypanosomes and Plasmodium falciparum), bacteria (such as mycobacteria and Chlamydia), and viruses (such as hepatitis C and dengue) induce and target LDs during their life cycles. The current view is that LDs support infection, providing microorganisms with substrates for effective growth.

RATIONALE

Successful innate defense is critical for survival, and host species have efficiently coevolved with pathogens to develop a plethora of immune responses. Multiple cues, including cellular stress and danger-associated molecular patterns such as lipopolysaccharide (LPS), induce LD formation. Thus, LD localization and dynamics may potentially be advantageous for organizing an intracellular host defense. We have investigated the possibility that mammalian LDs have a direct and regulated role in innate immunity.

RESULTS

We show that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated during polymicrobial sepsis and by LPS. Light and electron microscopy demonstrated specific association of LDs and bacteria in human macrophages, suggesting the existence of docking mechanisms that facilitate the engagement of antibacterial LD proteins with bacteria.

A comparative mass spectrometry profiling of proteins differentially associated with LDs in response to LPS (LPS-LDs) revealed the profound remodeling of the organelle proteome. A stringent evaluation identified 689 proteins differentially regulated on LPS-LDs (317 enriched and 372 reduced). Ingenuity Pathway Analysis revealed an enrichment of innate immune system–related components and reduction of metabolism-related LD-resident proteins. Additional analyses suggested that LDs serve as innate immune hubs, integrating major intra- and extracellular immune responses.

Among the five members of the perilipin family of LD surface proteins (PLINs), PLIN5 was the only one down-regulated on LPS-LDs. PLIN5 reduction promoted physical and functional disconnection of LPS-LDs and mitochondria, with a concomitant reduction of oxidative metabolism and ketogenesis. Forced PLIN5 reexpression increased the number of LD-mitochondria contacts, reducing LD-bacteria interactions and compromising the antimicrobial capacity of cells.

By contrast, PLIN2 was the most up-regulated PLIN on LPS-LDs. Gene interaction analysis revealed that multiple immune proteins nucleated around PLIN2 in response to LPS. LPS-LDs accrued several interferon-inducible proteins such as viperin, IGTP, IIGP1, TGTP1, and IFI47. Furthermore, LPS-LDs also accumulated cathelicidin (CAMP), a broad-spectrum antimicrobial peptide with chemotactic properties. Cells overexpressing a LD-associated CAMP were more resistant to different bacterial species, including Escherichia coli, methicillin-resistant Staphylococcus aureus, and Listeria monocytogenes.

CONCLUSION

These results demonstrate that LDs form a first-line intracellular defense. They act as a molecular switch in innate immunity, responding to danger signals by both reprogramming cell metabolism and eliciting protein-mediated antimicrobial mechanisms. Mechanisms of LD trafficking and docking with phagocytic and parasitophorous membranes, observed here and described for several pathogens, may facilitate the delivery of immune proteins located on the LD surface. Intracellular LDs can provide infected cells with several biological benefits, serving as a location to attract pathogens as well as coordinating different immune systems that operate simultaneously against different classes of pathogens. LDs may also sequester cytotoxic compounds (such as antimicrobial peptides), reducing damage to other cellular organelles. In view of the widespread resistance to current antibiotics, this study helps decipher molecular mechanisms involved in antimicrobial defense that could be exploited for development of new anti-infective agents.

LDs mediate innate immune defense.

Serial blockface scanning electron microscopy data reconstruction showing an infected macrophage. Bacteria (blue) and LDs (green) in the three-dimensional dataset have been colored and projected onto a single image. LDs associate with the bacteria surface (black square). This interaction is proposed to bring a specific set of antipathogenic proteins in contact with the membrane-enclosing bacteria (inset).

Abstract

Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and a source of nutrients for intracellular pathogens. We demonstrate that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated by danger signals. In response to lipopolysaccharide (LPS), multiple host defense proteins, including interferon-inducible guanosine triphosphatases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD-bacterial contacts. Thus, LDs actively participate in mammalian innate immunity at two levels: They are both cell-autonomous organelles that organize and use immune proteins to kill intracellular pathogens as well as central players in the local and systemic metabolic adaptation to infection.

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