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Cell-Based Neurodegenerative Disease Modeling

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive upper and lower motor neuron (MN) degeneration with unclear pathology. The worldwide prevalence of ALS is approximately 4.42 per 100,000 populations, and death occurs within 3–5 years after diagnosis. However, no effective therapeutic modality for ALS is currently available. In recent years, cellular therapy has shown considerable therapeutic potential because it exerts immunomodulatory effects and protects the MN circuit. However, the safety and efficacy of cellular therapy in ALS are still under debate. In this review, we summarize the current progress in cellular therapy for ALS. The underlying mechanism, current clinical trials, and the pros and cons of cellular therapy using different types of cell are discussed. In addition, clinical studies of mesenchymal stem cells (MSCs) in ALS are highlighted. The summarized findings of this review can facilitate the future clinical application of precision medicine using cellular therapy in ALS.

ALS is believed to result from a combination of genetic and environmental factors (Masrori and Van Damme 2020). ALS exists in two forms: familial ALS (fALS) and sporadic ALS (sALS). fALS exhibits a Mendelian pattern of inheritance and accounts for 5–10% of all cases. The remaining 90–95% of cases that do not have an apparent genetic link are classified as sALS (Kiernan et al., 2011). At the genetic level, more than 20 genes have been identified. Among them, chromosome 9 open reading frame 72 (C9ORF72), fused in sarcoma (FUS), TAR DNA binding protein (TARDBP), and superoxide dismutase 1 (SOD1) genes have been identified as the most common causative genes (Riancho et al., 2019). Beyond genetic factors, the diverse pathological mechanisms of ALS-associated neurodegeneration have been discussed (van Es et al., 2017). The clinical symptoms of ALS are heterogeneous, with main symptoms including limb weakness, muscle atrophy, and fasciculations involving both upper and lower MNs.

Abstract: The mechanistic basis of chronic liver disease is still only partially understood

Harmeet Malhi & team discover ER-stress mediated S100A11 upregulation drives progression of fatty liver disease, revealing a new target for future treatments:

The figure shows reduction within the high-fat,-fructose, and-cholesterol,-lipotoxicity-influenced enhancer (FFC-LIE) mouse groups compared with FFC-scramble controls.

Address correspondence to: Harmeet Malhi, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55,905, USA. Phone: 507.284.0686; Email: [email protected].

Cerebral Microvascular Perfusion Assessed in Elderly Adults by Spin-Echo Dynamic Susceptibility Contrast MRI at 7 Tesla

Perfusion measures of the total vasculature are commonly derived with gradient-echo (GE) dynamic susceptibility contrast (DSC) MR images, which are acquired during the early passes of a contrast agent. Alternatively, spin-echo (SE) DSC can be used to achieve specific sensitivity to the capillary signal. For an improved contrast-to-noise ratio, ultra-high-field MRI makes this technique more appealing to study cerebral microvascular physiology. Therefore, this study assessed the applicability of SE-DSC MRI at 7 T. Forty-one elderly adults underwent 7 T MRI using a multi-slice SE-EPI DSC sequence. The cerebral blood volume (CBV) and cerebral blood flow (CBF) were determined in the cortical grey matter (CGM) and white matter (WM) and compared to values from the literature. The relation of CBV and CBF with age and sex was investigated.

Prognostic tool could help clinicians identify high-risk cancer patients

The MIT researchers have spent the past few years developing the Synthetic Survival Control causal inference framework, which enables them to answer complex “when-if” questions when using available data is statistically challenging. Their approach estimates when a target event happens if a certain intervention is used.

In this paper, the researchers investigated an aggressive cancer called nodal mature T-cell lymphoma, and whether a certain prognostic marker led to worse outcomes. The marker, TTR12, signifies that a patient relapsed within 12 months of initial therapy.

They applied their framework to estimate when a patient will die if they have TTR12, and how their survival trajectory would be different if they do not have this prognostic marker.

3D maps reveal hidden microenvironments shaping mouse brain connectivity

Recent technological and scientific advances have opened new possibilities for neuroscience research, which is in turn leading to interesting new discoveries. Over the past few years, many groups of neuroscientists worldwide have been trying to map the structure of the brain and its underlying regions with increasing precision, while also probing their involvement in specific mental functions.

As mapping the human brain in detail is often challenging and requires significant resources, many studies focus on other mammals, particularly mice or other rodents. Most mouse brain atlases delineated to date map the density of neurons or other brain cells (i.e., how many cells are packed in specific parts of the brain). In contrast, fewer works also tried to map the shape of neurons in the mouse brain and interactions between them.

Researchers at Fudan University and Southeast University recently set out to map dendrites (i.e., branch-like extensions of neurons via which they receive signals from other cells) in the mouse brain. Their paper, published in Nature Neuroscience, unveils groups of structures in the mouse brain that influence how neurons function and connect to other neurons, also known as microenvironments.

Einstein’s theory comes wrapped up with a bow: Astronomers spot star ‘wobbling’ around black hole

The cosmos has served up a gift for a group of scientists who have been searching for one of the most elusive phenomena in the night sky. Their study, presented in Science Advances, reports on the very first observations of a swirling vortex in spacetime caused by a rapidly rotating black hole.

The process, known as Lense-Thirring precession or frame-dragging, describes how black holes twist the spacetime that surrounds them, dragging nearby objects like stars and wobbling their orbits along the way.

Neutrino observatories show promise for detecting light dark matter

Dark matter is an elusive type of matter that does not emit, reflect or absorb light, yet is estimated to account for most of the universe’s mass. Over the past decades, many physicists worldwide have been trying to detect this type of matter or signals associated with its presence, employing various approaches and technologies.

As it has never been directly detected before, the composition and properties of dark matter remain mostly unknown. Initially, dark matter searches focused on the detection of relatively heavy particles. More recently, however, physicists also started looking for lighter particles with masses below one giga-electron-volt (GeV), which would thus be lighter than protons.

Researchers at SLAC National Accelerator Laboratory and The Ohio State University recently showed that signatures of these sub-GeV dark matter particles could also be picked up by neutrino observatories, large underground detectors originally designed to study neutrinos (i.e., light particles that weakly interact with regular matter).

Ghostly solar neutrinos caught transforming carbon atoms deep underground

Neutrinos are one of the most mysterious particles in the universe, often called “ghost particles” because they rarely interact with anything else. Trillions stream through our bodies every second, yet leave no trace. They are produced during nuclear reactions, including those that take place in the core of our sun.

Their tendency to not interact often makes detecting neutrinos notoriously difficult. Neutrinos from the sun have only been seen to interact on a handful of different targets. Now, for the first time, scientists have succeeded in observing them transform carbon atoms into nitrogen inside a vast underground detector.

How the cerebellum builds its connections with the rest of the brain during early development

For the first time, a team of researchers at the Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and Miguel Hernández University of Elche (UMH), has reconstructed how the cerebellum establishes its connections with the rest of the brain during the earliest stages of life.

The work, published in the journal Proceedings of the National Academy of Sciences, describes in detail the phases during which these neural connections emerge, expand, and are refined, offering the first comprehensive map of the development of cerebellar projections across the mouse brain.

Although the cerebellum has traditionally been associated with motor control, growing evidence shows that it also plays a role in processes such as emotional regulation, social behavior, and other cognitive functions. However, until now, it was not precisely known when it began interacting with other regions of the brain, communication that is fundamental for these cerebellar roles. This gap motivated the work of the group Development, Wiring and Function of Cerebellar Circuits, led by Juan Antonio Moreno Bravo at the IN.

‘Three-hit model’ involving genes and environment describes possible causes of autism

A new University of California San Diego School of Medicine study offers a unified biological model to explain how genetic predispositions and environmental exposures converge to cause autism spectrum disorder (ASD).

The study, published in Mitochondrion, describes a “three-hit” metabolic signaling model that reframes autism as a treatable disorder of cellular communication and energy metabolism. The model also suggests that as many as half of all autism cases might be prevented or reduced with prenatal and early-life interventions.

“Our findings suggest that autism is not the inevitable result of any one gene or exposure, but the outcome of a series of biological interactions, many of which can be modified,” said study author Robert K. Naviaux, M.D., Ph.D., professor of medicine, pediatrics and pathology at UC San Diego School of Medicine.

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