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Category: biotech/medical – Page 34

Genetic atlas reveals how human liver cells divide their labor

If scientists could shrink themselves to microscopic size and take a journey through the human body—like the submarine crew in the 1966 science fiction classic “Fantastic Voyage”—one of their first stops would no doubt be the liver. The unique structure of our largest internal organ comprises small, hexagonal functional units called lobules, each carrying out more than 500 functions simultaneously. Studies from the 1970s and 1980s revealed that liver cells divide these many tasks among themselves according to their location within each subunit; however, the technology available at the time provided only a blurred picture of this division of labor.

In a new study published in Nature, scientists from the Weizmann Institute of Science, together with colleagues at Sheba Medical Center and the Mayo Clinic, present the first genetic atlas of a healthy human liver at a resolution of 2 microns. The findings show that the division of labor in the human liver differs from that of other mammals and is more extensive than previously recognized, helping explain why certain regions of the liver are particularly vulnerable to fatty liver disease.

In recent years, technological advances have made it possible to identify which genes are active in each individual cell while also mapping the cells’ precise spatial positions within the tissue. Still, a comprehensive map of functional division in the human liver remained elusive, largely due to the difficulty of obtaining tissue samples from healthy donors.

By cutting selected synapses, brain circuit ‘editing’ could make memory stronger and rewire how learning works

Every thought, memory, and feeling we experience depends on trillions of tiny connection points in the brain called synapses. These are the junctions where one neuron passes signals to another, forming the vast communication network known as the connectome—the brain’s wiring diagram. Although scientists have developed powerful tools to increase or decrease neural activity, directly redesigning the brain’s physical wiring has remained far more difficult.

A research team led by Dr. Sangkyu Lee and Director C. Justin Lee at the Center for Memory and Glioscience within the Institute for Basic Science (IBS), in collaboration with Dr. Kea Joo Lee of the Korea Brain Research Institute (KBRI), has now developed a molecular tool that makes such structural editing possible. The new platform, called SynTrogo (Synthetic Trogocytosis), enables researchers to induce astrocytes to selectively remodel synaptic connections in a targeted brain circuit. The paper is published in the journal Nature Communications.

The brain already has a natural mechanism for refining its wiring. During development and throughout life, unneeded or weak connections are removed in a process known as synaptic pruning, much like trimming unnecessary branches from a tree. This pruning is partly carried out by astrocytes—star-shaped glial cells that closely surround synapses and help maintain the neural environment. When this process becomes dysregulated, either through too much or too little pruning, it has been linked to disorders such as schizophrenia, autism spectrum disorder, and Alzheimer’s disease.

Implantable islet cells could control diabetes without insulin injections

Most diabetes patients must carefully monitor their blood sugar levels and inject insulin multiple times per day, to help keep their blood sugar from getting too high. As a possible alternative to those injections, MIT researchers are developing an implantable device that contains insulin-producing cells. The device encapsulates the cells, protecting them from immune rejection, and it also carries an onboard oxygen generator to keep the cells healthy.

This device, the researchers hope, could offer a way to achieve long-term control of type 1 diabetes. In a new study, they showed that these encapsulated pancreatic islet cells could survive in the body for at least 90 days. In mice that received the implants, the cells remained functional and produced enough insulin to control the animals’ blood sugar levels.

“Islet cell therapy can be a transformative treatment for patients. However, current methods also require immune suppression, which for some people can be really debilitating,” says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. “Our goal is to find a way to give patients the benefit of cell therapy without the need for immune suppression.”

Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells

Although radioresistant and circulating tumor cell survival has been attributed to altered metabolism, the metabolic impact of radiation therapy on stromal cells is unknown. Corn et al. demonstrate radiation-induced mitochondrial and metabolic changes in fibroblasts that are regulated by autophagy and drive growth in triple-negative breast cancer.

Lifestyle-Driven Variations in Nutrimiromic MicroRNA Expression Patterns across and beyond Genders

The importance of diet and lifestyle in maintaining overall health has long been recognised. MicroRNAs (miRNAs) have emerged as key players in the intricate interplay between health and disease. This study, including 305 participants, examined the role of miRNAs from capillary blood as indicators of individual physiological characteristics, diet, and lifestyle influences. Key findings include specific miRNAs associated with inflammatory processes and dietary patterns. Notably, miR-155 was associated with subjects with metabolic diseases and upregulated in age. Additionally, the study revealed diet-related miRNA expressions: high consumption of vegetables, fruits, and whole grains correlated with increased levels of miR-let-7a and miR-328, both implicated in anti-inflammatory pathways, and decreased expression of pro-inflammatory miR-21.

Activated neutrophils are a hallmark of acute lung injury

Here, Dolly Mehta & team find loss of ERG in endothelial cells alters neutrophil transcriptome towards inflammatory lineage via IL8/CXCR2 and CXCR2 blockade with Reparixin reduces inflammation, neutrophil infiltration, and improves survival in a pneumonia model.

The figure shows mouse lungs 30 minutes after antibody administration, with increased number of neutrophils (green) in Erg-null mice compared with Ergfl/fl mice. Endothelium (red).

1Department of Pharmacology and Regenerative Medicine, and.

2Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois Chicago, College of Medicine, Chicago, Illinois, USA.

Address correspondence to: Dolly Mehta, Department of Pharmacology and Regenerative Medicine, University of Illinois, Chicago, College of Medicine, 835 S. Wolcott Avenue, Chicago, Illinois 60,612, USA. Phone: 312.355.0236; Email: [email protected].

Immune system uses a conveyor belt-like process to edit defective antibodies, new research finds

The immune system’s B cells create antibodies that can mount a response against just about anything—either destroying a pathogen or instructing the rest of the immune system to go after the offender. But what happens when these antibodies malfunction?

Researchers at Boston Children’s Hospital have identified the previously unknown mechanism for how immune cells can go back and self-edit the genes that code for these antibodies, essentially recycling them into newer versions.

The workings of this new mechanism, published in Nature, were uncovered in the laboratory of Frederick Alt, Ph.D., of the Program in Cellular and Molecular Medicine at Boston Children’s and a Howard Hughes Medical Center Investigator.

CRISPR Technology: Transforming the Future of Medicine and Diagnostics

Among the many promising possibilities of using CRISPR-based therapeutics, their translational use in monogenic human genetic diseases has the potential to provide long-term therapy after a single treatment. Genetic disorders can be treated with the help of CRISPR by editing the defective (disease-causing) gene or by editing the enhancer or regulator of the defective gene. Numerous studies, which are summarized in the table below (Table ), have shown promising results by using these two approaches.

3. Examples of CRISPR-Based Therapeuticsfor the Treatment of Genetic Disorders.

DiseaseCRISPR targetapproachmajor outcome of the studyreferenceDuchenne muscular dystrophydystrophin gene (DMD)single or multiplexed sgRNAs were developedto restore thedystrophin reading frame by targeting the mutational hotspot at exons45–55 and introducing shifts within exons or deleting one ormore exonsdystrophin expression is restored in vitroOusterout et al. Huntington’sdiseaseHuntingtin gene (HTT)HTT 5′ UTR was targetedimpropermaturation of the transcript and reducing the expressionof the disease-causing alleleKolli et al.a dual sgRNA approachwas used in vitro toexcise a 44kb promoter region upstream of a mutant HTT gene to silence its expressionexpression of the Huntington’sdisease-causing variant wasablatedShin et al.glaucomamyocilin gene (MYOC)Knocked down the expression of mutant MYOC in a mouse model of primary open-angle glaucomareductionof ER stress, lower intraocular pressure, and thepreventability of further glaucomatous damage in mouse eyes was observed. The authors also demonstrated the feasibility of utilizing CRISPR/Cas9in human eyes with glaucomaJain et al.hereditary tyrosinemiatype Ifumarylacetoacetate hydrolase gene (FAH)HDR-mediated point mutation correction in mouse hepatocytes.a significant proportion of alleles were correctedVanLith et al. Leber congenital amaurosis type 10 (LCA10)centrosomalprotein 290 gene (CEP290)AAV5-basedtherapy (EDIT-101) encapsulates Staphylococcusaureus Cas9 (SaCas9) and two sgRNAs targeting genomic locationsupstream and downstream of the intronic CEP290 pointmutation. The two sgRNAs enable cutting around the mutation to induceits removal or inversionnormal splicing of CEP290 pre-mRNA was restoredMaeder et al. Noonan syndromeleucine zipper like post translational regulator 1 gene (LZTR1)intron 16 of LZTR1 was targetedthe gene editing process could overcomethe disease phenotypeassociated with Noonan syndrome-associated cardiomyopathy in iPSC-derivedcardiomyocytes in vitroHanses et al. Angelman syndromeUBE3A-ATS Inc. RNAUBE3A-ATS Inc. RNA was targetedin cultured human neurons andin a mouse model of the diseasetargeting of UBE3A-ATSablated its function, leading to expressionof the paternal UBE3A gene and rescuing the diseasephenotypeWolter et al.congenital muscular dystrophy type 1A (MDC1A)laminin subunit alpha 1 gene (LAMA1)CRISPR activator mediated gene upregulation3.6-foldupregulation of LAMA1 was observedKemaladevi et al.genetic deafnesstransmembrane channel like 1gene (TMC1)non-homologous end joining(NHEJ)-mediated mutant Tmc alleledisruptiondeafness was prevented in mouse models upto one year postinjectionGyörgy et al.

Iatrogenic Cerebral Amyloid Angiopathy After Cardiac SurgeryTwo Case Reports

Authors describe 2 cases of likely iatrogenic cerebral amyloid angiopathy after cadaveric dura mater use for cardiac surgery during infancy. Both are remarkable for their early age at onset, lack of genetic risk factor, and demonstration of brain amyloidosis.

To alert on the risk of interhuman transmission of β-amyloid (Aβ) pathology leading to cerebral amyloid angiopathy (CAA) after non-neurosurgical procedures, here cardiovascular procedures, using cadaveric dura mater (DM) patches.

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