Lifeboat Foundation: Safeguarding Humanity
Toggle light / dark theme

Blog

Category: biotech/medical – Page 1,575

Aberrant activation of Wnt/β-catenin pathway is a key driver of colorectal cancer (CRC) growth and of great therapeutic importance. In this study, we performed comprehensive CRISPR screens to interrogate the regulatory network of Wnt/β-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and β-catenin–mediated endogenous transcription and redundant roles of T cell factor/lymphoid enhancer factor transcription factors in transducing β-catenin signaling. Compiled functional genomic screens and network analysis revealed unique epigenetic regulators of β-catenin transcriptional output, including the histone lysine methyltransferase 2A oncoprotein (KMT2A/Mll1). Using an integrative epigenomic and transcriptional profiling approach, we show that KMT2A loss diminishes the binding of β-catenin to consensus DNA motifs and the transcription of β-catenin targets in CRC. These results suggest that KMT2A may be a promising target for CRCs and highlight the broader potential for exploiting epigenetic modulation as a therapeutic strategy for β-catenin–driven malignancies.

Colorectal cancer (CRC) represents one of the major malignancies and a leading cause of cancer-related death worldwide. Aberrant Wnt/β-catenin pathway plays a pivotal role in colon carcinogenesis (1). Cytoplasmic β-catenin is phosphorylated by a protein complex containing adenomatous polyposis coli (APC), AXIN1 or AXIN2, casein kinase 1α (CK1α), and glycogen synthase kinase-3β (GSK3β), leading to β-catenin destruction through ubiquitin-proteasome system. Wnt binding to the LDL receptor related protein 5/6 (LRP5/6)–frizzled receptors results in the disassembly of the β-catenin–destruction complex and consequent accumulation of β-catenin. β-Catenin then enters into the nucleus and binds to T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to initiate the transcription of β-catenin downstream targets (2).

Nearly all colorectal tumors (CRC) harbor genetic mutations that lead to the hyperactivation of β-catenin signaling. For example, germline or spontaneous mutations in tumor suppressor APC may cause constitutive activation of β-catenin in colon stem cells and the development of colonic polyps, which may eventually evolve into colorectal carcinomas. Hyperactivated β-catenin initiates the expression of various downstream targets through binding to the promoter regions via TCF/LEF transcription factors. Studies using transcriptomic approaches have characterized various β-catenin–responsive targets, such as cMYC, AXIN2, ASCL2, LGR5, and CD44. Collectively, these targets promote proliferation (e.g., cMYC) and maintain a stem cell state (e.g., LGR5 and ASCL2), highlighting the potential value of developing treatments that target β-catenin signaling in cancer. However, β-catenin itself is an intractable drug target (6, 7).

Read more | >

Mutations in the RAB39B gene cause X-linked intellectual disability (XLID), comorbid with autism spectrum disorders or early Parkinson’s disease. One of the functions of the neuronal small GTPase RAB39B is to drive GluA2/GluA3 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) maturation and trafficking, determining AMPAR subunit composition at glutamatergic postsynaptic neuronal terminals. Taking advantage of the Rab39b knockout murine model, we show that a lack of RAB39B affects neuronal dendritic spine refinement, prompting a more Ca2+-permeable and excitable synaptic network, which correlates with an immature spine arrangement and behavioural and cognitive alterations in adult mice. The persistence of immature circuits is triggered by increased hypermobility of the spine, which is restored by the Ca2+-permeable AMPAR antagonist NASPM.

Read more | >

While the world was distracted with the rampant spread of a novel coronavirus, 2020 also witnessed an explosion in another deadly pathogen that could pose a threat to global public health.

H5N8, a subtype of highly pathogenic avian influenza virus (HPAIV), was identified decades ago, but during 2020 a series of emerging and ongoing H5N8 outbreaks in avian populations across dozens of countries have led to the death or slaughter of millions of birds worldwide.

“The affected geographic regions have been expanding continuously, and at least 46 countries have reported highly pathogenic H5N8 AIV outbreaks,” virus researchers Weifeng Shi and George F. Gao write in a new perspective article in Science, warning of the dangers of H5N8 if we don’t closely monitor and contain this worrisome trend.

Read more | >

The adhesion and colonization or biofilm formation include primary stage in bacterial infections. Major adhesion virulence factors in this step include type I fimbriae (FimH) and pilli structures for attachment to the host cells7,8. Furthermore, numerous bacteria secrete toxins and extracellular enzymes which play a crucial role in the apoptosis or necrosis of epithelial cells or immunocytes. Various virulence factors of A. baumannii such as adhesins genes like kpsMII (group 2 capsule synthesis) and fimH, tratT (serum resistance associated), fyuA (yersiniabactin receptor) and iutA (aerobactin receptor) have been investigated previously9,10. An important polysaccharide for biofilm formation is encoded by pgaABCD locus11. Biofilm production is a strategy to escape from harsh conditions and immune responses, hence play as reservoirs for drug-resistant systemic infections. Biofilm-producing A. baumannii has been isolated from several infectious origins such as pneumonia and devise-associated infections. Bacterial within biofilm can resist significantly more against antibiotics compared to planktonic mode of growth12. Hence, biofilm-mediated infections are in relapse more frequently13.

Therefore, there is an urgent need to enhance the effects of antimicrobials against pathogenic bacteria. In recent years, interest has enhanced towards application of nanoparticles as therapeutic regimens14,15,16,17,18,19,20,21. Silver nanoparticles (AgNPs), which have low toxicity in ecosystems and have high rate of surface capacity, can inhibit accumulation of biofilm materials responsible for evasion and protection22,23,24.

The aim of this study was to isolate A. baumannii from wound infections, determine their resistance and virulence profile, and assess the impact of AgNPs on the bacterial growth, virulence and biofilm-related gene expressions in the isolated strains.

Read more | >

It’s been nearly two decades since medical science has produced a new treatment for Alzheimer’s. Is that drought about to end?

June 7 will be a big day in the life of Jeff Borghoff — not to mention the more than 6 million other Americans living with Alzheimer’s disease.

On that date, the U.S. Food and Drug Administration is expected to announce whether it will give its blessing to the first new drug for the treatment of Alzheimer’s since 2003.

Borghoff fervently hopes the answer is yes. The 57-year-old resident of Forked River has been taking the drug for several years now, and he’s convinced it has helped significantly slow the progression of his dementia.

Read more | >

A team of researchers from Verve Therapeutics and the Perelman School of Medicine at the University of Pennsylvania has developed a CRISPR gene-editing technique that lowered the levels of cholesterol in the blood of test monkeys. In their paper published in the journal Nature, the researchers describe their technique.

Prior research has shown that in some people, the PCSK9 gene codes excess PCSK9 protein production (which occurs mostly in the liver)—leading to an increase in lipoprotein cholesterol levels in the bloodstream. This is because it interferes with blood cells with LDL receptors that “grab” LDL and remove it. For this reason, have developed therapies that reduce the production of PCSK9 protein. However, most do not work well enough, which is why there is still so much atherosclerotic cardiovascular disease. In this new effort, the researchers have tried another approach—altering the PCSK9 gene to make it stop coding for PCSK9 protein production.

The approach involved using a base editing technology made up of messenger RNA encoding for an along with guided RNA that was packaged in a lipid nanoparticle. Notably, the base editing technique was able to substitute a single nucleotide with another in the DNA without cutting the double helix. Prior research has shown the technique to be more precise, which means fewer errors than other CRISPR techniques. In their work, the researchers replaced an adenine with a guanine and a thymine with a cytosine, completely incapacitating the gene. Implementation of the therapy involved a one-time injection into the liver of cynomolgus monkeys.

Read more | >

Using a robotic ‘Third Thumb’ can impact how the hand is represented in the brain, finds a new study led by UCL researchers.

The team trained people to use a robotic extra and found they could effectively carry out dextrous tasks, like building a tower of blocks, with one hand (now with two thumbs). The researchers report in the journal Science Robotics that participants trained to use the thumb also increasingly felt like it was a part of their body.

Designer Dani Clode began developing the device, called the Third Thumb, as part of an award-winning graduate project at the Royal College of Art, seeking to reframe the way we view prosthetics, from replacing a lost function, to an extension of the human body. She was later invited to join Professor Tamar Makin’s team of neuroscientists at UCL who were investigating how the can adapt to body augmentation.

Read more | >