Chimeric antigen receptor (CAR) T cells are genetically modified T cells expressing CARs, initially developed to recognize tumor antigens and kill cancer cells that evade T-cell recognition. Because of their impressive success in hemato-oncologic malignancies, CAR T cells are being repurposed with redesigned constructs for safety and sustained efficacy to target refractory systemic autoimmune or neurologic diseases.
Mitochondrial ATP production by oxidative phosphorylation (OXPHOS) is essential for cellular functions, such that mitochondria are known as the powerhouses of the cell (Verschueren et al., 2019). The mitochondrial ETC consists of five enzyme complexes in the inner membrane of the mitochondria. ETC generates a charge across the inner mitochondrial membrane, which drives ATP synthase (complex V) to synthesize ATP from ADP and inorganic phosphate.
Several studies have shown impairments of all five complexes in multiple areas of the AD brain (Kim et al., 2000, 2001; Liang et al., 2008). Mitochondrial dysfunction in AD is apparent from a decrease in neuronal ATP levels, which is associated with the overproduction of ROS, and indicates that mitochondria may fail to maintain cellular energy. A substantial amount of ATP is consumed in the brain due to the high energy requirements of neurons and glia. Since an energy reserve (such as fat or glucose) is not available in the central nervous system (CNS), brain cells must continuously generate ATP to sustain neuronal function (Khatri and Man, 2013). Mitochondria are the primary source of cellular energy production, but aged or damaged mitochondria produce excess free radicals, which can reduce the supply of ATP and contribute to energy loss and mitochondrial dysfunction in AD. Importantly, oxidative damage of the promoter of the gene encoding subunit of the mitochondrial ATP synthase results in reduced levels of the corresponding protein, leading to decreased ATP production, nuclear DNA damage to susceptible genes, and loss of function (Lu et al., 2004; Reed et al., 2008).
In advanced stages of AD, substantial nitration of ATP synthase subunits can take place, leading to the irregular function of the respiratory chain (Castegna et al., 2003; Sultana et al., 2006; Reed et al., 2009). Likewise, ATP-synthase lipoxidation occurs in the hippocampus and parietal cortex of patients with mild cognitive impairment (Reed et al., 2008). Compromised OXPHOS contributes to a characteristic mitochondrial dysfunction in AD brains, leading to decreased ATP production, elevated oxidative stress, and ultimately cell death (Reddy, 2006; Reddy and Beal, 2008; Du et al., 2012). The specific mechanisms of OXPHOS deficiency in AD remain a long-standing scientific question, but the role of mitochondrial F1Fo ATP synthase dysfunction in AD-related mitochondrial OXPHOS failure is emphasized by emerging evidence (Beck et al., 2016; Gauba et al., 2019).
The SARS-CoV-2 (severe acute respiratory syndrome coronavirus responsible for the COVID-19 disease) uses the Spike proteins of its envelope for infecting target cells expressing on the membrane the angiotensin converting enzyme 2 (ACE2) enzyme that acts as a receptor. To control the pandemic, genetically engineered vaccines have been designed for inducing neutralizing antibodies against the Spike proteins. These vaccines do not act like traditional protein-based vaccines, as they deliver the message in the form of mRNA or DNA to host cells that then produce and expose the Spike protein on the membrane (from which it can be shed in soluble form) to alert the immune system. Mass vaccination has brought to light various adverse effects associated with these genetically based vaccines, mainly affecting the circulatory and cardiovascular system.
Brain development is a complex process involving, for example, the precise diversification and distribution of cells into distinct areas. The researchers behind the present study have developed a new method called spatial tri-omics, that enables them to simultaneously measure in a specific area of the brain: 1) the activity of genes, 2) how this activity is regulated by epigenetic changes, and 3) if this activity ultimately leads to the production of proteins.
The study is based on analyses of mouse and human brains at different stages of development. The authors generated a spatiotemporal tri-omic atlas of the mouse brain from postnatal day 0 (P0) to P21 and compared corresponding regions with the human developing brain.
“We’ve been able to use this multidimensional method to track brain development over time and map changes from birth to a young age in different parts of the brain, as well as study how the brain reacts to inflammation,” explains the senior author.
An investigation into why blood doesn’t always behave as doctors expect has revealed a super-rare mutation in an extremely uncommon variation of blood.
Testing more than 544,000 blood samples in a hospital in Thailand revealed three people carrying a never-before-seen version of the B(A) phenotype – a genetic quirk estimated to occur in about 0.00055 percent of people, or roughly one in 180,000.
This discovery, says a team led by hematologist Janejira Kittivorapart of Mahidol University in Thailand, suggests that there may be more rare blood variants out there, too subtle for standard testing to detect.
Researchers have discovered new regions of the human genome particularly vulnerable to mutations. These altered stretches of DNA can be passed down to future generations and are important for how we study genetics and disease.
The regions are located at the starting point of genes, also known as transcription start sites. These are sequences where cellular machinery starts to copy DNA into RNA. The first 100 base pairs after a gene’s starting point are 35% more prone to mutations compared with what you’d expect by chance, according to the study published in Nature Communications.
“These sequences are extremely prone to mutations and rank among the most functionally important regions in the entire human genome, together with protein-coding sequences,” explains Dr. Donate Weghorn, corresponding author of the study and researcher at the Center for Genomic Regulation in Barcelona.
Life’s instructions are written in DNA, but it is the enzyme RNA polymerase II (Pol II) that reads the script, transcribing RNA in eukaryotic cells and eventually giving rise to proteins. Scientists know that Pol II must advance down the gene in perfect sync with other biological processes; aberrations in the movement of this enzyme have been linked to cancer and aging. But technical hurdles prevented them from precisely determining how this important molecular machine moves along DNA, and what governs its pauses and accelerations.
A new study fills in many of those knowledge gaps. In a paper published in Nature Structural & Molecular Biology, researchers used a single-molecule platform to watch individual mammalian transcription complexes in action. The result is a clear view of how this molecular engine accelerates, pauses, and shifts gears as it transcribes genetic information.
“What’s really striking is how this machine functions almost like a finely tuned automobile,” says Shixin Liu, head of the Laboratory of Nanoscale Biophysics and Biochemistry. “It has the equivalent of multiple gears, or speed modes, each controlled by the binding of different regulatory proteins. We figured out, for the first time, how each gear is controlled.”