Central Nervous System Cysts

English 繁體中文 “Ω-NaBen exemplifies a novel molecular entity much improves the biophysicochemical properties of the sodium benzoate.” Dr. Guochuan Emil Tsai said. Los Angeles, California, March 18, 2025 A recent study by SyneuRx has revealed superior pharmaceutical properties of Ω(omega)-NaBen, a novel crystalline form of sodium benzoate (NaBen). Ω-NaBen is the last alphabet of Greek. Ω-NaBen reflects the ultimate supreme value of the Nostradamus compound he first discovered and purified in 1556. In the study, Ω-NaBen can therapeutically improve all three major symptom domains of schizophrenia model, including positive, negative, and cognitive symptoms. Ω-NaBen also shows enhanced aqueous solubility and therefore improves the bioavailability and antipsychotic effects. In addition, Ω-NaBen also has much better crystal-stability either by itself or combined clozapine. The findings of Ω-NaBen have been published in the peer-reviewed journal, CNS & Neurological Disorders – Drug Targets. NaBen can increases the synaptic D-serine level to enhance NMDA receptor-mediated neurotransmission and therapeutically improve the symptoms of schizophrenia and cognition and memory of dementia. Nevertheless, the therapeutic effect is not dose-efficient due to the low bioavailability, therefore requires large unrealistic dosages. To improve NaBen, SyneuRx have discovered all crystalline forms of NaBen. Among them, Ω-NaBen exhibits exceptional bioavailability and therapeutic effects in the preclinical study. A multi-center clinical study (ClinicalTrials.gov Identifier: NCT03094429) is currently ongoing for assessing the safety and efficacy of Ω-NaBen as an add-on therapy with clozapine in refractory schizophrenia. Once developed successfully, the combination of clozapine and Ω-NaBen, a novel and superior crystalline NaBen, can work as a therapy beyond the last line treatment of schizophrenia—clozapine therapy. Professor Dr. Guochuan Emil Tsai from UCLA, highlighted, “Ω-NaBen exemplifies an effective strategy for the patients with schizophrenia and taking the last line of treatment, clozapine; it extend the frontier of the treatment of schizophrenia.” Privacy PolicyTerms of Use Contact Mission Leadership Team Major Milestone Antiviral Platform NMDA Platform Pipeline SNA11 SNG12 SND12 Press Release Publication Media

New findings describe how the enzyme CST is recruited to the end of the telomere, where it maintains telomere length with the help of subtle chemical changes made to the protein POT1. The length of telomeres that protect the ends of our chromosomes should be tightly regulated. Those that are too long predispose to cancer, and those that are too short lose their protective ability, resulting in telomere disorders with serious health consequences. Our cells prevent this excessive shortening by adding telomeric DNA to the ends of chromosomes. Researchers at Rockefeller recently showed that this process is mediated by two enzymes: telomerase and the CST-Polα/primase complex. Having determined how telomerase is recruited, scientists were left with a fundamental question: how does CST-Polα/primase find its way to the telomere? Now, a new study published in Cell demonstrates that CST is recruited to the end of the telomere and regulated by subtle chemical changes made to POT1, a protein in the shelterin complex involved in telomere maintenance and implicated in cancer risk. The findings provide new insight into how human telomeres function at the molecular level, with implications for numerous diseases and disorders. "After the discovery of telomerase, it took decades to figure out how it gets to the telomere. Now, just months after discovering that CST-Polα/primase is the second critical enzyme required for telomere maintenance, we understand the details of how it is recruited," says Titia de Lange, the Leon Hess professor. "Moreover, we've found out how this process is regulated." Recruiting and regulating CST Telomeres have two different types of strands, G-rich and C-rich. Scientists have long known how telomerase maintains the length of the G-rich strand, but only recently was it recognized that the same problem also exists for the C-rich strand. A recent study from the de Lange lab identified the CST-Polα/primase complex as the key regulator responsible for keeping that strand intact. What remained to be seen was how CST, and its associated enzyme Polα-primase, travels to telomere to facilitate C-strand maintenance across replication cycles. Sarah Cai, a PhD candidate at Rockefeller, began investigating this piece of the telomere puzzle. Building on a decade of the de Lange lab's groundwork on CST, Cai added cryo-EM to the techniques used in this study while being co-advised by Rockefeller's Thomas Walz. "The interdisciplinary nature of the study is one of the most exciting parts," Cai says. "It was a very successful double-lab effort, making use of many different technologies." Walz, whose research focuses on cryo-EM, noted how Cai incorporated AlphaFold, a deep-learning algorithm that can predict the unique 3D structures of proteins, into her work. With the combined power of biochemistry, structural biology, and cell biology, the team ultimately confirmed that CST is recruited to telomeres by the POT1 protein. Once CST-Polα/primase is onsite, the addition and removal of phosphate groups from POT1 appears to function as an on/off switch that coordinates the final steps of telomere replication. Phosphorylated POT1 ensures that CST-Polα/primase remains inactive until telomerase has finished its job, upon which the dephosphorylation of POT1 activates CST-Polα/primase to add the finishing touches to the telomere. Telomere disorders and cancer Next, the team will look for specific enzymes that attach and remove phosphates during this process, controlling the on/off switch on POT1, and determining their role in regulating CST-Polα/primase recruitment and activity. A better understanding of how CST is recruited to the telomere cannot come fast enough for patients suffering from telomere disorders, such as Coats plus syndrome, a severe multi-organ disease characterized by abnormalities in the eyes, brain, bones, and GI tract. "For a long time, we didn't know why mild alterations in single amino acids would cause such a devastating disease," Cai says. "We now have a better idea of how these mutations affect the recruitment of this critical telomere maintenance machine and lead to Coats plus syndrome." The findings will also impact their cancer research. The de Lange lab has spent decades studying how telomere shortening contributes to tumor suppression and genome instability in cancer, and the present research may ultimately help answer questions that lie at the heart of tumor development. "Anything critical to telomere length regulation may well be critical to cancer prevention too," de Lange says. "This is a major focus of our lab, and one of the reasons we'll be looking into the interplay between CST-Polα/primase and telomerase more closely in the future."

New findings suggest the end-replication problem, an old standby of biology textbooks, is twice as intricate as once thought. Half a century ago, scientists Jim Watson and Alexey Olovnikov independently realized that there was a problem with how our DNA gets copied. A quirk of linear DNA replication dictated that telomeres that protect the ends of chromosomes should have been growing shorter with each round of replication, a phenomenon known as the end-replication problem. But a solution was forthcoming: Liz Blackburn and Carol Greider discovered telomerase, an enzyme that adds the telomeric repeats to the ends of chromosomes. "Case closed, everybody thought," says Rockefeller's Titia de Lange. Now, new research published in Nature suggests that there are two end-replication problems, not one. Further, telomerase is only part of the solution -- cells also use the CST-Polα-primase complex, which has been extensively studied in de Lange's laboratory. "For many decades we thought we knew what the end-replication problem was and how it was solved by telomerase," says de Lange. "It turns out we had missed half the problem." The leading-strand problem Since the description of the DNA double helix, it is known that DNA has two complementary strands running in opposite directions -- one from 5' to 3'; the other from 3' to 5'. When DNA is replicated, the two strands are separated by the replication machinery, also called the replisome. The replisome copies the 3' to 5' strand without interruption, a process referred to as leading-strand synthesis. But the other strand is synthesized in short backward steps from many fragments (Okazaki fragments) that are later stitched together. The process is fairly direct until the ends of the chromosomes. When copying the telomere, leading-strand DNA replication should copy the CCCTAA repeats to generate the TTAGGG repeat strand, while lagging-strand synthesis should do the opposite, making new CCCTAA repeats. The end-replication problem arises because leading strand synthesis fails to reproduce the last part of the telomere, leaving a blunt leading-end telomere without it characteristic and crucial 3' overhang. Telomerase solves this problem by adding single-stranded TTAGGG repeats to the telomere end. As for the lagging-strand, DNA synthesis should not have a problem. It could start the last Okazaki fragment somewhere along the 3' overhang. "The DNA replication machinery cannot not fully duplicate the end of a linear DNA, much the same way that you can't paint the floor under your feet" says Hiro Takai, senior staff scientist in the de Lange lab and lead author on the paper. The lagging-strand problem As descriptions of biological processes go, this model looked watertight. Until Takai made a surprising discovery while working on cells that lacked molecular machinery called the CST-Polα-primase complex. He and others had previously shown that CST-Polα-primase can replenish CCCTAA repeats at telomeres that had been attacked by DNA-degrading enzymes known as nucleases. This new data revealed something unexpected: not only was the leading strand in need of help -- he found evidence that the end of the lagging strand could also not be synthesized by the replisome. Takai's work suggested that the end-replication problem was twice as serious as previously thought, impacting both strands of DNA. "The results just didn't fit with the model for telomere replication," de Lange says. "At that point, Hiro and I realized that either his results were not right or the model was wrong. As his results seemed very solid to me, we needed to revisit the model." De Lange contacted Joseph T. P. Yeeles, a biochemist who studies DNA replication at the Laboratory of Molecular Biology in Cambridge (the same lab where Watson and Crick worked on the structure of the DNA double helix). Yeeles agreed that it would be good to take a close look at how the replisome behaves at the end of a linear DNA template. Could the replisome use a 3' overhang to make the last Okazaki fragment, as was proposed? The results of Yeeles' in vitro replication experiments were very clear. The replisome does not generate Okazaki fragments on the 3' overhang; it actually stops lagging-strand synthesis long before the leading strand reaches the 5' end. This second end-replication problem means that both strands of DNA will shorten with each division. Telomerase was only preventing this from happening at the leading strand and Hiro's data suggested that CST-Polα-primase fixed the second end-replication problem, that of the lagging strand. Takai spent the next four years designing new assays to confirm Yeeles' findings in vivo. He was able to measure how much DNA is lost due to the lagging-strand end-replication problem, revealing how many CCCAAT repeats need to be added by CST-Polα-primase to keep telomeres intact. The results change our understanding of telomere biology -- requiring revision of the textbooks. But the findings may also have clinical implications. Individuals who inherit mutations in CST-Polα-primase suffer from telomere disorders, such as Coats plus syndrome, which is characterized by an eye disorder and abnormalities in the brain, bones, and GI tract. Through a better understanding of how we maintain our telomeres, strides could one day be made in addressing these devastating disorders.