Bringing A Power Tool From Math Into Quantum Computing (Quantum)

Scientists design a novel quantum circuit that calculates the fast Fourier transform, an indispensable tool in all fields of engineering.

The Fourier transform is an important mathematical tool that decomposes a function or dataset into a its constituting frequencies, much like one could decompose a musical chord into a combination of its notes. It is used across all fields of engineering in some form or another and, accordingly, algorithms to compute it efficiently have been developed–that is, at least for conventional computers. But what about quantum computers?

A novel quantum circuit that calculates the Fourier transform in a much quicker, versatile, and more efficient way. ©Tokyo University of Science

Though quantum computing remains an enormous technical and intellectual challenge, it has the potential to speed up many programs and algorithms immensely provided that appropriate quantum circuits are designed. In particular, the Fourier transform already has a quantum version called the quantum Fourier transform (QFT), but its applicability is quite limited because its results cannot be used in subsequent quantum arithmetic operations.

To address this issue, in a recent study published in Quantum Information Processing, scientists from Tokyo University of Science developed a new quantum circuit that executes the “quantum fast Fourier transform (QFFT)” and fully benefits from the peculiarities of the quantum world. The idea for the study came to Mr. Ryo Asaka, first-year Master’s student and one of the scientists on the study, when he first learned about the QFT and its limitations. He thought it would be useful to create a better alternative based on a variant of the standard Fourier transform called the “fast Fourier transform (FFT),” an indispensable algorithm in conventional computing that greatly speeds things up if the input data meets some basic conditions.

To design the quantum circuit for the QFFT, the scientists had to first devise quantum arithmetic circuits to perform the basic operations of the FFT, such as addition, subtraction, and digit shifting. A notable advantage of their algorithm is that no “garbage bits” are generated; the calculation process does not waste any qubits, the basic unit of quantum information. Considering that increasing the number of qubits of quantum computers has been an uphill battle over the last few years, the fact that this novel quantum circuit for the QFFT can use qubits efficiently is very promising.

Another merit of their quantum circuit over the traditional QFT is that their implementation exploits a unique property of the quantum world to greatly increase computational speed. Associate Professor Kazumitsu Sakai, who led the study, explains: “In quantum computing, we can process a large amount of information at the same time by taking advantage of a phenomenon known as ‘superposition of states.’ This allows us to convert a lot of data, such as multiple images and sounds, into the frequency domain in one go.” Processing speed is regularly cited as the main advantage of quantum computing, and this novel QFFT circuit represents a step in the right direction.

Moreover, the QFFT circuit is much more versatile than the QFT, as Assistant Professor Ryoko Yahagi, who also participated in the study, remarks: “One of the main advantages of the QFFT is that it is applicable to any problem that can be solved by the conventional FFT, such as the filtering of digital images in the medical field or analyzing sounds for engineering applications.” With quantum computers (hopefully) right around the corner, the outcomes of this study will make it easier to adopt quantum algorithms to solve the many engineering problems that rely on the FFT.

References: Asaka, R., Sakai, K. & Yahagi, R. Quantum circuit for the fast Fourier transform. Quantum Inf Process 19, 277 (2020). https://doi.org/10.1007/s11128-020-02776-5

Provided by Tokyo University Of Science

NYUAD Study Finds Key Protein Related To The Disease-Causing Malformation Of Fat Tissue (Medicine)

The impairment of adipogenesis, the process in which fat cells (also known as adipocytes) accumulate to become fat tissue, can lead to many diseases such as diabetes, obesity, and heart conditions. The process of adipogenesis is regulated by a series of signals which program the adipocytes to express specific genes and congregate into adipose tissue.

Mohamed Al-Sayegh and Piergiorgio Percipalle. ©NYU Abu Dhabi.

A team of researchers from NYU Abu Dhabi (NYUAD), led by Associate Professor of Biology Piergiorgio Percipalle in collaboration with Research Assistant Professor Mohamed Al-Sayegh, recently studied the molecular basis of adipogenesis and discovered that the protein actin (a specific variant referred to as β-actin) has an important role in activating the genes which need to be expressed in order to create fat tissue. This further understanding of the adipogenesis process can be applied to future research on diseases caused by malfunctioning fat tissue formation.

In the paper titled β-actin contributes to an open chromatin for activation of the adipogenic pioneer factor CEBPA during transcriptional reprogramming, published in the journal Molecular Biology of the Cell, Percipalle and his team investigates adipogenesis in embryonic mouse tissue to determine how critical the role of β-actin is in the process. It was found that in the fat cells lacking β-actin, the series of genetic signals was impaired, which affected the expression of the genes needed to form fat tissue.

As many diseases are caused by the accumulation of adipose tissue in certain areas, understanding the molecular process of adipose tissue formation is vital. The details of the connection between impaired adipogenesis and metabolic diseases such as diabetes, obesity, and cardiovascular diseases are currently unknown. This study’s findings about the importance of the β-actin protein provide guidance into further tissue-based disease research.

“To understand how to treat diseases, we must have a deeper understanding of the causes of the diseases,” said Percipalle. “This research has shown that the signaling pathway within adipose cells is an intricate system in which β-actin plays an important role. With this new knowledge, we can pursue a closer look into the molecular mechanisms of adipogenesis and find new insights into how to treat related diseases.”

References: M. A. Al-Sayegh, S. R. Mahmood, S. B. Abul Khair, X. Xie, M. El Gindi, T. Kim, A. Almansoori, and P. Percipalle, “β-actin contributes to an open chromatin for activation of the adipogenic pioneer factor CEBPA during transcriptional reprograming”, Molecular Biology of the Cell, 2020. https://doi.org/10.1091/mbc.E19-11-0628 https://www.molbiolcell.org/doi/10.1091/mbc.E19-11-0628

Provided by NYU

RUDN University Doctors Suggested Ways To Reduce Obstetrical Complications In Endometriosis Patients (Medicine / Gynecology)

A team of doctors from RUDN University with their Italian colleagues had studied the data of existing studies on the effect of endometriosis on pregnancy and childbirth and suggested ways to reduce obstetrical complications in women with this condition. The results of the work were published in The Journal of Maternal-Fetal&Neonatal Medicine.

A team of doctors from RUDN University with their Italian colleagues had studied the data of existing studies on the effect of endometriosis on pregnancy and childbirth and suggested ways to reduce obstetrical complications in women with this condition. © RUDN University

Endometriosis is a pathological process accompanied by growth of benign of tissues (that are morphologically and functionally similar to endometrium) outside the uterine cavity. In the premenstrual phase, the endometrium becomes thicker, and if the ovum is not fertilized, it sheds and is removed from the uterine cavity with the menstruations. This process is almost painless in healthy women but in patients with endometriosis, it is accompanied by the inflammation of surrounding tissues. Such patients suffer from chronic pelvic pain, menstrual cramps, painful intercourse, and often infertility. 10% to 15% of women of reproductive age have endometriosis and 30% to 40% experience birth complications. Despite such prevalence of endometriosis, the patterns of obstetrical complications haven’t been properly studied yet. A team of doctors from RUDN University with their Italian colleagues was had studied the data of earlier works and proposed the ways for preventing obstetrical complications in women with this condition.

“Earlier studies focused on the biological factors that affect the gestation course in women with endometriosis. We know that patients with endometriosis may experience miscarriages, preterm birth, or other complications due to immunological and endocrinal disorders in the endometrium. However, the mechanism of obstetrical complications is still a not well-clarified issue. That is why we conducted a systematic review of the literature and studied the effects of endometriosis on pregnancy taking into account such factors as treatment and conception methods, as well as stage and localization of the pathological process. We also suggested ways for preventing obstetrical complications in patients with a history of endometriosis,” said Doctor Anna V. Borisova, PhD, assistant at the Department of Obstetrics and Gynecology with the Course of Perinatology, RUDN University.

The team analyzed the results of earlier studies taking into account each possible complication: preterm birth, hypertensive complications in pregnancy, placental abnormalities, risk of cesarean section, underweight of the fetus, and stillbirth. Based on the results of the study, the team suggested several methods to improve pregnancy prognosis. Namely, laparoscopy was mentioned as the main treatment option in case of adhesions. Laparoscopy is a modern surgical method that allows doctors to destroy the adhesions between peritoneal and pelvic organs using special endoscopic devices. This helps combat infertility and reduces discomfort and pain in patients with endometriosis. According to the team, the conception’s methods should be chosen based on the stages of the disease. Patients with advanced stages of endometriosis are recommended to undergo hormone therapy and women after surgery — in vitro fertilization with embryo transfer (IVF/ET). The team had suggested that all patients with diagnosed endometriosis should start taking 400 micrograms of folic acid in advance before conception to reduce the risks of preterm birth and spina bifida in the fetus leading to anencephaly (a lethal developmental defect in which a fetus has no cerebral hemispheres and calvarial bones).

“The results of different studies are controversial: some of them did not take concomitant hormone therapy into account; and some had methodological limitations. However, we managed to develop a rather clear picture of all possible obstetrical complications in patients with endometriosis, establish causal relations, and identify issues for further discussion,” added Romeo Konnon, PhD, assistant professor at the Department of Obstetrics and Gynecology with the Course of Perinatology, RUDN University.

References: Anna V. Borisova, Setonde Romeo D. Konnon, Valentina Tosto, Sandro Gerli & Viktor E. Radzinsky (2020) Obstetrical complications and outcome in patients with endometriosis, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2020.1793326

Provided by RUDN University

Breakthrough Blood Test Developed For Brain Tumors (Medicine)

Genetic mutations that promote the growth of the most common type of adult brain tumors can be accurately detected and monitored in blood samples using an enhanced form of liquid biopsy developed by researchers at Massachusetts General Hospital (MGH).

Comparing blood samples from patients with gliomas with tumor biopsy tissues from the same patients, Leonora Balaj, PhD, Bob S. Carter, MD, and other MGH investigators in the Department of Neurosurgery found that a novel digital droplet polymerase chain reaction (ddPCR) blood test they pioneered could accurately detect and monitor over time two mutations of the gene TERT. The mutations, labeled C228T and C250T, are known to promote cancer growth and are present in more than 60 percent of all gliomas, and in 80 percent of all high-grade gliomas, the most aggressive and life-threatening type.

Their discovery, which has the potential to substantially improve the diagnosis and monitoring of gliomas, is reported in the journal Clinical Cancer Research.

Gliomas are tumors of glia, central and peripheral nervous system cells that support and protect neurons, the cells that transmit electrical impulses.

Liquid biopsy is a method for detecting cancer by looking for fragments of tumor DNA that circulate in blood. The technique has been shown to be sensitive at detecting the presence of some forms of cancer, but brain tumors have until now posed a formidable barrier.

“Liquid biopsy is particularly challenging in brain tumors because mutant DNA is shed into the bloodstream at much lower level than any other types of tumors,” Balaj says.

“By ‘supercharging’ our ddPCR assay with novel technical improvements, we showed for the first time that the most prevalent mutation in malignant gliomas can be detected in blood, opening a new landscape for detection and monitoring of the tumors,” she says.

The researchers first tested the performance of the ddPCR assay in tumor tissue and found that the results were in perfect agreement with the results from an independently performed clinical laboratory assessment of TERT mutations in the tumor specimens.

They then looked at samples of blood plasma matched to patient tumors and found that the ddPCR assay could detect TERT mutations both in samples from MGH as well as from similarly matched plasma and tumor samples from collaborators at other institutions.

The ddPCR assay has an overall sensitivity (ability to detect the presence of a glioma) of 62.5 percent, which is a tenfold improvement over any prior assay for TERT mutations in the blood for brain tumors, compared to the standard of tissue-based detection of TERT mutations.

The test is easy to use, quick, and low cost, and could be performed in most laboratories, Balaj says. Importantly, the test can also be used to follow the course of disease. “We envision the future integration of tests like this one into the clinical care of our patients with brain tumors,” says Carter, chief of Neurosurgery and co-director of the MGH Brain Tumor Center. “For example, if a patient has a suspected mass on MRI scanning, we can take a blood sample before the surgery and assess the presence of the tumor signature in the blood, and then use this signature as a baseline to monitor as the patient later receives treatment, both to gauge response to the treatment and gain early insight into any potential recurrence.”

The team’s goal is to expand this blood test to be able to differentiate many types of brain tumors.

References: Koushik Muralidharan, Anudeep Yekula, Julia L. Small, Zachary S. Rosh, Keiko M. Kang, Lan Wang, Spencer Lau, Hui Zheng, Hakho Lee, Chetan Bettegowda, Michael R Chicoine, Steven Kalkanis, Ganesh M. Shankar, Brian V Nahed, William T. Curry, Pamela S. Jones, Daniel P. Cahill, Leonora Balaj and Bob S Carter, “TERT promoter mutation analysis for blood-based diagnosis and monitoring of gliomas”, Clinical Cancer Research, 2020. DOI: 10.1158/1078-0432.CCR-20-3083

Provided by Massachusetts General Hospital

Scientists Identify Sensor Protein That Underlies Bladder Control (Medicine)

A team co-led by scientists at Scripps Research has found that the main sensor protein enabling our sense of touch also underlies the feeling of having a full bladder and makes normal bladder function possible.

An image of sensory neurons, with those that detect signals in the bladder labeled in magenta and the “mechanosensor” protein PIEZO2 in cyan. (Courtesy of Adam Coombs.)

The discovery, published Oct. 14 in Nature, marks a key advance in basic neurobiology and may also lead to better treatments for bladder control and urination problems, which are common especially among the elderly.

“We tend to take urination for granted, and it has been under-studied, yet it’s a huge burden when something goes wrong with this system,” says the study’s lead author Kara Marshall, PhD, a postdoctoral research associate in the Department of Neuroscience at Scripps Research. “Now we’ve identified a crucial part of how urination normally works.”

Marshall and her colleagues focused in this study on the PIEZO2 protein, a “mechanosensor” that detects the physical stretching of tissues where it resides. They found that PIEZO2 is expressed in cells of the bladder and is necessary for normal urinary continence and functioning in both mice and humans.

“Who would have imagined that the same mechanosensor protein enabling our sense of touch also alerts us that our bladder is full?” says co-senior author Ardem Patapoutian, PhD, Professor and Presidential Endowed Chair in Neurobiology at the Dorris Neuroscience Center at Scripps Research, and a Howard Hughes Medical Institute investigator.

In 2010, Patapoutian and his lab first identified PIEZO2 and its sister protein PIEZO1 as mechanosensors that sense mechanical distortions of tissues. For that feat, among others, Patapoutian was a co-recipient of the prestigious 2020 Kavli Prize in Neuroscience.

Like most sensor proteins, the PIEZOs are ion-channel proteins, which are embedded in their host cell’s outer membrane and, when triggered by a stimulus, allow a flow of charged atoms into the cell. Sensor ion-channel proteins are usually found in sensory neurons in the skin, joints and other organs. On a given neuron, when enough of these channels open to admit ion flows, the neuron will fire a nerve signal to the brain.

For PIEZOs, the stimulus that triggers the opening of the ion channel is the stretching of the cell membrane due to mechanical forces on the local tissue. In studies over the past decade, Patapoutian and his colleagues have shown that PIEZO2 is expressed is different organs and tissues throughout the body. For example, they exist in lung tissues to sense lung stretch and help regulate breathing, in blood vessels to sense blood pressure and in the skin to mediate the sense of touch.

The new study was a collaboration with Alexander Chesler, PhD, and Carsten Bönnemann, MD, senior investigators at the National Institutes of Health. Chesler and Bönnemann, and their colleagues, have been studying people born with genetic mutations that result in the functional loss of PIEZO2. These individuals suffer various impairments in sensory pathways known to be PIEZO2-related.

For the study, NIH investigators found that these PIEZO2-deficient individuals, in addition to their other sensory deficits, lack the normal sense of having a full bladder. They typically urinate on a schedule to avoid incontinence and have trouble completely emptying their bladder when they do urinate.

Patapoutian, Marshall and their colleagues showed in experiments that the loss of PIEZO2 has similar effects in mice. The urinary tract uses PIEZO2 protein in both bladder sensory neurons and in bladder-lining cells called umbrella cells to detect stretch and facilitate urination, indicating a two-part sensor system. As they determined in experiments, bladder neurons in mice normally respond robustly with nerve signals when the bladder is filled but are almost completely silent during bladder filling if they lack PIEZO2.

The mice lacking PIEZO2 in their lower urinary tracts also showed abnormal urination reflexes in the muscles controlling the urethra, the duct in which urine flows from the bladder. That suggests that in mice and most likely in people, the mechanosensor protein is needed both for normal bladder-stretch sensation and for normal urination.

The team is currently following up with research on the distinct roles of bladder neurons and umbrella cells, and how they signal to each other. They are also investigating the possible roles of other mechanosensors, such as PIEZO1, in bladder control and urination.

“Mice without PIEZO2 had clear urination deficits, but ultimately were still able to urinate, so that suggests another mechanosensory protein may be involved,” Marshall says.

References: Marshall, K.L., Saade, D., Ghitani, N. et al. PIEZO2 in sensory neurons and urothelial cells coordinates urination. Nature (2020). https://doi.org/10.1038/s41586-020-2830-7

Provided by Scripps Research Institute

Oncotarget: Efavirenz Induces DNA Damage Response Pathway In Lung Cancer (Medicine)

The cover for Issue 41 of Oncotarget features Figure 7, “IPA ATM-signaling pathway in (A) EFV treated MRC-5 and (B) A549 cells,” recently published in “Efavirenz induces DNA damage response pathway in lung cancer” by Marima, et al. which reported that the cell-cycle related genes are potential gene targets in understanding the effects of efavirenz in lung cancer.

IPA ATM-signaling pathway in (A) EFV treated MRC-5 and (B) A549 cells. The green and the red colours indicate down and up-regulation. The activated p53 irrespective of the expression levels of ATM activates its downstream targets such as p21, GADD45A, BRCA1 and NBS, inhibiting cell cycle progression and initiating DNA repair and growth arrest mechanism. ©Mahaba Marima

The present study aimed at investigating the expression changes of cell-cycle related genes in response to EFV drug treatment in human non-small cell lung carcinoma and normal lung fibroblast cells.

The loss in nuclear integrity in response to EFV was detected by 4′, 6-diamidino-2-phenylindole staining. Gene expression profiling was performed using human cell cycle PathwayFinder RT2 Profiler™ PCR Array.

The expression changes of 84 genes key to the cell cycle pathway in humans following EFV treatment was examined.

Interestingly, the p53 signaling pathway was activated irrespective of the repressed ATM pathway in A549 cells as revealed by the Ingenuity Pathway Analysis.

Dr. Rahaba Marima from The University of Pretoria as well as The University of the Witwatersrand said, “The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) is frequently used in human immunodeficiency virus (HIV) treatment, and forms part of the first-line Highly Active Antiretroviral Treatment (HAART) treatment against HIV/AIDS.”

Xulu and Hosie showed that ARV drugs including EFV caused apoptosis in the Human Squamous Cell carcinoma from Uterine Cervix cells and observed a change in morphological features such as rounding-up of cells, retraction of filopodia, blebbing and maintenance of plasma membrane integrity- characteristic features of apoptosis.

Due to the fact that the cell cycle is a tightly regulated process, eukaryotic cells respond to external stimuli such as DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair.

A previous study performed by the Marima Research group, involved assessing the effects of EFV on lung cancer cells at the cellular level on the physiological health of treated cells.

To date, several studies including Hecht et al., have revealed the cytotoxic effects of EFV against several cancer cells, but to our knowledge, no study yet has shown the anti-proliferative effects of EFV on lung epithelial cancer cells in relation to primary lung fibroblast cells.

In conjunction with preceding studies on EFV′s cyto-and-genotoxicity, this Oncotarget study is the first to reveal EFV mediated ATM/ATR genotoxicity in lung cells.

“In conjunction with preceding studies on EFV′s cyto-and-genotoxicity, this Oncotarget study is the first to reveal EFV mediated ATM/ATR genotoxicity in lung cells”
The Marima Research Team concluded in their Oncotarget Research Paper that the treatment of MRC-5 and A549 cells with EFV alters the gene expression of important factors that are essential in the maintenance of genomic stability in relation to the cell cycle.

This is particularly observed in the cancerous cells, with the significant down-regulation of AURKB and MAD2L2. Even though the normal p53 expression was shown here, p27, CASP3, Cyclin G1 and G2, NBN, RAD1 and RAD17 were significantly up-regulated.

Interestingly, the S-phase and DNA replication genes were downregulated; MCM4 in particular was –3.65 significantly down-regulated.

Depending on the severity of these effects in the physiological health of normal cells, EFV poses as a promising drug that can be used in synergy with chemo/radiotherapy.

Posttranscriptional gene regulation targeted by EFV in lung cells would also be interesting to pursue.

References: Marima R., Hull R., Dlamini Z., Penny C. Efavirenz induces DNA damage response pathway in lung cancer. Oncotarget. 2020; 11: 3737-3748. Retrieved from https://www.oncotarget.com/article/27725/text/

Provided by Impact Journals LLC

STAT3 Identified As Important Factor In Emotional Reactivity (Neuroscience)

MedUni Vienna researchers led by Daniela Pollak from the Division of Neurophysiology and Neuropharmacology showed that STAT3 plays an important role in the serotonergic system as a molecular mediator.

Numerous scientific studies indicate that inflammatory processes play a key role in the development of psychiatric disorders. One of the areas of particular interest is the interleukin 6/STAT3 signal transduction pathway, which is associated with depression, schizophrenia, and bipolar disorder. In a study published in leading journal Molecular Psychiatry, MedUni Vienna researchers led by Daniela Pollak from the Division of Neurophysiology and Neuropharmacology showed that STAT3 plays an important role in the serotonergic system as a molecular mediator for controlling emotional reactivity, thereby establishing a mechanistic link between the immune system, serotonergic transmission and affective disorders such as depression.

A) STAT3 immunoreactivity was evaluated within 5-HT-positive cells (ROI: white outlines shown in STAT3 channel) in images of the DR area (representative 4 × 5 stitched 60X images; scale bar: 100 µm), illustrating a visible reduction of STAT3 signal within the specified ROI (i.e., serotonergic cells) in KO animals. White dashed boxes mark the detailed area depicted in (B). (B) Corresponding single panel images of 5-HT and STAT3 immunoreactivity and a merged image in control and KO mice (60X, scale bar: 50 µm). (C) Quantification of STAT3 immunoreactivity within the ROI confirmed the reduction of STAT3 expression in KO serotonergic neurons of the DR. (D, E) STAT3 KO mice displayed significantly increased serotonergic firing frequencies compared to controls. 5-HT: 5-hydroxytryptamine; A.U.: arbitrary units; DR: dorsal raphe; KO: knockout; ROI: region of interest; STAT3: signal transducer and activator of transcription 3. All data are presented as mean ± SD. *p < 0.05.

The STAT3 signal transduction pathway is activated in response to a series of immunogenic and non-immunogenic stimuli, i.e. those that can and those that cannot trigger an immune response. “It was found that STAT3 is involved in nervous system functions that are important for controlling behaviour in physiological and pathological situations. In an earlier study, we had managed to show that STAT3 also regulates the expression of the serotonin transporter gene (Note: SERT),” explains Pollak.

Changes in serotonergic transmission, that is to say the transmission of information from one neuron to another using serotonin as a messenger substance, correlate closely with pathological changes in depression or other affective disorders. However, the interaction between the STAT3 signal transduction pathway and the neuronal information flow in the brain and its importance in regulating emotional behaviour has not yet been explored.

STAT3 deficiency reduces emotional reactivity

The published work therefore specifically investigated the significance of the STAT3 signal transduction pathway in the serotonergic system of the midbrain – an emotional regulation centre – by targeted inhibition of STAT3 in a mouse model. Says Pollak: “Where STAT3 was selectively absent from the serotonergic system of the midbrain, the mice displayed reduced, negative emotional reactivity in their behaviour and a diminished response to the effects of amphetamine in the brain. These effects could be detected in mice with reduced STAT3 expression both in a genetic and in a viral model, so that it was possible to rule out developmental changes and to show that an acute manipulation of STAT3 in the adult organism impacts on emotional behaviour.”

In animals lacking in STAT3, there was also found to be a change in the neuronal activity of serotonergic cells of the midbrain. Changes in molecular networks that are significant in neuropsychiatric illnesses were also found on the level of gene expression. “The results of our study indicate that STAT3 plays an important role as a molecular mediator in the serotonergic system for controlling emotional reactivity, thereby establishing a mechanistic link between the immune system, serotonergic transmission and affective disorders.”

Service: Molecular Psychiatry

“STAT3 in the raphe nuclei gates behavioural reactivity and regulates gene networks associated with neuropsychiatric disorders”. Sonali N. Reisinger, Spyridon Sideromenos, Orsolya Horvath, Sophia Derdak, Ana Cicvaric, Francisco Monje, Martin Bilban, Martin Häring, and Micaela Glat and Daniela D. Pollak.

References: Reisinger, S.N., Sideromenos, S., Horvath, O. et al. STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-00904-2

Provided by Medical University Of Vienna

RNA Editing Of BFP Using Artificial APOBEC1 Deaminase To Restore The Genetic (Medicine)

Various genetic diseases caused by point mutations have no established therapeutic approaches. Prof. Tsukahara and colleagues (Japan Advanced Institute of Science and Technology) are studying a therapeutic method using artificial RNA editing. It was announced that this year’s Nobel Prize in Chemistry will be given to the two scientists who discovered CRISPR/Cas9 for genome editing. Although genome editing is drawing attention as a gene repair technology, genome editing such as CRISPR/Cas9 may result in permanent alterations in genomic DNAs, potentially affecting multiple loci. Currently, it is very difficult to perform accurate genome editing in all targeted cells in vivo. So, it is possible to edit the genome in a fertilized egg, embryo, or cells, however, it is not suitable for gene therapy in humans. Moreover, genome editing raises ethical concerns. Therefore, we believe that genome editing is a suitable method for “ex vivo” techniques, or for use in fertilized eggs, but not throughout a patient’s body. In contrary, changes resulting from the RNA editing are not permanent because they do not affect the genome sequence, and can be done in sequence-specific manner. Therefore, for the purpose of therapeutic treatments, RNA editing is preferable to genome editing, says Prof. Tsukahara. Artificial site-directed RNA editing is an important technique for modifying genes and ultimately regulating protein function. We are trying to modify the genetic code of transcripts (RNA) by artificial RNA editing for the treatment of genetic disorders.

Various genetic diseases caused by point mutations have no established therapeutic approaches. Prof. Tsukahara and colleagues (Japan Advanced Institute of Science and Technology) are studying a therapeutic method using artificial RNA editing. ©JAIST

RNA editing is a physiological process and widespread in living organisms to produce various proteins with different functions from a single gene. In mammals, C or A of the RNA chain is base sequence-specifically hydrolytically deaminating, whereby C is replaced by U and A by I (inosine). These base conversions occur as a result of deamination of A or C, which has been found to be catalyzed by ADAR and APOBEC family enzymes, and then change genetic codes in RNAs. In this paper, we succeeded for the first time in the world in artificial C-to-U conversion of mutated RNA using APOBEC1.

Many genetic diseases are caused by T-to-C point mutations. Hence, editing of mutated genes represents a promising strategy for treating these disorders. We engineered an artificial RNA editase by combining the deaminase domain of APOBEC1 (apolipoprotein B mRNA editing catalytic polypeptide 1) with a guideRNA (gRNA) that is complementary to the target messenger RNA (mRNA). In this artificial enzyme system, the gRNA is bound to a MS2 stem-loop, a deaminase domain is fused to the MS2 coat protein and has the ability to convert mutated target nucleotides from C-to-U. As a target RNA, we used RNA encoding blue fluorescent protein (BFP) that was derived from the gene encoding GFP by a 199T > C mutation. Upon transient expression of both components (deaminase and gRNA), we observed GFP by confocal microscopy, indicating that mutated 199C in BFP had been converted to U, restoring the original sequence of GFP. This result was confirmed by PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) and Sanger’s sequencing using cDNA from transfected cells, revealing an editing efficiency of approximately 21%. Deep RNA sequencing result showed that off-target editing was sufficiently low in this system. We successfully developed of an artificial RNA editing system using artificial deaminase (APOBEC1) in combination with the MS2 system that could lead to therapies that treat genetic diseases by restoring wild-type sequences at the mRNA level.

References: Bhakta, S., Sakari, M. & Tsukahara, T. RNA editing of BFP, a point mutant of GFP, using artificial APOBEC1 deaminase to restore the genetic code. Sci Rep 10, 17304 (2020). https://doi.org/10.1038/s41598-020-74374-5

Provided by Japan Advanced Institute Of Science And Technology

A New Protein Discovered That Repairs DNA (Medicine)

Researchers from the University of Seville, in collaboration with colleagues from the Universities of Murcia and Marburg (Germany) have identified a new protein that makes it possible to repair DNA. The protein in question, called cryptochrome, has evolved to acquire this and other functions within the cell.

Ultraviolet radiation can damage the DNA, leading to mutations that disrupt cell function and can allow cancer cells to grow out of control. Our cells have DNA repair systems to defend themselves against this sort of damage. One of these systems is based on a protein, photolysis, which uses blue light to repair DNA damage before it leads to mutations.

Over the course of evolution, the genes for photolysis duplicated and became specialised, creating new proteins, cryptochromes, which have honed their ability to perceive blue light and now perform other functions in cells. For example, cryptochromes use blue light as a signal to regulate plant growth and the rhythm that controls daily activity (the circadian rhythm) in fungi and animals.

The authors of this study discovered that in the fungus Mucor circinelloides, a human pathogen, cryptochromes are the protein responsible for DNA repair after exposure to ultraviolet radiation, a function that should be performed by photolysis. They also suggest that cryptochromes in this fungus acquired their ability to repair DNA during evolution from an ancestral cryptochrome that was not able to repair DNA. This discovery illustrates how proteins change as their functions evolve.

The results have been published in an article in the prestigious journal Current Biology.

References: Eusebio Navarro, Nils Niemann, Dennis Kock, Luis M. Corrochano, Alfred Batschauer, Victoriano Garre, “The DASH-type Cryptochrome from the Fungus Mucor circinelloides Is a Canonical CPD-Photolyase”, Cell Biology, 2020 DOI: https://doi.org/10.1016/j.cub.2020.08.051

Provided by University Of Seville