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Mutation in Gene (NUP160) for Nuclear Pore Complex Protein Linked to Steroid-Resistant Nephrotic Syndrome

Mutations in the NUP160 gene, which encodes one protein component of the nuclear pore complex nucleoporin 160 kD, are implicated in steroid-resistant nephrotic syndrome, an international team reports in an article published online on March 25, 2019 in the Journal of the American Society of Nephrology (JASN). Mutations in this gene have not been associated with steroid-resistant nephrotic syndrome previously. The JASN article is titled “Mutations in NUP160 Are Implicated in Steroid-Resistant Nephrotic Syndrome.” “Our findings indicate that NUP160 should be included in the gene panel used to diagnose steroid-resistant nephrotic syndrome to identify additional patients with homozygous or compound-heterozygous NUP160 mutations," says Zhe Han (photo), PhD, an Associate Professor in the Center for Genetic Medicine Research at Children's National in Washington, DC, and the study's senior author. The kidneys filter blood and ferry waste out of the body via urine. Nephrotic syndrome is a kidney disease caused by disruption of the glomerular filtration barrier, permitting a significant amount of protein to leak into the urine. While some types of nephrotic syndrome can be treated with steroids, the form of the disease that is triggered by genetic mutations does not respond to steroids. The patient covered in the JASN article had experienced persistently high levels of protein in the urine (proteinuria) from the time she was 7. By age 10, she was admitted to a Shanghai hospital and underwent her first renal biopsy, which showed some kidney damage. Three years later, she had a second renal biopsy showing more pronounced kidney disease. Treatment with the steroid prednisone; cyclophosphamide, a chemotherapy drug; and tripterygium wilfordii glycoside, a traditional therapy, all failed.

Synthetic Peptide (TNF-Derived TIP Peptide) Shows Promise of Protecting Kidneys from Nephritis

A synthetic peptide (TNF-derived TIP peptide) appears to directly disrupt the destructive inflammation that occurs in nephritis, enabling the kidneys to better recover and maintain their important functions, investigators report. Whether they gave the TIP peptide body-wide or delivered it directly to the kidneys, it reduced the movement of immune cells into the kidneys, resolved inflammation and damage, and improved kidney function, without increasing blood pressure, the scientists reported in an article published online on March 20, 2019 in Kidney International. The article is titled “The TNF-Derived TIP Peptide Activates the Epithelial Sodium Channel and Ameliorates Experimental Nephrotoxic Serum Nephritis.” Serious infection or injury, and diseases like uncontrolled hypertension and diabetes, can cause acute or chronic nephritis, which affects both kidneys and the million filtering units in each. Particularly when nephritis is chronic, patients often wind up in kidney failure and on dialysis, which has basic scientists and physicians alike looking for better interventions. So, the investigators in this study gave the TIP peptide the same way it might one day be given to patients, within a few days of signs of kidney inflammation. The scientists found that, in an animal model of moderate nephritis, the administration of the TIP peptide allowed the animals to avoid hallmark problems like excessive inflammation and protein in the urine, a sign of kidney dysfunction, says Rudolf Lucas, PhD, a vasculate biologist who is an Associate Professor in the Vascular Biology Center at the Medical College of Georgia (MCG) at Augusta University, and senior author of the Kidney International article.

Understanding Gene Interactions Holds Key to Personalized Medicine, Scientists Say in Cell Perspective

When the Human Genome Project was completed, in 2003, it opened the door to a radical new idea of health - that of personalized medicine, in which disease risk and appropriate treatment would be gleaned from one's genetic makeup. As more people had their genomes sequenced, disease-related genes would start coming into view-- and while this is true in many ways, things also turned out to be much more complicated. Sixteen years on, tens of thousands of people have had their genomes sequenced, yet it remains a major challenge to infer future health from genome information. Part of the reason may be that genes interact with each other to modify trait inheritance in ways that are not totally clear, write University of Toronto (U of T) Donnelly Centre researchers in an invited perspective published in March 21, 2019 in Cell. The title of the open-access Cell article is “Global Genetic Networks and the Genotype-to-Phenotype Relationship.” "All the genome sequencing data is highlighting the complexity of inheritance for the human genetics community," says Brenda Andrews, PhD, University Professor and Director of U of T's Donnelly Centre for Cellular and Biomolecular Research and a senior co-author, whose lab studies interactions between genes. "The simple idea of a single gene leading to a single disease is more likely to be an exception than a rule," she says. Dr. Andrews and Charles Boone, PhD, who is also a senior co-author, are Professors in the U of T's Donnelly Centre and the Department of Molecular Genetics, as well as Senior Fellows of the Genetic Networks program at the Canadian Institute for Advanced Research, which Dr. Boone co-directs.

Western Bias in Human Genetic Studies Is “Both Scientifically Damaging and Unfair”—Prominent Geneticists Call for Concerted Effort to Increase Diversity in Human Genomic Studies

Despite efforts to include more diversity in research, people of European ancestry continue to be vastly overrepresented and ethnically diverse populations largely excluded from human genomics research, according to the authors of a commentary published on March 21, 2019, in a special issue of Cell on human genetics. This lack of diversity in studies has serious consequences for science and medicine. For one thing, the authors say, the bias in the data limits scientists' understanding of the genetic and environmental factors influencing health and disease. It also limits the ability to make accurate predictions of a person's disease risk based on genetics and to develop new and potentially more effective treatment approaches. "Leaving entire populations out of human genetic studies is both scientifically damaging and unfair," says co-author Sarah Tishkoff (@SarahTishkoff), PhD, Professor, Departments of Genetics & Biology, Perelman School of Medicine, University of Pennsylvania. "We may be missing genetic variants that play an important role in health and disease across ethnically diverse populations, which may have deleterious consequences in terms of disease prevention and treatment." Dr. Tishkoff and her colleagues, including Giorgio Sirugo, MD, PhD, Senior Research Investigator, University of Pennsylvania, and Scott M. Williams, PhD, Professor, Director, Epidemiology & Biostatistics Graduate Studies Program, Case Western Reserve University School of Medicine, report that, as of 2018, individuals included in genome-wide association studies (GWAS) were 78% European, 10% Asian, 2% African, 1% Hispanic, and <1% all other ethnic groups. GWAS studies search the genome for small variations that occur more frequently in people with a particular disease or other trait than in people without the disease or trait.

Major Depressive Disorder: Neurons from SSRI Non-Responders Have Longer Neuron Projections Than Responders; Gene Analysis Reveals That SSRI Non-Responders Also Have Low Levels of Protocadherin Genes (PCDHA6 & PCDHA8) Involved in Forming Neuronal Circuits

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medication for major depressive disorder (MDD), yet scientists still do not understand why the treatment does not work in nearly thirty percent of patients with MDD. Now, Salk Institute researchers have discovered differences in growth patterns of neurons of SSRI-resistant patients. The work, published in Molecular Psychiatry on March 22, 2019, has implications for depression as well as other psychiatric conditions such as bipolar disorder and schizophrenia that likely also involve abnormalities of the serotonin system in the brain. "With each new study, we move closer to a fuller understanding of the complex neural circuitry underlying neuropsychiatric diseases, including major depression," says Salk Professor Fred “Rusty” Gage (, PhD, President of the Salk Institute, Professor-Laboratory of Genetics, and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, and the study's senior author. “This paper, along with another we recently published (January 30, 2019 in Molecular Psychiatry), not only provides insights into this common treatment, but also suggests that other drugs, such as serotonergic antagonists, could be additional options for some patients." The title of the new article is “Altered Serotonergic Circuitry in SSRI-Resistant Major Depressive Disorder Patient-Derived Neurons” ( The earlier paper is titled “Serotonin-Induced Hyperactivity in SSRI-Resistant Major Depressive Disorder Patient-Derived Neurons” (

Chronic Pain--Scientists Close in on Origins; New Human Study ID’s Top 10 Genes for Future Focus—All 10 Are Involved in Immune Signaling & Response; Expression of These Genes “Strikingly” Different in Males vs Females; Results "Should Have Broad Impact"

A new study by researchers at The University of Texas (UT) at Dallas, UT MD Anderson Cancer Center, UT Health Science Center at Houston, and Baylor College of Medicine has produced evidence of the source of chronic pain in humans, revealing several new targets for pain treatment. The research reported in the paper--published online on March 19, 2019 in Brain, one of the world's oldest neurology journals--examined specialized nerve cells clustered near the base of the spine. The open-access article is titled “Electrophysiological and Transcriptomic Correlates of Neuropathic Pain in Human Dorsal Root Ganglion Neurons.” Researchers took advantage of an exceedingly rare opportunity to study these nerves, called dorsal root ganglia (DRG), removed from cancer patients undergoing surgery at MD Anderson. The researchers catalogued variations in RNA expression in the dorsal root ganglia cells of patients differing by pain state and sex. Using RNA sequencing, a specialized form of gene sequencing, on those DRG cells yielded a list of promising biochemical pathways for which researchers might be able to devise analgesic (pain-relieving) drugs. "This surgery is not done at many places," said Dr. Ted Price, PhD, a senior author of the paper and Eugene McDermott Professor of Neuroscience in the UT Dallas School of Behavioral and Brain Sciences. "Our patient cohort of 21, though it doesn't sound like many, is huge, relative to any prior human chronic pain study using RNA sequencing." Chronic pain is labeled as neuropathic when it is caused by damage to nerve cells. Examples include phantom limb syndrome, pain resulting from a stroke, and the "pins and needles" sensations associated with diabetes.

New Class of Drugs (PARG Inhibitors) Could Treat Ovarian Cancer

A team of researchers across The University of Manchester (UK) has shown that a new class of drugs is able to stop ovarian cancer cells from growing. The Cancer Research UK- and Wellcome Trust-funded study, publishedon online on March 18, 2019 in Cancer Cell (, showed that the drugs, called poly ADP (adenosine diphosphate) ribose glycohydrolase (PARG) inhibitors, can kill ovarian cancer cells by targeting weaknesses in their ability to copy their DNA. The open-access article is titled “DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly (ADP-ribose) Glycohydrolase Inhibitors.” The first-in-class PARG inhibitor PDD00017273, was discovered in the Drug Discovery Unit at the Cancer Research UK Manchester Institute, part of The University of Manchester, as part of a targeted program to discover PARG inhibitors for the clinic. This program is currently being progressed through a collaboration with IDEAYA Biosciences, Inc. (, an oncology-focused biotechnology company committed to the discovery of breakthrough synthetic lethality medicines and immuno-oncology therapies. These findings are promising for patients diagnosed with ovarian cancer, the sixth most common cause of cancer in women in the UK and a cancer that causes more than 4,000 deaths each year in the UK. "Sadly, for the majority of women diagnosed with ovarian cancer, the cancer relapses within 12 to 18 months of their first treatment, and so there is a pressing need to develop new therapies to treat this condition" said lead scientist Professor Stephen Taylor from The University of Manchester.

Mobile DNA Element Found in Mosquito Parasite (Wolbachia) Has Potential for Infectious Disease Control

Controlling mosquito-borne illnesses, such as Dengue or West Nile virus, has historically been difficult due to a lack of effective vaccines and concerns about the environmental impact of insecticides. Thus, scientists have turned to manipulating Wolbachia, a parasitic bacterium within mosquitoes, as a way to control the reproductive fitness of mosquito populations that transmit human disease. In a new study published on March 5, 2019 in Nature Communications, an international team, including scientists from the Marine Biological Laboratory (MBL) and the University of Chicago, identified a new mobile DNA element in Wolbachia, which may contribute to improved control strategies for mosquito vectors of disease. The open-access article is titled “The Wolbachia Mobilome in Culex pipiens Includes a Putative Plasmid.” Led by former MBL scientists Julie Reveillaud, PhD, of INRA, France, and Sarah Bordenstein of Vanderbilt University (USA), the researchers reconstructed near-complete genomes of Wolbachia isolated from individual ovaries of four Culex pipiens mosquitoes. In the process, the scientists identified a novel plasmid -- a circular piece of DNA that can replicate independently of the chromosomes. Because a plasmid is a mobile DNA element, it can transfer from one cell to another and can have great implications for the fitness and evolution of a microbial species. Mobile genetic elements that can spread through different Wolbachia cells, and thus across a Wolbachia population, hold promise for controlling mosquito populations that may carry disease. "Our data show that this novel plasmid is widespread across natural Wolbachia populations that infect C. pipiens mosquitoes throughout the world, which implies it has an essential role.

Guided by Human “Super Smeller,” Scientists Use Mass Spectrometry to ID Volatile Biomarkers for Parkinson’s Disease; Novel Findings May Enable Development of Noninvasive, Biomarker-Based Test That Will Permit Early Detection of Parkinson’s

Parkinson's disease (PD) is a neurodegenerative disorder that leads to progressive brain cell death and extensive loss of motor function. Despite much research being conducted on this disease, there are no definitive diagnostic tests currently available. Now, researchers report the identification of compounds that make up the signature odor of the disease with the help an individual who can detect PD through smell. They reported their findings on March 20, 2019 in ACS Central Science, published by the American Chemical Society. The open-access article is titled “Discovery of Volatile Biomarkers of Parkinson’s Disease from Sebum.” Ancient physicians, including Hippocrates, Galenus, and Avicenna, used scent as a diagnostic tool, and although olfactory tests are not common in modern medicine, diseases such as diabetes are often associated with a particular smell. However, there has been little evidence to tie scent to neurodegenerative disorders. Enter Joy Milne (photo), a "Super Smeller," a grandmother whose late husband Les was diagnosed with PD in 1986. Milne has an extremely sensitive sense of smell, and this enables her to detect and discriminate odors not normally detected by those of average olfactory ability. Milne can distinguish the unique odor of PD, which she can detect in subjects' sebum long before clinical symptoms appear. Sebrum is a light yellow, waxy, lipid-based biofluid that is secreted by the sebaceous glands and moisturizes and protects the hair and the skin, particularly the skin on the forehead and upper back. Sebum is made up of triglycerides, free fatty acids, wax esters, squalene, cholesterol esters, and cholesterol. Excessive production of sebrum is a known symptom of PD.

University of Wisconsin-Madison Team Finds Key to Common Cancer Pathway-- Novel Regulators of p53 Identified; Discovery Related to “Guardian of the Genome” Protein Could Unlock New Therapies

Scientists have long known that the protein p53, when mutated, is a critical factor in the onset of many different kinds of cancer. In its unmutated form, however, it is known to protect against cancer. These dueling qualities make the p53 protein and the gene that codes for it among the most studied in biology, yet the molecular mechanisms that govern its stability and function have yet to be fully understood. On March 18, 2019, in Nature Cell Biology, a team led by University of Wisconsin-Madison (UW-Madison) cancer researchers Richard A. Anderson PhD, Professor, Head of Phosohoinositide Signaling Laboratory, and Vincent Cryns, MD, Chief of the Division of Endocrinology, Diabetes & Metabolism at the University of Wisconsin School of Medicine and Public Health, reported the discovery of an unexpected regulator of the critical protein, opening the door to the development of drugs that could target it. The article is titled “A Nuclear Phosphoinositide Kinase Complex Regulates p53.” "p53, like Janus, has two faces," says Dr. Anderson, referencing the two-faced Roman god of gates and doorways. "The p53 gene is the most frequently mutated gene in cancers, and, when mutated, it switches its function from a tumor suppressor to an oncogene that drives the majority of cancers." Typically, explains Dr. Anderson of the UW School of Medicine and Public Health, the p53 protein serves as "the guardian of the genome," initiating the repair of DNA damaged by ultraviolet radiation, chemicals, or other means, and preventing tumor growth. When mutated, however, the protein goes rogue, becoming more stable and abundant than its unmutated counterpart, accumulating in the nucleus of the cell and causing cancer. The UW research team, which includes study lead authors and postdoctoral fellows Dr. Suyong Choi and Dr.

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