“Niemann-Pick disease has never been considered an immune disorder,” says study leader Nan Yan, Ph.D., associate professor of immunology and microbiology. “These findings put it in a whole new light.”

Niemann-Pick disease type C, which affects about 1 in every 150,000 people worldwide, has long been considered a disease of cholesterol metabolism and distribution, a topic well-studied at UT Southwestern, where faculty members Michael Brown, M.D., and Joseph Goldstein, M.D., won the Nobel Prize in 1985 for their discovery of low-density lipoprotein (LDL) receptors, which led to the development of statin drugs.

When the Npc1 gene is mutated, cholesterol isn’t sent where it’s needed in cells, causing the progressive decline in motor and intellectual abilities that characterize Niemann-Pick. Yan’s lab, which doesn’t study cholesterol metabolism, made its discovery by chance while researching an immune protein known as STING, short for stimulator of interferon genes.

STING is a critical part of the body’s defense against viruses, typically relying on another protein known as cyclic GMP-AMP synthase (cGAS) to sense DNA and turn on immune genes to fight off viral invaders. The cGAS enzyme was identified at UT Southwestern.

STING journeys to different organelles to perform various tasks before it ends up in lysosomes, which serve as cellular garbage dumps. Disposal of STING is critical for an appropriate immune response, explains Yan; research from his lab and others has shown that when STING isn’t properly discarded, it continues to signal immune cells, leading to a variety of autoimmune conditions.

To determine what proteins interact with STING as it travels through cells, Yan and his colleagues used a technique called proximity labeling, which causes other proteins around a protein of interest to glow. After analyzing their data, Yan’s team was surprised to find that STING interacts with a protein that’s located on the surface of lysosomes and is produced by the Npc1 gene.

Because STING had never been implicated in Niemann-Pick disease type C, Yan and his team investigated whether it might play a role. The researchers removed the gene for STING from mice in which the Npc1 gene had also been deleted. Deleting Npc1 typically causes progressive problems in motor function, but animals with both the Npc1 and Sting genes deleted remained healthy.

Further research suggested that the protein produced by Npc1 has a binding site for STING that allows it to enter lysosomes for disposal. When the protein produced by Npc1 is missing, STING remains in cells, propagating Niemann-Pick disease type C. When Yan and his colleagues analyzed cells from human Niemann-Pick disease type C patients, they found that several immune-stimulating genes were overactive, as would be expected if STING disposal was defective.

In addition, Yan found that STING signaling is activated independently of cGAS in Niemann-Pick disease. This expands STING biology beyond its conventional role in host defense against infection.

Yan says that his lab and others are investigating the use of experimental drugs that inhibit STING to treat various autoimmune conditions. These compounds may also be useful for Niemann-Pick disease type C.

“If we can demonstrate that these compounds are effective in our animal models,” Yan says, “we may be able to offer an effective therapy to Niemann-Pick disease patients.”

Other UTSW researchers who contributed to this study include Ting-Ting Chu, Xintao Tu, Kun Yang, Jianjun Wu, Joyce J. Repa, and a variety of other UT Southwestern experts in neuroscience and cholesterol biology. This study also relied on technical support from UTSW’s Whole Brain Microscopy, Proteomics Core, Live Cell Imaging Core and Transgenic Core facilities.

This work is supported by National Institutes of Health, Cancer Prevention and Research Institute of Texas, the Burroughs Wellcome Fund, and the Ara Parseghian Medical Research Foundation.

Brown, a Regental Professor, holds the W. A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research and the Paul J. Thomas Chair in Medicine. Goldstein, a Regental Professor, holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research and the Paul J. Thomas Chair in Medicine. Yan is the Rita C. and William P. Clements, Jr. Scholar in Medical Research.

In a first-of-its-kind study that combines assessments of the risks of toxic emissions (e.g., fine particulate matter), nontoxic emissions (e.g., greenhouse gases) and people’s vulnerability to them, University of Notre Dame postdoctoral research associate Drew (Richard) Marcantonio, doctoral student Sean Field (anthropology), Associate Professor of Political Science Debra Javeline and Princeton’s Agustin Fuentes (formerly of Notre Dame) found a strong and statistically significant relationship between the spatial distribution of global climate risk and toxic pollution. In other words, countries that are most at risk of the impacts of climate change are most often also the countries facing the highest risks of toxic pollution.

They also measured other variables, including the correlation of the spatial distribution of toxic environments, total mortality due to pollution and climate risk, and they found a strong interconnection. They write in their in their forthcoming PLOS paper, “Global distribution and coincidence of pollution, climate impacts, and health risk in the Anthropocene”: “Deaths resulting from toxic pollution are highest where the distribution of toxic pollution is greatest and, critically, also where the impacts of climate change pose the greatest risk.”

“It is not surprising to find that these risks are highly correlated, but this article provides the data and analysis to inform policy, data and analysis that were previously lacking,” Javeline said.

To complete the study, Javeline, Marcantonio, Field and Fuentes used data from three indexes. ND-GAIN is an index of 182 countries that summarizes a country’s vulnerability and exposure to climate impacts risks and its readiness to improve climate resilience. EPI ranks 180 countries on 24 performance indicators across 10 issue categories covering environmental health and ecosystem vitality. Lastly, GAHP estimates the number of toxic pollution deaths for a country, including deaths caused by exposure to toxic air, water, soil and chemical pollution globally.

In order to make their results the most advantageous for policymakers, the authors created what they call “Target,” a measure that combines a country’s climate impacts risk, toxic pollution risk and its potential readiness to mitigate these risks. Based on these criteria, the top 10 countries they recommend concentrating on are Singapore, Rwanda, China, India, Solomon Islands, Bhutan, Botswana, Georgia, the Republic of Korea and Thailand. Among those countries appearing at the bottom of the list are Equatorial Guinea, Iraq, Jordan, Central African Republic and Venezuela. These nations are most likely to have outstanding governance issues that currently stand in the way of effectively addressing pollution.

“Notably, our results find that the top one-third of countries at risk of toxic pollution and climate impacts represent more than two-thirds of the world’s population, highlighting the magnitude of the problem and unequal distribution of environmental risk. Given that a large portion of the world’s population lives in countries at higher toxic pollution and climate impacts risk, understanding where and how to target in pollution risk mitigation is critical to maximizing reductions of potential human harm,” they write.

The authors also note that by mitigating toxic pollution in large countries with high populations such as China and India, neighboring countries will also benefit. China’s Air Pollution and Prevention and Control Action Plan of 2013, which specifically targets toxic emissions, is producing impressive results. Researchers have found a 40 percent reduction in toxic emissions since the plan was enacted.

“The idea of Target is to highlight where action can be taken to reduce risk to human health and flourishing, but how that targeting is done — e.g., incentives vs. sanctions — requires moral reflection to determine what actions should be taken and who should take them. This is especially true given the general inverse relationship between who is most responsible for producing these risks versus who is most at risk,” Marcantonio said.

During the 2021-22 academic year, the University, through its annual Notre Dame Forum, will engage in a series of conversations devoted to the theme “Care for Our Common Home: Just Transition to a Sustainable Future.” Inspired by Laudato Si’ and Pope Francis’ continued emphasis on these issues, the forum will feature a wide range of discussions and events over the coming year. Since its establishment in 2005, the Notre Dame Forum has featured major talks by leading authorities on issues of importance to the University, the nation and the larger world, including the challenges and opportunities of globalization, the role of presidential debates, immigration and the place of faith in a pluralistic society.

Designing new nanomaterials is an important aspect of developing next-generation devices used in electronics, sensors, energy harvesting and storage, optical detectors, and structural materials. To design these materials, researchers create interatomic potentials through atomistic modeling, a computational approach that predicts how these materials behave by accounting for their properties at the smallest level. The process to establish materials’ interatomic potential — called parameterization — has required significant chemical and physical intuition, leading to less accurate prediction of new materials design.

The researchers’ platform minimizes user intervention by employing multi-objective genetic algorithm optimization and statistical analysis techniques, and screens promising interatomic potentials and parameter sets.

“The computational algorithms we developed provide analysts with a methodology to assess and avoid traditional shortcomings,” said Horacio Espinosa, James N. and Nancy J. Farley Professor in Manufacturing and Entrepreneurship and professor of mechanical engineering and (by courtesy) biomedical engineering and civil and environmental engineering, who led the research. “They also provide the means to tailor the parameterization to applications of interest.”

The findings were published in a study titled “Parametrization of Interatomic Potentials for Accurate Large Deformation Pathways Using Multi-Objective Genetic Algorithms and Statistical Analyses: A Case Study on Two-Dimensional Materials” on July 21 in Nature Partner Journals — Computational Materials.

Xu Zhang and Hoang Nguyen, both students in Northwestern Engineering’s Theoretical and Applied Mechanics (TAM) graduate program, were co-first authors of the study. Other co-authors included Jeffrey T. Paci of the University of Victoria, Canada, Subramanian Sankaranarayanan of Argonne National Laboratory, and Jose Mendoza of Michigan State University.

The researchers’ framework uses training and screening datasets obtained from density functional theory simulation results, followed by an evaluation step that includes principal component analysis and correlation analysis.

“We defined a sequence of steps to reach an iterative learning approach given specific optimization objectives,” said Espinosa, who directs the TAM program. “Our statistical approach enables users to realize conflicting optimization goals that are important in setting limits of applicability and transferability to the parametrized potentials.” These relations can reveal underlying physics behind some phenomena that seem to be irrelevant to each other.

The team identified a positive correlation between the accuracy of interatomic potential and the complexity and number of the stated parameters — a phenomenon believed to be true in the field, but previously unproven using quantitative methods. This level of complexity must be met by a commensurate amount of training data. Failure to do so, especially data carrying critical information, leads to reduced accuracy.

The researchers found, for example, that to improve the fidelity of interatomic potentials, non-equilibrium properties and force-matching data are required.

“This included a better description of large deformation pathways and failure in materials,” Nguyen said.

“While these are not conventional properties that people target during parametrization, they are critical in understanding the reliability and functionality of materials and devices,” Zhang said.

The new approach also helps remove the barrier of user experience to enter this research field. “Through this work, we hope to make a step forward by making the simulation techniques more accurately reflect the property of materials. That knowledge can be expanded upon and eventually impact the design of devices and technology we all use,” Zhang said.

Next, the researchers will use their models to expand their investigation to study fracture and deformation in 2D materials, as well as the role of defect engineering in toughness enhancements. They are also developing in situ electron microscopy experiments that will reveal atomistic failure modes, providing a way to assess the predictive capabilities of the parameterized potentials.

The research was supported by the National Science Foundation (award number CMMI 1953806). Computational resources were provided by the Center of Nanoscale Materials at Argonne National Laboratory and the Quest High Performance Computing Cluster at Northwestern University. Use of the Center for Nanoscale Materials, an Office of Science user facility, was supported by Office of Basic Energy Sciences within the US Department of Energy’s Office of Science (contract number DE-AC02-06CH11357).

The analysis used mortality and fertility data to model rates of COVID-19-associated orphanhood (death of one or both parents) and deaths of custodial and co-residing grandparents (ages 60-84) from March 1, 2020 to April 30, 2021, across 21 countries. This study was funded in part by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

In the paper, “COVID-19-associated deaths” referred to the combination of deaths caused directly by COVID-19 and those caused indirectly by other associated causes, such as lockdowns, restrictions on gatherings and movement, decreased access or acceptability of health care and of treatment for chronic diseases.

Traumatic experiences, such as the loss of a parent or caregiver, are associated with increases in substance use, mental health conditions, and other behavioral and chronic health conditions. NIDA supports research aimed at understanding the impact of trauma on young people, preventing substance use after experiencing hardship, and treating substance use in populations that experience trauma.

“Studies like this play a crucial role in illuminating the COVID-19 pandemic’s long-lasting consequences for families and the future mental health and wellbeing of children across the globe,” said NIDA Director Nora D. Volkow, M.D. “Though the trauma a child experiences after the loss of a parent or caregiver can be devastating, there are evidence-based interventions that can prevent further adverse consequences, such as substance use, and we must ensure that children have access to these interventions.”

To estimate pandemic-associated orphanhood and caregiver deaths, the study used excess mortality and COVID-19 mortality data for 21 countries that accounted for 77% of global COVID-19 deaths during 2020 and early 2021. These include Argentina, Brazil, Colombia, England and Wales, France, Germany, India, Iran, Italy, Kenya, Malawi, Mexico, Nigeria, Peru, Philippines, Poland, Russian Federation, South Africa, Spain, United States, and Zimbabwe.

The authors estimate that 1,134,000 children lost a parent or custodial grandparent due to COVID-19-associated death. Of these, 1,042,000 children were orphaned of a mother, father, or both — most lost one, not both parents. Overall, 1,562,000 children are estimated to have experienced the death of at least one parent or a custodial or other co-residing grandparent (or other older relative).

The countries with the highest numbers of children who lost primary caregivers (parents or custodial grandparents) included South Africa, Peru, United States, India, Brazil, and Mexico. The countries with rates of COVID-19-associated deaths among primary caregivers (>1/1000 children) included Peru, South Africa, Mexico, Brazil, Colombia, Iran, United States, Argentina, and Russia.

The study found that for every country, COVID-19 associated deaths were greater in men than women, particularly in middle- and older-ages. Overall, there were up to five times more children who lost a father than who lost a mother.

“We know from our research that loss of a parent or caregiver can upend children’s lives and potentially affect their development if they are not in a stable home setting. If we take into consideration variants of concern or possible severity of illness among youth, we must not forget that the pandemic continues to pose a threat to parents and caregivers — and their children,” said Chuck A. Nelson, III, Ph.D., study author, Boston Children’s Hospital.

While research on the science of substance use and addiction remains the primary focus of NIDA’s work, NIDA is supporting COVID-19 research, and has issued over $15 million in funding for COVID-19-related projects since the start of the pandemic that could leverage current infrastructure, projects, or scientific knowledge and resources.